Siegfried Schmitt, PhD, is Vice President Technical at Parexel International, Siegfried.Schmitt@parexel.com.

Siegfried Schmitt

Ask the Expert: Drug Approval Submissions

Could a pharmaceutical company’s regulatory affairs department become the target of a regulatory inspection? Susan J. Schniepp, distinguished fellow with Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical, at Parexel, say that it can, and companies that assume otherwise are exposing themselves to risk.

According to Schniepp, inspectors are not auditing the electronic submission mechanism itself because the eCTD system is already validated, and paper submissions are essentially obsolete in both the United States and the European Union. What's inspectable is the accuracy and completeness of the information within those submissions, and whether the company is following what it submitted. That scrutiny typically surfaces during chemistry, manufacturing, and controls (CMC)-focused inspections, such as pre-approval inspections, and becomes especially complicated when a company relies on a contract manufacturing organization (CMO) that may only have access to a fraction of the full submission.

Schmitt added that regulatory affairs departments function as a relay point: they receive condensed information, such as confirmation that an analytical method was validated per 

.), rather than the full underlying validation report. That compression creates risk. If information is incomplete, inaccurate, or garbled somewhere in the handoff from manufacturing to regulatory affairs (often through quality assurance as an intermediary), the resulting submission can be wrong. Inspectors, he noted, may specifically probe how communication pathways function between manufacturing sites, CMOs, and regulatory affairs.

Schniepp pointed to concrete gaps that often go unaddressed: submissions frequently state that a compendial method is used without including verification that the method actually works under the conditions in that specific lab. Similarly, when a proprietary test method is developed at an R&D site and later transferred to a manufacturing site, the tech transfer documentation supporting that move may not be part of the submission, raising the question of whether the company’s regulatory affairs department can answer for it if asked.

The conversation also covered the reverse information flow: feedback from regulators, such as an approved label change, must be communicated back into operations—to packaging teams, for instance—and executed correctly, particularly for companies managing multiple SKUs across many countries. Both panelists emphasized that inspectors have found regulatory affairs departments operating outside the company's quality system, mistakenly believing they're exempt from standard operating procedures (SOPs). Schniepp was unequivocal that regulatory affairs must operate within the quality management system, even though quality doesn't dictate every regulatory task. Any change must go through formal change control and be supported by documentation in the submission or a subsequent update; undocumented changes put the entire validated process in question.

Schniepp raised a further liability: regulatory affairs departments receiving clinical data must have some means of confirming that data have not been falsified. Cases exist where fabricated data made it into submissions because no one cross-checked it against the reporting site, and that gap becomes a serious liability once discovered.

Schmitt closed by noting inspections of regulatory affairs typically require a trigger—inspectors generally focus their attention on operational sites first. But especially in Europe, inspectors do verify that what's stated in the license matches actual site practice. He recommends that processes be kept as simple and robust as possible, because complexity is what generates gaps. His practical recommendation for manufacturers: ensure regulatory affairs staff are properly trained, operate under clear SOPs, and understand that they are not exempt from inspection scrutiny.

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

“Our regulatory affairs department handles all the submissions to regulatory agencies. Is there a chance the department may be inspected?”

Susan J. Schniepp is distinguished fellow at Nelson Labs and a member of 

Siegfried Schmitt is vice president, Technical at Parexel and a member of 

Videos

Susan J. Schniepp, distinguished fellow with Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical, at Parexel, explain a company’s regulatory affairs department is subject to inspections by regulators and should, therefore, be prepared.

regulatory actions are coming together in an effort to move biologics, gene therapy, and the ATMP platform forward quickly, say Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, technical, Parexel Consulting.

Q. My company manufactures biologics, and we saw some recent actions by the FDA, USP, and the EU. How do these regulatory actions impact us as a biologics manufacturer?

