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

Siegfried Schmitt

Ask the Expert: Post-Approval Changes

Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, provide advice on how to handle post-approval changes in this episode of Ask the Expert. The drug manufacturing process is never static, explains Schmitt, and therefore, companies should anticipate future changes from either production volume, process optimization, or technological innovation. The key question is how much of this can be anticipated and addressed before filing.

Schniepp outlines the regulatory mechanisms available, focusing on the system in the United States. With prior-approval changes, companies wait for the FDA to sign-off before implementing. For changes being effected in 30 days (CBE-30), companies can proceed after a 30-day waiting period absent an objection by the FDA objection. CBE is an even faster pathway rarely used today. She notes companies sometimes register alternative methods (eg, both high-performance liquid chromatography and ultra-high-pressure liquid chromatography) at filing time to build in flexibility. Schniepp recommends comparability protocols as a useful tool for managing scale-up changes.

According to Schmitt, pre-approval submissions typically prioritize speed to market, though companies should also consider requesting pre-approval for anticipated changes to avoid the time and cost burdens of post-approval processes, particularly costly Type II variations in Europe. However, resource constraints often limit how much forward planning occurs before approval, because teams are focused on the approval itself.

Schniepp highlights annual reportable changes (eg, certain equipment upgrades or method changes with demonstrated comparability) as another avenue requiring less regulatory scrutiny, urging companies to carefully study relevant guidance documents.

Schniepp emphasizes that a company’s risk tolerance should drive its change-management strategy; some organizations are highly risk-averse and prefer prior approval, while others are more comfortable leveraging annual reports for faster implementation. Both experts agree there’s no one-size-fits-all approach; each company must develop its own change management strategy based on its specific risk appetite and resources.

Click the video above to watch Sue and Siegfried answer the question: “We are coming to a regulatory filing, and we know there's a possibility of post-approval changes being pre-approved. Do you have any advice?”

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

In this episode of Ask the Expert, Siegfried Schmitt, PhD, vice president, Technical at Parexel, and Susan J. Schniepp, distinguished fellow at Nelson Labs, discuss how companies should approach post-approval changes to their CMC regulatory filings.

Ask the Expert: Complying with Standards

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In this episode of Ask the Expert, Susan J. Schniepp, distinguished fellow with Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical, with Parexel answer the question of whether pharmaceutical companies must comply with pharmacopeias, such as the 

Schniepp explains that pharmacopeial monographs, which are specifications and test procedures, are validated, recognized by regulators under good manufacturing practices (GMPs). In the United States, USP defines a monograph as “a written document that reflects the quality attributes of medicines approved by the US Food and Drug Administration” that provide quality expectations and include tests and information regarding identity, strength, purity, and performance.

However, "general information chapters" offering broader guidance are generally considered advisory rather than mandatory. Companies may deviate from these recommendations, but must document and justify how their alternative approach still achieves GMP compliance.

Schmitt notes that the USP is developed by a non-government organization; however, the European and Japanese pharmacopeias are government-issued, making them more directly enforceable. He points out that there are other voluntary standards (e.g., GAMP, ISO, ANSI, and NIST) and organizations like the Parenteral Drug Association operate within an ANSI-accredited framework, issuing technical reports and white papers as best-practice guidance where official standards don’t exist.

Schmitt and Schniepp stress that merely citing a standard (e.g., "we followed GAMP") doesn't guarantee compliance. According to Schmitt, there have been cases where companies claimed adherence but lacked the required documentation such as validation plans.

Schniepp adds that adopting a compendial method still requires labs to perform their own verification, because original validation data come from the submitter (government or innovator), not the adopting lab. Variations from lab to lab, such as equipment differences (e.g., high-performance liquid chromatography vs. ultra-high-performance liquid chromatography), requires that labs must confirm the method works on its own systems, essentially a mini robustness check.

Schmitt brings up an interesting point manufacturers should consider. In China, companies must maintain the original-language pharmacopeia and demonstrate someone can actually read it, because translations may be inaccurate.

Compendial compliance is nuanced, requiring companies to interpret regulations, verify methods locally, and document deviations rather than assume automatic compliance.

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

“We have just acquired the latest versions of the 

. We are not clear if it is mandatory to comply with these pharmacopeias. Do we need to comply?”

An overview of USP monographs. USP. Accessed August 5, 2026. 

https://www.usp.org/about/public-policy/overview-of-monographs

In this episode of Ask the Expert, Susan J. Schniepp, distinguished fellow with Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical, with Parexel, clear up some of the confusion about what does and does not need to be complied with regarding standards set by international pharmacopeias.

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, 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. 