Susan J. Schniepp is a fellow at Regulatory Compliance Associates, Inc. and a member of Pharmaceutical Technology's Editorial Advisory Board.

Susan J. Schniepp

Ask the Expert: Quality Control Units

After an FDA inspection of a pharmaceutical manufacturing facility, any deviations the inspector might find during the inspection are reported on a Form 483 and sent to the manufacturer. If the company fails to properly respond to the agency, FDA will follow up with a warning letter. A common theme seen on warning letters is that companies fail to properly establish a quality control unit. So how should a company respond if they receive such a citation?

“Well, you see the mere fact that they actually received a warning letter means that their initial response to the observations by the FDA inspectors were considered inadequate or incomplete,” Siegfried Schmitt, vice president of Technical at Parexel, explains. “I think it's therefore essential to admit that this shortcoming has happened, and so they should make sure that the response they now give to this warning letter is really a complete and convincing one and provides a remediation plan that will be acceptable to the authorities.

 video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss what manufacturers should do when they receive a warning letter from FDA for an insufficient quality control unit.

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

“My company received an FDA warning letter for failure to create a quality control unit. What is the best way to respond to FDA?”

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates and a member of 

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

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. This new video series will expand on topic areas to include development and manufacturing concerns to help those working in the industry better understand bio/pharmaceutical requirements. Have a question you would like answered? Send it to PTProjects@mmhgroup.com, and it may appear in a future episode or print column.

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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 how to address an FDA warning letter citation for a failure to establish a quality control unit.

Question mark background | Image Credit: © Leigh-Prather - © Leigh Prather - stock.adobe.com

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.

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.

Considerations for Complying with 21 CFR 211.110, Draft Guidance

Susan J. Schniepp, is distinguished fellow at Regulatory Compliance Associates, and Rona LeBlanc-Rivera, PhD, is principal consultant, Regulatory Affairs at Regulatory Compliance Associates.

When referring to this article, please cite it as Schniepp, S.J. and LeBlanc-Rivera, R. Drug Shortages and Complying with FDA’s 21 CFR 211.110 Guidance. 

Articles

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

Q: I work for a small contract manufacturing company that produces aseptically filled sterile injectable products for some clients. We are constantly being audited and told we are not in compliance with current good manufacturing practices (CGMPs) for sterile manufacturing. Some of the requirements can be costly to implement and maintain. Are there any requirements that we can eliminate, such as smoke studies, and still be considered to be in compliance?

A: The short answer is no. The CGMP requirements for aseptic sterile manufacturing are in place to ensure product quality and patient safety. Each requirement plays a vital role in determining the suitability of the product and the conditions under which it was manufactured. Under section 501(a)(2)(B) of the Food, Drug, and Cosmetic (FD&C) Act, a drug is deemed to be adulterated if: “ the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess” (1).

 Volume 4, Annex 1, Manufacture of Sterile Medicinal Products gives similar advice by stating: “The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test” (2). Let’s look at just a few requirements to illustrate why they are important.

Media fills are a supporting activity for determining the suitability of the product. Media fills are important because they demonstrate that the process controls are performed appropriately, cleanliness is maintained throughout the fill, and contamination risks are not introduced by the personnel or the process. Another supporting activity are smoke studies. The primary objective of smoke studies is to demonstrate that the filling stations have sufficient design and control to reduce potential contamination and to identify areas that may be away from or adjacent to the filling area that may contribute to any potential contamination during operations. Particulate monitoring during operations is important for demonstrating that the air quality was controlled before, during, and after the operations were conducted.

Environmental monitoring is another supporting activity critical to ensuring product quality. The information from this activity will provide assurance that ongoing operations are kept in control. This is also a process control that shows that operations conducted in the qualified areas are able to maintain the appropriate cleanliness on an ongoing basis.

Another critical support activity is the cleaning/disinfectant/sanitization process. The object of cleaning and disinfecting is to achieve appropriate microbiological cleanliness levels for the class of cleanroom for an appropriate period of time. Cleaning and disinfection of cleanrooms are an important part of contamination control, especially for manufacturing lines that produce more than one product. These are just some of the requirements needed to support the manufacturing of sterile medicinal products.

Aseptically filled sterile products are the highest risk products to manufacture. The supporting requirements are fundamental in ensuring patient safety and product quality, and they must be an integral part of a company’s ability to comply with the regulations.

 (Government Printing Office, Washington, DC). 

www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-225

EC. Annex 1 Manufacture of Sterile Medicinal Products. 

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates.

®
Vol. 48, No. 12
December 2024
Page: 34

When referring to this article, please cite it as Schniepp, S. Complying with CGMPs for Sterile Manufacturing. 

All CGMP requirements, including supporting activities, are critical in aseptic sterile manufacturing to ensure product quality and patient safety, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates.

Complying with CGMPs for Sterile Manufacturing

Q: I work for a 503B compounding organization. A customer has asked us to manufacture a drug product that includes a food-grade component because it is less expensive than the compendial-grade material. Is this an acceptable substitution?

A: No. Substituting a food-grade material when a compendial material is available is not acceptable. US 21 United States Code (USC) 351 states that a drug is considered adulterated if it “purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standard set forth in such compendium” (1). This section of the USC goes on to state, “No drug defined in an official compendium shall be deemed to be adulterated under this paragraph because it differs from the standard of strength, quality, or purity therefore set forth in such compendium, if its difference in strength, quality, or purity from such standard is plainly stated on its label.”