A. The US Pharmacopeia (USP) has released methods for biologics, without specifications, in an effort to help biologic manufacturers, because this is a rapidly growing field. So, this should help people So, this should help people in terms of their chemistry, manufacturing, and controls (CMC) sections, with methods, and then they can set the specifications depending on the product they're developing.

The European Medicines Agency (EMA) announced an agreement for its Critical Medicines Act that came out in 2025.

 This act addresses controlling drug shortages and eliminating some of those roadblocks, such as suppliers, because there may be critical elements a company needs to manufacture a biologic that are available from only one source; if that supplier has a problem, everybody has a problem.

The other recent action is from the FDA. The agency issued a draft guidance on leveraging prior knowledge in the development of human gene therapy products incorporating genome editing.

 The guidance says that, instead of establishing your own holistic platform, you can reference studies and information that have been published to enhance your CMC section or your filing.

These regulatory documents are open to public comment, and companies should consider submitting their comments and/or concerns, including the USP standards.

Let’s discuss the potential intentions of the regulators in taking these actions. These products are typically lifesaving products when we look at biologics. These are products that not only patients want to see urgently, but regulators are also supporting the industry in getting them to market.

But not only that, there is a supply chain behind it because you cannot make everything in-house. You need suppliers. And it may be for some of these raw materials and excipients, they may be very difficult to get hold of. And some may be very difficult to transport. So, there are many different aspects to this. And some of the technical ideas are to perhaps manufacture close to where your patients are.

Because the knowledge of these products may be limited to a few people or a few firms, the FDA draft guidance is trying to expand that knowledge by allowing companies to use information that's previously been published for their product, to be able to expedite approval of these lifesaving methods.

And coming back perhaps also to the manufacturing; you could, for example, traditionally file for a product in the United States, and then you file in Europe and maybe other jurisdictions. And you may typically have a product that you start making in the US, and then you ship it over to other markets. That's not always an option with biologics, especially because cell and gene therapy products may not be conducive to such shipments.

And something that all the regulators like to see now is to have manufacture much more within the market where they are regulating, which may mean, with this distributed manufacturing, that we are probably getting away more and more from the centralized large production facilities to more smaller, closer to the patient facilities where we have shorter supply chains.

But how do we get all our suppliers to supply us to these locations rather than to just one? So, there are many aspects that need to be considered. It's important that companies provide their input to the regulators because they want to hear what is feasible and what is practical.

USP publishes product-specific emerging biologics standards for public comment. News release. USP. June 1, 2026. Accessed July 9, 2026. 

https://www.usp.org/news/usp-publishes-product-specific-emerging-biologics-standards-for-public-comment

 welcomes political agreement on Critical Medicines Act

. News release. European Commission. May 11, 2026. Accessed July 9, 2026. 

https://ec.europa.eu/commission/presscorner/detail/en/ip_26_1017

FDA issues draft guidance to help accelerate cell and gene therapies for patients. News release. FDA. June 2, 2026. Accessed July 9, 2026. 

https://www.fda.gov/news-events/press-announcements/fda-issues-draft-guidance-help-accelerate-cell-and-gene-therapies-patients

Articles

USP has issued product-specific analytical methods for emerging biologics without predefined specifications, enabling sponsors to tailor acceptance criteria while strengthening CMC packages. In Europe, the EMA-backed Critical Medicines Act targets shortage prevention and supply-chain resilience, particularly where single-source inputs create systemic vulnerability. FDA’s draft guidance on genome-edited gene therapies encourages leveraging published prior knowledge to expedite CMC development and regulatory review. Collectively, these actions support faster patient access and push manufacturing toward more distributed, in-market models. Public comment is actively solicited.

Three regulatory actions are converging to move biologics, gene therapy, and the ATMP platform forward quickly, say Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, technical, Parexel.

Regulatory Actions Impacting Biologics

Q. My company got a complaint from a patient that their prefilled syringe failed to inject. We make the drug product and purchase the syringe. How do we investigate a problem with the commercial syringe component that we used?

