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

Susan J. Schniepp

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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. 

Articles

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.

Elements for a Sustainable Environmental Monitoring Program

Compliance can be greatly improved by concentrating on the basic elements of CAPA investigations, advises Kate Rice, global quality systems manager, Nelson Laboratories, and Susan J. Schniepp, distinguished fellow, Regulatory Compliance Associates.

I work in quality assurance, and we consistently get inspection observations regarding the incompleteness of our corrective and preventive action (CAPA) activities. What advice can be offered to improve the quality of our CAPAs?

A: You and your company are not alone. Incomplete CAPA investigations continually ranks in the top five citations by FDA and constitute a critical component of quality management systems in the pharmaceutical industry. As many well know, CAPAs stand out as meticulously scrutinized records by regulatory bodies; therefore, it is imperative to take appropriate actions not only to rectify and prevent non-conformities, and potential issues in processes, products, or systems but also to prevent regulatory audit findings.

The effectiveness of a CAPA plan relies on its ability to address various types of actions tailored to the specific needs and challenges encountered. Understanding all types of actions is pivotal for ensuring compliance, enhancing product quality, and fostering continuous improvement within pharmaceutical operations. The following information delineates each type of action and when it should be applied.

Containment entails immediate and interim measures aimed at preventing further spread or recurrence of an issue before implementing a CAPA. It’s crucial to initiate containment measures promptly upon identifying high-risk issues, without waiting for the completion of the investigation. Containment actions reduce the issue’s impact while the investigation is ongoing.

Corrections involve immediate actions to rectify occurrences or symptoms that have already transpired. These actions target the immediate issues to mitigate imminent risks or adverse effects. Corrections are executed without delving into root cause investigations, aiming to quickly restore compliance with established standards and procedures.

Corrective actions address the root cause of problems once a comprehensive investigation has been completed. They are long-term solutions designed to mitigate issues and prevent recurrence. Upon implementation of corrective actions, containment measures may cease.

Preventive actions are proactive measures implemented to anticipate, mitigate, or eliminate potential risks before they occur. Unlike corrective actions, which address existing issues, preventive actions focus on identifying and addressing vulnerabilities in processes, systems, or products to prevent future occurrences of non-conformities or other issues.

Effectiveness checks monitor the implemented solutions to provide evidence that the initial problem was solved and there has been no recurrence of the identified issue. The amount of data that needs to be collected to prove the fix was effective will vary on the complexity of the problem being addressed.

In summary, correction addresses occurrences before issue identification, while containment halts issues during root cause determination until corrective action ensues. Containment actions cease upon corrective action implementation. Effectiveness checks provide data confirming the correction was successful. Considering all these action types for a CAPA record enhances preparedness for regulatory scrutiny. Implementing CAPA actions meticulously underscores a commitment to quality, compliance, and continuous improvement within pharmaceutical operations.

Kate Rice is global quality systems manager, Nelson Laboratories, and Susan J. Schniepp, is distinguished fellow, Regulatory Compliance Associates.

When referring to this article, please cite it as Rice, K. and Schniepp, S.J. Focusing on Effectiveness for CAPAs. 

Focusing on Effectiveness for CAPAs

Q. I just started working for an independent product contract manufacturing company, and we are installing new computers in all the critical areas. What do we need to validate?

A. There isn’t a lot of detail in your question so let’s assume you are in fact installing computerized systems in your operation. FDA defines a computer system as a “functional unit of one or more computers and input/output devices, peripherals and associated software, used in common for all or part of a program and storing all or part of the data necessary for program execution” (1). The relevant International Council for Harmonisation (ICH) Q7 document says computer systems are both “hardware components and associated software, appointed and assembled to perform a specific function or group of functions” and “process or operation integrated with a computer system” (2).The European Union’s EudraLex defines a computer system as a “system individually designed to suit a specific business process” (3). These systems could include a laboratory information management system (LIMS), a documentation management system (DMS), and/or a electronic batch record system (ERB).

The need to validate these different systems is driven by FDA’s definition of validation, which says, “Validation is the confirmation by objective evidence, that the previously established requirements for the use of a process or system are met” (1). Bottom line, computerized systems that have an impact on product quality, patient health and safety, and on GxP practices that impact production processes, storage of data for finished products, documentation management of processes and procedures, electronic records, etc. must be validated to ensure the integrity of manufactured product.

Now that we established why you need to validate computerized systems, let’s look at general concepts that might help with your approach to validation. The validation plan should include the installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) testing protocols and change control procedures. Each part of the validation plan should be executed in a specific order. For example, you need to complete the IQ before you start executing the OQ. When you write protocols for validating your systems, you need to make sure you address data integrity for each system. You need to ensure that the electronic records and signatures generated by your system meet the ALCOA + data integrity concepts of being attributable, legible, contemporaneous, original, accurate, complete, consistent, enduring, and available.

By establishing a validation plan and ALCOA+, you can be confident that your computerized system is capable of generating reports and data that attests to the safety and quality of the products your company manufactures.

 Part 11, Electronic Records, Electronic
Signatures, 2003.

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

, The Rules Governing Medicinal Products in the European Union, Volume 4 Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 11: Computerised Systems, 2011.

Susan J. Schniepp is distinguished fellow at Nelson Laboratories, LLC.

When referring to this article, please cite it as Schniepp, S. Computer Validation Confirms Evidence. 

Validating computerized systems is required to demonstrate adherence to data integrity, says Susan J. Schniepp, distinguished fellow at Nelson Laboratories, LLC.