Industry: Pharmaceutical

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Drug Shortages and Complying with FDA’s 21 CFR 211.110 Guidance

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Rona LeBlanc-Rivera, PhD, principal consultant, Regulatory Affairs at Regulatory Compliance Associates, answer some questions about FDA’s January 2025 21 CFR 211.110 guidance document.

 

Q: How does FDA’s guidance, Considerations for Complying with 21 CFR 211.110, impact our current approach in complying with 21 Code of Federal Regulations (CFR) 211.110 (1)?

A: This guidance is currently in draft. However, when finalized, it will describe areas to be considered to ensure batch uniformity and drug product integrity. The guidance also discusses quality considerations for drug products manufactured using advanced in-process manufacturing techniques. Allowing flexibility to use new technological advances to determine drug product integrity and batch uniformity during manufacturing could reduce product reject rates because in-process results could be reported sooner (perhaps in-real time) and manufacturing corrections could be made to ensure the batch integrity. Drug products manufactured using advanced in-process techniques may have non-traditional quality considerations to determine the suitability of the product, and this guidance allows for flexibility and latitude on how to implement these controls effectively. It should be noted that the scope of this guidance pertains to commercial processes and not to products in development. The drug substance/API is also not within the scope of this guidance.

 

Q: How flexible is FDA in allowing alternative approaches to in-process controls, and what would be the process for gaining approval for such approaches?

A: FDA does allow manufacturers some flexibility to use better and more efficient methods to meet current good manufacturing practice (CGMP) requirements. It is recommended that companies gather the data and seek early FDA feedback regarding the use of alternative approaches for both in-process and quality parameters before submission of an application. Companies trying to introduce novel and new in-process test controls that yield more accurate and real-time measurements will have more success in getting approval by partnering with the FDA early in the process of introducing the new technology to the manufacturing process.

 

Q: What are FDA’s expectations for in-process material sampling frequency and methodology?

A: In-process sampling would be dictated by the nature of the drug and manufacturing process. It is not always feasible to obtain an in-process sample. In this guidance, FDA advises that innovative technologies may allow in-line, at-line, or on-line measurements in lieu of physical sample removal for testing.

 

Q: How does this guidance address the role of in-process controls in preventing drug shortages?

A: In the guideline, FDA states that it “supports the adoption of advanced manufacturing as a foundation for improving the overall quality and availability of drug products for patients.” Exploring how to improve manufacturing oversight through the use of the innovative technologies mentioned above could help enhance supply chain stability and eliminate some drug shortages. Advanced in-process and quality parameter controls may help reduce production failures that contribute to these shortages.

 

Q: If a more efficient in-process control method could reduce shortages but it is not covered in the guidance, how should companies seek FDA approval?

A: For an FDA-approved drug product, the application holder should gather the necessary data and documentation for filing a supplement (i.e., CBE [changes being effected]-30, PAS [prior approval supplement]) to their application regarding the use of alternative approaches. FDA would then review and provide comments on the proposed change and help identifying the best pathway forward for regulatory acceptance of innovative manufacturing techniques.

 

This new guidance offers flexibility to manufacturers, including contract manufacturing organizations, to introduce new, more efficient methodologies to measure batch uniformity and product integrity required to determine product suitability to ensure continued access to necessary pharmaceutical products. It is up to pharmaceutical industry to work with FDA and determine the best implementation strategy for realizing the benefits of modernizing manufacturing processes.

 

Reference

1. FDA. Considerations for Complying with 21 CFR 211.110, Draft Guidance (CDER, January 2025).

 

About the Article

 

Pharmaceutical Technology
Vol. 49, No. 3
Page: 34

 

 

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Ask the Expert: Complying with 21 CFR 211.110

In this episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss the implications of FDA’s new draft guidance on complying with 21 CFR 211.110.

 

Link to the Video and Article on Pharmaceutical Technology

 

In January 2025, FDA published a draft guidance document that provides considerations for complying with 21 Code of Federal Regulations (CFR) 211.110 (1). This specific section of the CFR focuses on production and process controls for sampling and testing of in-process materials and drug products. The guidance, Considerations for Complying With 21 CFR 211.110, Guidance for Industry, Draft Guidance, applies to human drug products and biologics, but not to the manufacture of APIs. The guidance document also discusses how process models can be incorporated into commercial manufacturing control strategies.

 

In this episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss the implications of this draft guidance and best practices for complying.

 

“What [the guidance document] really seems to be aimed at is new manufacturing techniques that are coming on board and some flexibility for biopharmaceuticals as we get into, you know, personalized medicines, continuous manufacturing, and the use of artificial intelligence (AI) to identify some of the key process parameters for new manufacturing and processes … giving manufacturers more flexibility in that arena,” explains Schniepp.

 

“FDA is trying to look to the future, is trying to address what’s current, what’s happening now. And as you said, use of AI; although, I don’t think a lot of companies are really, really implementing this yet in day-to-day operations. Perhaps another aspect here of this guidance is it speaks a lot about continuous manufacturing, which, again, in my experience, is a process that’s rarely applied in most of manufacturing because the vast majority of processes are still back by batch,” says Schmitt.

 

Reference

1. FDA. Considerations for Complying With 21 CFR 211.110, Guidance for Industry, Draft Guidance (CDER, CBER, January 2025).
https://www.fda.gov/media/184825/download

 

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Drug Digest: Advances in Small-Molecule Manufacturing

In this exclusive Drug Digest video interview Anil Kane from Thermo Fisher Scientific will be tackling the topic of advances in small-molecule manufacturing and several other experts will provide brief commentaries on associated topics. Regulatory Compliance Associates’ (RCA) distinguished fellow and a member of the Editorial Advisory Boards for Pharmaceutical Technology, Susan J. Schniepp is featured in this interview for her industry insight into small-molecule manufacturing.