A. The drug manufacturer is responsible in the end for whatever the product does, even if it’s made up of components where the manufacturer doesn’t really have a lot of control over.

The question is, how well have you assessed the quality of the product? Have you assessed the supplier of this syringe? Because it’s all too easy to say, “Oh, something is off the shelf.”

But just because a product has been used by many doesn’t mean it’s suitable for everyone.

If the complaint is coming from the patient and the patient is self-administering the product, did they get instructions from the physician before they got the medication? Is this human error on the part of the patient?

Even if the patient did something wrong. The manufacturer needs to take this into account and should create either patient instruction or a device that is suitable for everyone. Because you can’t just say, “Well, we only sell to those who are capable and who do it right all the time.” That would be wrong.

The device, when you look at the regulations, needs to be fit for purpose, and fit for purpose means if you have a patient population that is from young to old, from very able to handicapped, then you need to provide for all of those.

And one way to do this, to prepare for this at least, is to perform usability tests If these usability tests weren’t done with a wide enough population of potential patients, perhaps you need to go back to these tests and see if they were good enough. Did they really understand, or were these already people who were used to do such testing?

We need to be very careful with testing because we can only test a certain limited number of people. And what we have here is real-world evidence if you want, and that points to where we have a gap here.

Complaint numbers can go up and down. It’s very unpredictable. The key thing is you don’t just need to have a procedure to address complaints, but you should revisit your procedure in intervals to look at not just what the regulators are saying, but also how the business environment has changed.

Look at your communication and supply chain and check your quality agreement for its robustness and to see who is responsible for these types of complaints. Because, if you don’t spell out who is responsible in your supply agreement, there may be finger pointing. This is a shortcoming with a lot of quality agreements; they may not be granular enough.

Drug manufacturers retain ultimate accountability for performance of combination products, even when key delivery components are sourced “off the shelf.” A failed prefilled syringe complaint requires a structured investigation spanning component supplier qualification, device suitability for the intended patient population, and potential use errors during self-administration. Human factors considerations are central: instructions and device design must accommodate broad user capabilities. Complaint handling should leverage real‑world signals, periodically reassess procedures against evolving regulatory and business contexts, and ensure robust quality agreements that clearly assign responsibilities across the supply chain.

Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss how companies can investigate patient complaints involving prefilled syringes and combination products.

Investigating Patient Complaints About Combination Products

Ask the Expert: Enhancing Out-of-Specification Procedures

Welcome to the Ask the Expert video series. This series is an extension of PharmTech’s long-running print column in which industry experts answer common quality and regulatory questions from the industry. Have a question you would like answered? Send it to 

, and it may appear in a future episode or print column.

Why do pharmaceutical companies continue to receive regulatory observations regarding out-of-specification (OOS) procedures despite clear guidance from regulators?

The issue is rarely the regulatory process itself, but rather how companies apply and interpret it, according to Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical at Parexel.

A significant challenge is the creation of overly restrictive internal procedures that cause problems with the procedure, such as requiring the original analyst to complete an investigation before taking leave, which results in a delay in the investigation. To move past these bottlenecks, the experts advocate for robust trending instead of treating OOS results as isolated events. Trending helps identify recurring issues with specific methods, personnel, or aging equipment, which is often neglected in budget cycles.

Furthermore, trending should serve as a key performance indicator focused on the quality and timeliness of the investigation, rather than an unrealistic goal of having zero OOS results. Schniepp and Schmitt emphasize that investigations must extend beyond the laboratory. They recommend process mapping the entire chain of events—including sampling, which is frequently performed by manufacturing personnel without sufficient lab or quality assurance department oversight. By performing a risk assessment on the entire process, companies can predict where human error is likely to occur, allowing for faster root cause identification.

