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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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. 

Articles

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.

Computer Validation Confirms Evidence

Q: My company is a contract manufacturer. Our final product inspection process consistently delays timely release of the manufactured products to our clients. Is there a best process/practice for performing final
product inspection?

A: This is not a new problem for the industry. To me, some of the issue is the fact that we call the specific activity of the overall physical product evaluation the “final product inspection.” In my opinion, the physical product evaluation should start at the beginning: the receipt of the individual components (stoppers, vials, labels, etc.) that are used in manufacturing. Each component should pass an incoming quality inspection with defined acceptable quality limits (AQL) and clear directions for rejection of the component should it exceed the AQL. The specific elements to be looked at on incoming inspection will vary depending on the component.

Let’s assume your company manufactures sterile injectable products and the major component you will use in manufacturing is a glass vial. The first step in the process is to perform an incoming inspection of the glass vials. The number of vials to inspect from the shipment will depend on the number of vials contained in the shipment. The sample size to be inspected should be recorded in the appropriate standard operating procedure (SOP). The specific defects to be inspected should also be included in the SOP. When evaluating these defects, most companies employ definitions of critical, major, and minor to the reject/accept criteria. In the case of vials, critical might be defined as likely to cause harm to the patient; major might be defined as leads to impairment to the patient; and minor would be defined as cosmetic defect causing no threat to the patient. Defining the acceptance criteria upfront may save you a lot of time at the end of the process.

Once the vial is accepted, it will be used in the manufacturing process. Defects that exist in the vial after initial acceptance may be detected during this step of the process. Many manufacturing lines have automatic sensors that detect vial imperfections and eliminate the vial from the batch before it is sent for labeling. It is important for the line operators to be trained to recognize when there is an increase in rejected vials because this could mean that the incoming inspection did not pick up the vial defect. Again, if the defect can be detected and categorized at this process stage, it will save time at the product release stage.

The last stage for potential vial inspection before labeling would be visual inspection of the stoppered vial. Some companies perform this step manually with trained visual inspectors while others utilize visual inspection equipment to perform the final inspection of the vial before labeling. Companies using vial inspectors typically focus those inspectors on looking for particulates in the vial, but they should also be trained to recognize vial defects. Regardless of which inspection format is used, there should be SOPs and AQLs governing the inspection process.

Final product inspection results should be included as part of your batch release documentation, so it is important to have repeatable, defined process/processes in place at all stages of the manufacturing process that is/are suitable for the product being inspected. The more time you spend upfront in the component inspection process, the more efficient your final inspection and batch release process will be to ensure timely product release to your clients.

When referring to this article, please cite it as Schniepp, S. Final Product Inspection: Making the Most of Your Processes. 

Final product inspection results should be included as part of the batch release documentation, says Susan J. Schniepp, distinguished fellow at Nelson Laboratories, LLC.

Final Product Inspection: Making the Most of Your Processes

Q: Do I need to comply with all aspects of the various pharmacopeias? (e.g., 

United States Pharmacopeia–National Formulary

A: This would seem like a straightforward answer, but as with most issues related to the pharmaceutical industry, it is a bit complicated. Each pharmacopeia has various sections the industry must comply with including monographs, defining the test methods and purification for excipients, APIs, and drug products. These specific monographs often refer to general test procedures (loss on drying, pH, residue on ignition) that are consistently performed respective of the materials. The conditions for performing the test are included in the monograph, while the details of how to perform the tests are included in the general chapter. Individual monographs will specify the use of a certified reference standard that serves as the measure to which your specific item should be compared to in determining its suitability for use. It is acceptable to use in-house reference standards as long as the company has mapped its in-house standard to the official standard. The important detail to remember is to requalify your in-house standard when the lot number of the official standard changes.

Not all information in the pharmacopeias needs to be complied with. The 

 has a section called general information chapters, which are basic guidance advice for performing various operations such as environmental monitoring. Although these chapters are not legally enforceable, users should take notes and document their process when it conflicts with pharmacopeia’s advice. Like the 

 that are not legally binding. These would be general method analysis of substances used in the manufacture of medicines if they are not referenced in a monogram. The pharmacopeias allow for alternative methods to be used providing they are validated and the results generated from the alternative method yields comparable results to the compendium method. All the pharmacopeias have a process for updating their contents. It is up to the users of the pharmacopeias to make sure they are using the current version published by the governing authority for the specific pharmacopeia.

If you follow this simple advice, you should have no trouble maintaining compliance to the compendia requirements.

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

When referring to this article, please cite it as Schniepp, S.J., Complying with Compendial Requirements. 

Maintaining compliance to compendial requirements should be straightforward, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates.