 

Link to the Video and Article on Pharmaceutical Technology

 

In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, and Patrick Lavery, Editor, Pharmaceutical Technology Group, will be tackling the topic of advances in small-molecule manufacturing with Anil Kane from Thermo Fisher Scientific. Additionally, their is  also some extra commentaries on the trends shaping the oral solid dosage market with Uwe Hannenberg from Recipharm, the manufacturing hurdles associated with challenging molecules with Jens Schmidt from Lonza, and some advice from our Ask the Expert columnists about changing excipient providers.

 

About Drug Digest

Drug Digest is a tech talk video series with the Pharmaceutical Technology editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

 

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Changes in Drug Labeling & Transparency

Posted on by Brandon Miller

The FDA is cracking down on labeling for drug products that will require companies to reevaluate and make changes to new and existing products if they wish to stay in compliance. To ensure companies can continue production without slowdowns, it is important to understand what changes are being implemented and how they will affect your products.

 

Greater Transparency in NDA and ANDA Labeling

In April 2024, the FDA released a draft guidance aimed at improving transparency in drug labeling, particularly for New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs), which cover generic drugs. Generic drug labeling must contain information to show that the proposed labeling is the same as that for the Reference Listed Drug (RLD), with certain permissible differences. Under 21 CFR 314.50, an NDA must contain a list of all components used in the manufacture of the drug product.  However, historically, there have been several instances whereby the NDA did not disclose all of its ingredients in the labeling,   leading to complications in the regulatory approval process for generic versions. This lack of transparency created delays and regulatory hurdles for ANDAs that relied on accurate ingredient information from their RLD.

 

Moving forward, the FDA is advocating for clearer and more comprehensive ingredient disclosures on NDA and ANDA labels. For example, labeling for non-oral drug products may need to contain the names of all inactive ingredients with limited exceptions.  This shift is intended to eliminate unnecessary review delays and improve the efficiency of ANDA approvals. While the exact compliance strategies remain unclear, the draft guidance from April 2024 is expected to shape regulatory expectations well into 2025 and beyond once the guidance becomes finalized.

 

This change marks a significant step toward improving the drug approval process. Greater transparency in ingredient listings will not only help generic drug manufacturers but also ensure that healthcare providers and consumers have access to complete information about their medications. The push for increased clarity aligns with broader FDA efforts to enhance drug safety and efficacy.

 

New Labeling Rules for OTC Drugs

Another critical update in drug labeling comes with the final rule for non-prescription (over-the-counter, or OTC) drugs under the Additional Condition of Nonprescription Use (ACNU) framework. Published in December 2024, this rule introduces new labeling requirements for certain OTC products to enhance consumer safety and regulatory oversight.

 

Under the ACNU framework, some OTC drugs will require additional steps before consumers can access them. These measures may include visiting the manufacturer’s website or completing a brief manufacture’s to determine whether the product is suitable for individual use. This regulatory approach seeks to strike a balance between expanding consumer access to safe and effective nonprescription medications while ensuring that people use them appropriately.

 

The implementation of this rule could significantly impact both consumers and pharmaceutical companies. On one hand, it enhances safety measures by ensuring that individuals receive proper guidance before using certain OTC drugs. On the other hand, companies will need to update their packaging, labeling and digital platforms to comply with the new requirements. Consumers may also need to adapt to these changes by engaging with manufacturers’ resources before purchasing certain OTC products. The final rule is intended to increase options for consumer access to appropriate, safe, and effective drug products, which could improve public health.

 

What to Expect

These labeling and transparency initiatives will likely play a major role in shaping the pharmaceutical landscape in the future. The FDA’s push for improved ingredient disclosure in NDAs and ANDAs is expected to streamline generic drug approvals and foster greater trust in drug labeling. Meanwhile, the ACNU framework will redefine how consumers interact with select OTC medications, prioritizing informed decision-making and responsible use.

 

Stakeholders, including drug manufacturers, healthcare providers, and consumers, should stay informed about these evolving regulations to ensure compliance and safe medication practices. As the FDA continues refining its policies, further clarifications and potential updates may emerge, reinforcing the agency’s commitment to transparency and consumer safety in the pharmaceutical industry.

 

Preparing for These Changes

For companies looking to stay ahead of these regulatory updates and maintain seamless approvals and production, it is essential to assess current processes and identify gaps in compliance with the new FDA guidelines. Engaging with third-party auditors with relevant expertise can help pinpoint deficiencies and develop a robust implementation strategy, ensuring compliance from the outset.

 

At RCA, we leverage our extensive network of industry experts, including former FDA consultants and leading auditors, to provide comprehensive support. Whether identifying and addressing compliance gaps or designing entirely new processes for emerging products, our team ensures a seamless transition to meet evolving regulatory expectations. Let us help you identify any gaps and help you form a clear strategy that will keep your drug labels in compliance today.

 

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2025 Pharmaceutical Outlook

In this episode of RCA Radio®, host Brandon Miller is joined by Anita Michael, Executive Pharma Compliance Expert & Principal Consultant and Rona LeBlanc-Rivera, Director, Regulatory Affairs both at Regulatory Compliance Associates. We explore possible changes in the Pharmaceutical industry in 2025 and provide you with insight on how to prepare yourself for these upcoming initiatives.

Listen in as we go over the expected reduction in the FDA’s work force, recently executed guidance documents, regulatory timelines, drug labeling transparency, the broadening scope of OTC products, the use of AI in the regulatory review, and how companies can use 3rd party inspections to help prepare themselves.

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].