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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Associates, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss the implications of FDA’s new draft guidance on complying with 21 CFR 211.110.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In January 2025, FDA published a draft guidance document that provides considerations for complying with 21 Code of Federal Regulations (CFR) 211.110 (1).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 The guidance, Considerations for Complying With 21 CFR 211.110, Guidance for Industry, Draft Guidance, applies to human drug products and biologics, but not to the manufacture of APIs.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Associates, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss the implications of this draft guidance and best practices for complying.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 Considerations for Complying With 21 CFR 211.110, Guidance for Industry, Draft Guidance (CDER, CBER, January 2025).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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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

 

 

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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

 

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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

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

 

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FDA Looks to Industry for Collaboration and Harmonization

Employees from the U.S. Food and Drug Administration (FDA) and Center for Devices and Radiological Health (CDRH) recently announced partnerships with new collaborative communities in the life sciences industry. A primary goal of this initiative is to optimize the success of medical device research and development programs. Another goal is enhancing speed-to-market by avoiding work-in-progress across the medical device industry, which should potentially improve long-term patient outcomes.

 

Further, the collaborative community’s initiative also coincides with the recent announcement the FDA will no longer be a member of the Global Harmonization Working Party (GHWP), whose priorities have influenced many research initiatives. This is a significant change in direction since the agency first joined the group in 2021.

 

What is a Collaborative Community?

 

A life sciences collaborative community includes a mix of both private and public sector colleagues, often including FDA employees. Communities are commonly organized by participants interested in identifying and resolving the most complex problems facing healthcare systems.

 

Additionally, these problems sometimes arise due to a lack of agreement on the best way(s) to address a growing problem in a disease state. Companies that have participated in the FDA approval process work within FDA guidelines and understand FDA regulations are frequently encouraged to engage and participate.

 

Finally, membership or agendas are not decided by FDA for a collective community. It is a sustainable group of individuals who have the ability to exist without FDA’s involvement. One of the new collaborative communities announced by FDA is the AI Initiative of AFDO/RAPS Healthcare Products Collaborative. This collaborative community is a joint venture between the Association of Food and Drug Officials (AFDO) and the Regulatory Affairs Professionals Society (RAPS) established in 2022.

 

Further, this collaborative group “supports idea-sharing, innovation, and action across the global healthcare products community by fostering purpose-driven discussions between regulators, industry, academia, and thought leaders about the most pressing issues facing the industry.”

 

A second new collaborative community announced by FDA is the Infection Management Collaborative Community. This group “aims to accelerate the development, availability, and adoption of safe and effective medical devices to prevent, diagnose, and manage infection; treat sepsis; and support sepsis patients and survivors.”

 

Sepsis cases continue to accelerate globally. The Institute for Health Metrics and Evaluation’s “Global Burden of Disease Study,” released in 2020, attributed 11 million patient fatalities to sepsis in 2017—nearly 20% of total global deaths. Such data indicate the condition is rapidly approaching global crisis levels.

 

Why Leave the GHWP?

 

A primary reason for leaving the GHWP may involve the strategic plan launched by CDRH late last year. The document establishes a four-year timeline for working towards greater international harmonization.

 

The FDA has been moving closer toward widely accepted (and recognized) global standards, such as the shift to both ISO 13485 and 21 CFR 820. Harmonizing a complex, cross-functional agency like FDA is a considerable undertaking—therefore, if specific disease states are more significant to the agency than others, leaving the GHWP allows the potential for flexibility.

 

The strategic plan calls for CDRH to evaluate different types of opportunities each fiscal year in order to increase engagement across international harmonization programs. CDRH also is expected to receive additional funding and resources to help accelerate this engagement. These additional resources aim to allow the FDA to expand international harmonization and convergence programs already in progress and achieve these initiatives by FY 2027.

 

Details of the Strategic Plan

 

The second phase of the strategic plan is designed to increase discussions about implementing harmonized policies. Further, this new mechanism may require FDA to develop additional confidentiality agreements to increase the efficiency of research analysis and discussion under confidentiality commitments. CDRH will review the current list of approved regulatory partners and confidentiality protocols in place to align regulatory strategies across international agencies. 