For manufacturing environments involving contract partners, it is vital that all parties operate under the same OOS procedure to ensure the integrity of the investigation. The discussion concludes that a robust OOS program requires holistic training for all staff on the entire procedure, combined with electronic systems that provide immediate access to necessary data. By focusing on process transparency and trending, manufacturers can move from reactive troubleshooting to a defensible, controlled operation.

Watch the video above to find out how Schniepp and Schmitt answer the question, “We have routinely gotten regulatory observations on our out-of-specification (OOS) procedure? What can we do to make that procedure more robust?”

Investigating Out-of- Specification (OOS) Test Results for Pharmaceutical Production. Guidance for Industry. 

https://www.fda.gov/media/158416/download

MHRA. Out of Specification Guidance. March 2, 2018. 

https://mhrainspectorate.blog.gov.uk/2018/03/02/out-of-specification-guidance/

Siegfried Schmitt, PhD, is vice president, Technical at Parexel and a member of 

Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, provide advice on creating a robust out-of-specification procedure. 

Pharma Fundamentals Episode One: Using Virtual Control Groups to Reduce Animal Testing in Drug Development

Pharma Fundamentals Episode One: Virtual Control Groups in Drug Development

, Associate Director, Product Management, Digital Projects at Charles River

Mouse. | Image Credit: ©BillionPhotos.com -stock.adobe.com

 (EMA) issued a draft qualification opinion

 for a preclinical research methodology to reduce the use of animals in specific dose-range finding studies.

 The new approach method (NAM) would replace standard animal control groups with virtual groups, and once qualified, would allow EMA to accept evidence generated from virtual control groups in medicine approval applications.

 to limit the use of animals in drug development. In April 2025, the agency published its Roadmap to Reducing Animal Testing in to modernize drug development through human-relevant science.

 The core of the initiative is the advancement of NAMs, which include advanced in vitro systems (such as organ-on-a-chip), computational modeling, and artificial intelligence (AI). 

, the FDA draft guidance to reduce or eliminate 6-month primate studies for monoclonal antibodies. The agency also qualified its first AI-based drug development tool, AIM-NASH, and updated guidance to support a transition away from horseshoe crab-derived testing, a move that could spare over one million animals annually.

 To provide regulatory certainty, the FDA launched a searchable database documenting exactly where alternative methods are currently acceptable. Furthermore, the agency has prioritized international alignment, collaborating with global regulators to ensure these new strategies are accepted worldwide.

Virtual control groups are a NAM that can be used to support initiatives to reduce the use of animals in drug development and regulation. According to EMA, characterized control data identify appropriate virtual comparator animals to create virtual control groups that are then used to conduct testing that would be traditional performed on animals.

Laura Lotfi, associate director, Product Management, Digital Projects at Charles River, says that in addition to replacing, reducing, and refining the use of animals, virtual control groups may reduce study timelines and bring more “statistical power”. However, there are limitations to their use, including the reliability of the data.

“The data are highly dependent on the quality, the completeness of the underlying infrastructure that may contain sometimes biases or gaps that can affect the reliability of those results.

They may also be less suitable for certain scenarios,” Lotfi explains. “For example, there are some studies that involve new biological mechanism or rare endpoints, maybe some species that are not very well understood, where the limited historical data are not, quietly there yet, so there is a lack of sufficient historical data that are available. In those cases, traditional approaches may still be necessary.”

In the video above, Lotfi provides an explanation of how virtual control groups are used in drug development, their limitations, and the cost associated with their implementation.

