Archives: Published Articles

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

 

 

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].

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

 

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].

 

 

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.

 

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].

 

Non-Animal-Derived Reagents for Endotoxin Testing

In this episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice president, Technical at Parexel, discuss the new chapter, Chapter <86> Bacterial Endotoxins Test Using Recombinant Reagents.

 

Link to the Video and Article on Pharmaceutical Technology

 

In this episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice president, Technical at Parexel, discuss the new chapter, Chapter <86> Bacterial Endotoxins Test Using Recombinant Reagents, published by the United States Pharmacopeia–National Formulary November 2024. The chapter permits the use of non-animal-derived reagents for endotoxin testing and is part of USP’s commitment to expanding the use of animal-free methods and materials (1).

 

“Twenty years ago, the predominant test procedure for determining endotoxin level, or pyrogen level, as we called it, was the rabbit test. And we used to actually inject rabbits, which was a very subjective because you’d measure their temperature,” says Schniepp. And then we evolved to using the limulus amoebocyte lysate or LAL test, and there was the chromogenic [test] but they were all predicated off the horseshoe crab. So now we’re moving forward to reagents for this test, which is critical to the release of sterile injectables that does not involve animals. So absolutely, we should consider this.”

 

“I think it is also worthwhile mentioning that what is happening in the US is mirrored in other jurisdictions, for example, when you look at the European Medicines Agency [EMA], they support the use of animal free cell culture reagents as part of its efforts to reduce animal use in medicine testing,” adds Schmitt. “We don’t want to use rabbits. We don’t want to use horseshoe crabs, and it’s EMA’s innovation task force that encourages that use of alternative methods to animal models, and that, what they say is, will improve the scientific quality and also, of course, animal welfare.”

 

Click the video above to watch Sue and Siegfried answer the following question:

“USP just published a new chapter on the use of non-animal derived reagents. We are not currently using non-animal derived reagents. Is this something we should consider changing?”

 

Reference

1. USP. Chapter for Endotoxin Testing Using Non-Animal Derived Reagents Published for Early Adoption. Press Release. Nov. 1, 2024.

 

Important terms and acronyms

USP—United States Pharmacopeia

 

 

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].

 

Strategies for Contamination Control

A contamination control strategy should provide an overview of how contamination and containment practices work together to ensure product quality and patient safety, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates.

 

Q. My colleagues and I have been discussing the new requirement for a contamination control strategy (CCS) contained in the European Union’s 2022 Annex 1 revision. Can you provide some guidance on what should be included in the CCS?

 

A. The concept of contamination/containment control has been around for quite some time. The 2004 FDA Guidance for Industry states, “Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control” (1).

 

The revised Annex 1 guideline takes things a step further by stating, “A [CCS] should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical, and organizational) and monitoring measures employed to manage risks to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention” (2).

 

The guideline also states, “The CCS should consider all aspects of contamination control with ongoing and periodic review resulting in updates within the pharmaceutical quality system as appropriate. Changes to the systems in place should be assessed for any impact on the CCS before and after implementation” (2).

 

The Parenteral Drug Association’s (PDA’s) Technical Report states, “The ongoing evolution of contamination control principles that this document addresses is a shift to a holistic approach, where practices are designed to work together to achieve proactive contamination control and are evaluated for their collective effectiveness” (3).

 

What does this all mean to pharmaceutical manufacturers? Let’s start with what we have already in place. All companies should have contamination control elements addressing various aspects of the manufacturing process including but not limited to process design, microbial control, facilities, utilities, raw materials, environmental, personnel training and qualification, equipment qualification, and a robust quality management system.

 

Some of the specific contamination control elements included in these categories would be the existence of bioburden and endotoxin attributes, particulate monitoring, process validations, material and personnel flow, product quarantine practices, smoke studies, media fills, gowning qualification, cleanroom practices, microbial monitoring during production, cleaning validation, extractables/leachables, container closure integrity, etc.

 

The strategy in CCS is how the company ties all these elements together in a holistic approach that is interdependent, multi-disciplinary, and tailored to the operation. This requires the company to be deliberate in risk assessing how changes to any of the elements affects the other elements under the umbrella of the CCS.

 

The overall objective of the CCS is to describe what control elements are in place, why they are effective, and that potential contamination is controlled from the beginning to the end of the manufacturing process.
 

Article details

regulatory compliance

Pharmaceutical Technology
Vol. 47, No. 6
Page: 42

 

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].

 

Elements for a Sustainable Environmental Monitoring Program

Asking why things are done a certain way will help make an accurate assessment of an organization’s EM program, says Susan Schniepp, distinguished fellow at Regulatory Compliance Associates, and Zachary S. Anderson, global market segment lead—Sterility Assurance, Nelson Laboratories.

 

Q: I am evaluating a new contract development and manufacturing organization (CDMO) to manufacture some of our injectable products. Can you advise on some of the elements of their environmental monitoring (EM) program I should review, so I can ascertain its suitability?

 

A: Evaluating the suitability of an environmental monitoring program can be complicated. The evaluator needs to understand the multi-layered elements required for the successful and sustainable management of the EM program. Fundamentally, it is important to be familiar with the regulations that govern the manufacture of injectable products. FDA and the European Medicines Agency (EMA) have regulations that outline these expectations (1,2).

 

What is Contamination Control?

 

The revised Annex 1 guideline introduces the concept of contamination control strategy (CCS) by stating. “A contamination control strategy should be implemented across the facility to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical, and organizational) and monitoring measures employed to manage risks to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention” (2).

 

Why Review the Quality System?

 

The guideline also states, “The contamination control strategy should consider ongoing and periodic review resulting in updates within the pharmaceutical quality system as appropriate. Changes to the systems in place should be assessed for any impact on the CCS before and after implementation” (2). The 2004 FDA guidance states, “Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control” (1).

 

How does an FDA Inspection Work?

 

One of the first steps in the assessment would be to evaluate the manufacturer’s CCS based on the expectations outlined in the regulations. Using the CCS as a guide, the assessor can then focus on specific elements of the EM program as well as how the program is embedded into the quality management system (QMS). The following are questions to ask to help in the evaluation:

 

  • QMS: Is the EM program effectively integrated into the QMS, including corrective action and preventive action (CAPA) program that drives to root cause?
  • Technical expertise: Has the company hired experienced personnel and demonstrated maintenance of expertise? What are the ongoing training requirements for personnel in Quality Assurance, the laboratory and on the manufacturing floor? Are gowning requirements for all personnel who enter the manufacturing area documented? Are the re-qualification requirements for gowning clearly defined? Is the out-of-specification procedure understood and followed? Are employees trained on data recording and integrity? Does the program drive the recording of the appropriate level of detail?
  • Process controls. Are process controls for particulates and microbiological organisms robust enough to detect and manage changes in practice or gaps in process (e.g., data lags, emerging issues/environment degradation, product quality shifts, etc.)?

 

There are many more questions that should be asked to ascertain the suitability of an environmental monitoring program than listed above. The optimal way to approach such an evaluation is to become familiar with the regulations, review the company’s CCS program and drill down into specific areas of the program by asking targeted questions. Inevitably, you will encounter variations and “gray-area” interpretations. An astute evaluator will ensure variations are acknowledged (documented) and interpretations are justified in writing. Asking why things are done a certain way will help make an accurate assessment of an organizations EM program and help determine whether it suits your requirements.

 

Article details

RCA

 

 

 

 

 

Pharmaceutical Technology®
Vol. 48, No. 6
Page: 34

 

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].