This is supported in the language contained in the General Notices of the 

] are recognized in the laws and regulations of many countries throughout the world.” It also states, “In the United States under the Federal Food, Drug, and Cosmetic Act (FDCA), both 

 are recognized as official compendia. A drug with a name recognized in 

 must comply with compendial identity standards or be deemed adulterated, misbranded, or both. See, e.g., FDCA § 501(b) and 502(e)(3)(b); also US Food and Drug Administration (FDA) regulations, 21 

] § 299.5(a&b). To avoid being deemed adulterated, such drugs must also comply with compendial standards for strength, quality, and purity, unless labeled to show all respects in which the drug differs. See, e.g., FDCA § 501(b) and 21 

 § 299.5(c).”The General Notices goes on to state, “Compounded preparations, including drug products compounded by outsourcing facilities, may also be subject to applicable monographs” (2).

However, there may be situations where there is no compendial standard for the material you are being asked to use in the formulation. In that case, you need to perform an assessment that would allow you to introduce the material. However, before you go through the activity of introducing a non-compendial material into your facility, it is advisable to check to see if the material in question is supported by monograph requirements contained in either the European or Japanese pharmacopoeias. If neither of those compendia contain a monograph, the following questions may help you determine if the material in question is safe to bring into your facility:

How are you going to accept this material and bring it into your facility?

Because it is food grade, are there additional specifications you need to have based on the intended use of the finished drug product?

Are there additional tests you need to conduct? If so, then talk to the supplier. You must work with supplier to establish the conditions, criteria, specifications, under which you will accept this material and make sure the additional criteria are included on the Certificate of Analysis.

Determine what type of additional training needs to be conducted so you are assured you can perform the test methods for the new material.

Determine if the cleaning procedures are effective. Is there cross-contamination to consider for the new component?

Having a robust quality management system will help you to answer these questions. You should be able to understand the risks and how to obtain information on how to sample/store the material. All of this will be in your quality management system which will allow you to have a risk management plan.

21 USC 351: Adulterated Drugs and Devices. Title 21 Food and Drugs. Updated Sept. 16, 2024.

Susan J. Schniepp is a distinguished fellow at Regulatory Compliance Associates.

When referring to this article, please cite it as Schniepp, S.J. Using Compendial-Grade Materials for 503B Compounding Facilities.Pharmaceutical Technology 

Substituting a compendial-grade material with a food-grade material is not acceptable, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. 

Using Compendial-Grade Materials for 503B Compounding Facilities

Q: I am working on making our quality control test laboratory methods more sustainable and environmentally friendly. Do I need to let the regulatory authorities know I am undertaking this initiative?

A: This is a great initiative. Focusing on methods that minimize waste and eliminate the use of hazardous substances is in line with current industry and regulatory trends. Global regulatory authorities have long-term initiatives to encourage quality control (QC) laboratories to adopt sustainable methods within their companies. For example, the 

) has an initiative to remove the rabbit pyrogen test from the Ph. Eur. by 2026.

While you don’t need to inform the regulatory authorities of the initiative during the feasibility phase of exploring alternative methods utilizing sustainable technology, you will need to inform them of your intent to implement these methods when you are ready to use them as your primary methods for evaluating excipients for manufacturing and for releasing the final product for patient use.

One strategy for implementing sustainable testing for monographed items is to submit your test procedure along with the appropriate validation and comparability results to the compendial authorities showing the new method to be equivalent or better than the current existing test method(s). If the compendial authorities adopt the new procedure as part of the official monograph, and, assuming you have indicated in your filing that you follow the current compendia(s), you can just implement the change, noting the adoption of the new compendial procedure in the annual report per Appendix B in FDA’s 

Guidance for Industry, CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports

, which states “Any change made to comply with the official compendium, except relaxation of an acceptance criterion or deletion of a test (see 21 

The drawback to this approach is the unknown amount of time it may take the proposed change to work its way through the monograph revision process and become officially adopted. This approach could take years, and there is no guarantee that it will be successful because the global pharmacopoeias are not harmonized.

The filing requirements when implementing new test method changes to proprietary items can also be accomplished in an annual report, if you submit it as an alternate procedure according to the aforementioned document, according to the FDA guidance, which says, “For drug substance and drug product, the addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application or deletion of an alternative analytical procedure. The appropriate validation and comparability results against the original procedure will still need to accompany the annual report” (1).

Sustainable product safety tests are straightforward to conduct, but, before implementing them, the company must make sure they are sufficiently validated and yield comparable results to the original method, in addition to notifying the relevant regulatory bodies.

Guidance for Industry, CMC Postapproval Manufacturing Changes to Be Documented in Annual Reports

When referring to this article, please cite it as Schniepp, S.J. Going Green: Updating Your Filings.

The implementation of new quality control methods must be reported to regulators, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. 

Going Green: Updating Your Filings

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). The revised Annex 1 guideline introduces the concept of contamination control strategy (CCS) by stating. “A [CCS] 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). 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 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).

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.

Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice

Guidelines for Good Manufacturing Practice Medicinal Products for Human and Veterinary Use

, Annex 1: Manufacture of Sterile Medicinal Products (EC, 2022 rev.).

Susan Schniepp is distinguished fellow at Regulatory Compliance Associates. Zachary S. Anderson is global market segment lead—Sterility Assurance, Nelson Laboratories.

When referring to this article, please cite it as Schniepp, S. and Anderson, Z.S. 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.