Draft qualification opinion for Virtual Control Groups (VCG) to replace Concurrent Control Groups (CCG) in rat non-GLP Dose-Range Finding (DRF) studies. EMA. March 31, 2026. Accessed April 1, 2026. 

https://www.ema.europa.eu/en/documents/other/draft-qualification-opinion-virtual-control-groups-vcg-replace-concurrent-control-groups-ccg-rat-non-glp-dose-range-finding-drf-studies_en.pdf

EMA consults on virtual control groups to help reduce animal use in medicines development. EMA. Press release. March 31, 2026. Accessed April 1, 2026. 

https://www.ema.europa.eu/en/news/ema-consults-virtual-control-groups-help-reduce-animal-use-medicines-development

FDA’s Roadmap to Reducing Animal Testing in Preclinical Safety Studies. 

https://www.fda.gov/media/186092/download?attachment

FDA Achieves Year 1 Goals in Reducing Animal Testing in Drug Development. Press release. April 20, 2026. 

https://www.fda.gov/news-events/press-announcements/fda-achieves-year-1-goals-reducing-animal-testing-drug-development

Laura Lotfi, Associate Director, Product Management, Digital Projects at Charles River

Laura Lotfi, associate director, Product Management, Digital Projects at Charles River. Laura is a toxicologist that specializes in digital transformation within drug discovery and safety. She focuses on integrating advanced data platforms and innovative methodologies, such as virtual control groups.

Siegfried Schmitt, PhD, Vice President, Technical, Parexel

Siegfried Schmitt, PhD, is vice president, Technical at Parexel and a member of PharmTech’s Editorial Advisory Board.

Draft Qualification opinion for Virtual Control Groups 5 (VCG) to replace Concurrent Control Groups (CCG) in rat 6 non-GLP Dose-Range Finding (DRF) studies. 

New Approach Methodologies (NAMs). FDA.gov. Accessed April 27, 2026. 

https://www.fda.gov/science-research/science-and-research-special-topics/new-approach-methodologies-nams

CDER/Office of New Drugs Streamlined Nonclinical Studies and Acceptable New Approach Methodologies (NAMs). FDA.gov, Accessed April 27, 2026. 

https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/cderoffice-new-drugs-streamlined-nonclinical-studies-and-acceptable-new-approach-methodologies-nams

General Considerations for the Use of New Approach Methodologies in Drug Development Guidance for Industry, Draft Guidance

https://www.fda.gov/media/191589/download

Monoclonal Antibodies: Streamlined Nonclinical Safety Studies Guidance for Industry, Draft Guidance

https://www.fda.gov/media/189920/download

Guidance for Industry, Pyrogen and Endotoxins Testing: Questions and Answers (Edition 2)

S5(R3) Detection of Reproductive and Developmental Toxicity for Human Pharmaceuticals, Guidance for Industry

https://www.fda.gov/media/148475/download

Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations, Guidance for Industry

https://www.fda.gov/media/124829/download

S3A Guidance: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies: Focus on Microsampling Questions and Answers, Guidance for Industry

https://www.fda.gov/media/100027/download

M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Guidance for Industry

https://www.fda.gov/media/85885/download?attachment

FDA. Reducing Animal Testing in Nonclinical Studies Year One Progress and the Path Forward, April 2026. FDA.gov. Accessed April 27, 2026. 

https://www.fda.gov/media/191986/download?attachment

FDA’s Roadmap to Reducing Animal Testing in Preclinical Safety Studies


Innovative Science and Technology Approaches for New Drugs (ISTAND) Program


https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/innovative-science-and-technology-approaches-new-drugs-istand-program

Virtual Consortium for Translational/Transdisciplinary Environmental Research (ViCTER)


https://www.niehs.nih.gov/research/supported/translational/victer

Lotfi L, O'Neill TW, Wilcox A, Bulera S. Virtual control groups in nonclinical research: A Re-analysis of 20 studies using virtual control group data. 

https://doi.org/10.1016/j.yrtph.2026.106077

https://www.sciencedirect.com/science/article/pii/S0273230026000504?dgcid=author

Unlock Hidden Insights: Virtual Control Groups as a Data-Driven Novel Method. Webinar. 

https://www.criver.com/resources/webinar-pi-sa-unlock-hidden-insights-virtual-control-groups-data-driven-novel-method