 

Per the strategic plan, FDA was supposed to identify and begin engaging with regulatory authorities by the end of 2023. The primary objective is to create a database of regulatory bodies with whom sharing medical research could be most helpful toward the global harmonization of standards. CDRH has committed to creating this information-sharing mechanism to communicate best practices in medical device evaluation by the end of this year. 

 

The strategic plan details the similarities and differences in CDRH’s regulatory policy and widely accepted IMDRF policies. The plan also tasks the FDA with assessing and evaluating the technical specifications of IMDRF documents that include policies and practices approved by all regulatory authorities in the IMDRF Management Committee.

 

One of the goals of this regulatory process is to increase the understanding of technical descriptions and technical report writing for international regulatory agencies. Such improved knowledge could directly help CDRH with its internal assessment of international harmonization efforts, and the ways in which FDA’s process may differ compared with regulators worldwide.

 

The strategic plan (according to technical specification data) sets specific proposed timelines for CDRH to undertake advances toward global harmonization. The timelines are as follows:

 

  • CDRH will publish an assessment of at least nine IMDRF technical documents by the end of 2025.
  • CDRH will publish an assessment of at least 18 IMDRF technical documents by the end of FY 2026.
  • CDRH will publish an assessment of all remaining IMDRF technical documents by the end of FY 2027

 

The strategic plan continues to elaborate on the life sciences community and the impact non-FDA employees can have on future regulatory approval. These specific stakeholders may have a unique perspective based on their current occupation or the types of therapy a patient receives. Finally, the following audiences are specifically mentioned for providing first-hand experiences that FDA can leverage based on another regulatory authority’s approach to medical therapy: healthcare patients, life sciences manufacturers, conformity assessment bodies, and standards development organizations.

 

Finally, an annual communication plan is proposed to begin this year that includes developing a forum to assess and report on harmonization program efforts in progress. This forum is designed to connect with each of the audiences previously mentioned to help FDA identify opportunities for learning. Furthermore, this forum would be dependent on the level of interest and considerations of other stakeholders, including the life sciences industry specifically. 

 

Summary     

 

The life sciences industry is at a crossroads regarding its ability to quickly learn from clinical inputs. And while artificial intelligence (AI) is prompting an increase in successful patient outcomes, the industry must determine the best approach to improve healthcare data.

 

It remains to be seen how an enhanced approach to collaboration moves through the regulatory process from “qualified to validation.” The flexibility to live inside the regulatory box and think outside the box with AI is critical to success. These outcomes are now being considered earlier in the design stages because the regulatory process can often be unforgiving.

 

Healthcare partners should collaborate together to leverage AI’s utility at the point of care to improve patient care collaboration. While the primary partner for global regulatory research will continue to be the International Medical Device Regulators Forum (IMDRF), collaborative communities will challenge this “qualified to validation” approach. Addressing disease states with the highest mortalities is part of the partnership between IMDRF and other global regulatory bodies.  

 

Case in point: How can AI work towards developing infection management treatment strategies in a sepsis patient as the normal infection-fighting process is dramatically reduced? This is where technology and collaboration can help the current regulatory process evolve. What lessons could FDA learn through AI patient treatment strategies from a global audience? It is a universal disorder that kills many more people than it should.

 

If the life science community recognizes that AI is friendly to change, information will be shared globally. Consider for a moment disease states such as sepsis, sepsis syndrome, and septic shock—all of which represent different stages of the same condition. Industry stakeholders could bring a unique perspective of leveraging clinical inputs based on their current occupation or the types of therapy a patient receives.

 

About the Author

 

Rod Mell is executive head – Medical Devices at Regulatory Compliance Associates. A Sotera Health company, RCA is recognized within the healthcare industry for regulatory compliance consulting and its life science consultants’ ability to help companies successfully resolve complex life science challenges. Sotera Health Company and its three businesses—Sterigenics, Nordion, and Nelson Labs—is a global provider of mission-critical end-to-end sterilization solutions and lab testing, and advisory services for the healthcare industry.

 

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