 Z. What Lilly’s $2.75B bet on AI-discovered drug candidates means for drug development. 

https://www.pharmtech.com/view/what-lilly-s-2-75b-bet-on-ai-discovered-drug-candidates-means-for-drug-development

Thomas F. DCAT Week 2025: Quality and compliance for animal-derived products. 

https://www.pharmtech.com/view/dcat-week-2025-quality-and-compliance-for-animal-derived-products

Haigney S. USP permits use of non-animal-derived reagents for endotoxin testing. 

https://www.pharmtech.com/view/usp-permits-use-of-non-animal-derived-reagents-for-endotoxin-testing

Thomas F, Haigney S. Non-animal-derived reagents for endotoxin testing. 

https://www.pharmtech.com/view/non-animal-derived-reagents-for-endotoxin-testing

Haigney S. The impact of USP Chapter <86> on endotoxin testing. 

https://www.pharmtech.com/view/the-impact-of-usp-chapter-86-on-endotoxin-testing

Focusing on the Fundamentals of Formulation


https://www.pharmtech.com/view/focusing-on-the-fundamentals-of-formulation

https://www.pharmtech.com/view/ich-q6b-for-analytics

Design Quality in Pharmaceutical Design: A Primer for Facility Executives


https://www.pharmtech.com/view/design-quality-in-pharmaceutical-design-a-primer-for-facility-executives

 Pharma Fundamentals video series. Episodes in this educational series aim to provide knowledge in the basics needed for pharmaceutical development and manufacturing, such as chemistry and pharmacology, breaking things down to the basics to help those working in the industry to better perform their jobs. Be sure to check the episode webpage for more topic information and resources. We hope you enjoy the series.

Alternative methods to the use of animals in pharmaceutical testing are becoming more used and accepted. Laura Lotfi of Charles River breaks down the basics of virtual control groups in drug development.

Pharma Fundamentals: Using Virtual Control Groups to Reduce Animal Testing in Drug Development

Ask the Expert: Investigating Patient Complaints About Combination Products

Welcome to the Ask the Expert video series. This series is an extension of the PharmTech 

Group’s long-running print column in which industry experts answer common quality and regulatory questions from the industry. Have a question you would like answered? Send it to 

In this episode of Ask the Expert, Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, address the complexities of investigating patient complaints regarding pre-filled syringe (PFS) and combination products. Schniepp and Schmitt make it clear; for manufacturers who purchase commercial syringes for their drug products, the marketing authorization holder (MAH) remains ultimately responsible for product performance, regardless of their level of control over the component manufacturer.

Investigating these types of events comes with complications, such as the lack of physical evidence (eg, returned devices, photos, or videos) when products are self-administered at home. While the rise of home-administered medications like GLP-1s has tempted some firms to cite “human error” as a root cause, manufacturers must ensure devices are “fit for purpose” across diverse populations, including the elderly and those with disabilities. If real-world evidence reveals a performance gap, it may indicate that initial usability testing may not have been sufficiently varied or robust.

There are also limitations with traditional corrective and preventive actions and recall procedures for these types of complaints. Identifying specific patients for recalls is often impossible once a product is dispensed, and privacy laws, such as HIPAA in the United States, can hinder a manufacturer’s ability to gather critical patient-specific investigation data. Furthermore, responding to patient complaints requires different language than communicating with healthcare professionals to ensure the investigation's logic is understood.

To manage these risks, the experts stress the importance of highly granular quality agreements. These agreements must move beyond simple checklists to explicitly define which party takes the lead in investigations, preventing a “blame culture” between drug manufacturers and component suppliers. Finally, companies must regularly revisit complaint procedures to adapt to evolving business environments, such as direct-to-patient shipping, to ensure they can effectively defend their “effectiveness checks” during regulatory inspections.

Watch the video to find out how Sue and Siegfried answer the question, “My company got a complaint from a patient that their prefilled syringe failed to inject. We make the drug product and purchase the syringe. How do we investigate a problem with the commercial syringe component that we used?”