Complying with Compendial Requirements

Q: I work for a virtual company that outsources our manufacturing. We recently made a regulatory filing, and I wonder what information we need to share with our contract manufacturing organization (CMO)?

A: This is an easy question. Share everything you can. Whether you filed an investigational new drug application, a new drug application, an abbreviated new drug application, a biologics license application, or a marketing authorization application, the more information you share with your contract provider(s) the smoother the approval process will be for your organization. Because you are a virtual company, your approval inspections will most likely be at your designated manufacturing facility. If you are using a different facility to test your product, the contract testing laboratory also needs to have critical information to provide the best service because they might also be audited. So, in my opinion, the contract provider(s) need to know as much as the applicant.

In today’s regulatory environment, it is important for organizations to know the regulations with the same depth of knowledge and understanding as regulators. If an organization happens to be a contract manufacturer, it might also find itself in the position of providing that in-depth regulatory expertise to customers. In either case, the contract manufacturer and its customers must be able to work with each other and within the regulatory requirements to assure that the product manufactured and released for patients is of the highest quality. The partnership between the contract provider and contract giver must reflect the requirements and time commitments as defined in the regulations. The most efficient way to establish a transparent relationship where you have the freedom to share the necessary information is to establish a robust quality agreement with your contract provider(s). If you are using a contract manufacturing organization and a different contract testing organization, it is important for you to have quality agreements with both organizations. It is ideal if you can encourage your two contract providers to enter in a quality agreement with respect to your product filing.

Because you are using contract providers, complaints are an area where the more information that is shared between all parties, the sooner a resolution to the complaint investigation can be achieved. Another area where it is necessary for all parties to have access to critical information contained in your filing is investigations for out-of-specification (OOS) results. Whether you are using multiple contract organizations or just one, those organizations should have the information needed to perform a thorough investigation into complaints or the OOSs. The complaint standard operating procedure (SOP) and the quality agreements should address the turnaround requirements needed to investigate complaints associated with adverse or serious unexpected adverse events. For these complaints, the turnaround time must be able to accommodate tighter regulatory requirements. The license holder (i.e., the client) is required to submit a Field Alert within three working days after becoming aware of a reported problem either through a complaint or internal testing. In these cases, the complaint must be investigated quickly by the contract manufacturer and/or the contract test laboratory. The turnaround time for these types of investigations must be more expeditious than the timelines for handling routine investigations. OOS reports also require an expedited timeline for communicating confirmed results to the client because of the potential impact to product already distributed for use. When there are agreements in place that allow the sharing of information that can potentially be used for resolving investigation and ensuring they are completed in a timely manner, the stronger your compliance posture will be when it comes time for your pre-approval inspection.

In today’s environment, all parties must take responsibility for product quality and regulatory compliance through clear delineation and communication of responsibilities through quality agreements and internal SOPs.

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

When referring to this article, please cite it as Schniepp, S.J. Sharing Critical Information for the Best Outcome. 

The more information shared, the smoother the approval process, says 
Susan J. Schniepp, distinguished fellow with Regulatory Compliance Associates. 

Sharing Critical Information for the Best Outcome

Q. My colleagues and I have been discussing the new requirement for a contamination control strategy (CCS) contained in the European Union’s 2022 Annex 1 revision. Can you provide some guidance on what should be included in the CCS?

A. The concept of contamination/containment control has been around for quite some time. The 2004 FDA Guidance for Industry states, “Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control” (1). The revised Annex 1 guideline takes things a step further by stating, “A [CCS] should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical, and organisational) and monitoring measures employed to manage risks to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention” (2). The guideline also states, “The CCS should consider all aspects of contamination control with ongoing and periodic review resulting in updates within the pharmaceutical quality system as appropriate. Changes to the systems in place should be assessed for any impact on the CCS before and after implementation” (2).

The Parenteral Drug Association’s (PDA’s) Technical Report states, “The ongoing evolution of contamination control principles that this document addresses is a shift to a holistic approach, where practices are designed to work together to achieve proactive contamination control and are evaluated for their collective effectiveness” (3).

What does this all mean to pharmaceutical manufacturers? Let’s start with what we have already in place. All companies should have contamination control elements addressing various aspects of the manufacturing process including but not limited to process design, microbial control, facilities, utilities, raw materials, environmental, personnel training and qualification, equipment qualification, and a robust quality management system. Some of the specific contamination control elements included in these categories would be the existence of bioburden and endotoxin attributes, particulate monitoring, process validations, material and personnel flow, product quarantine practices, smoke studies, media fills, gowning qualification, cleanroom practices, microbial monitoring during production, cleaning validation, extractables/leachables, container closure integrity, etc. The strategy in CCS is how the company ties all these elements together in a holistic approach that is interdependent, multi-disciplinary, and tailored to the operation. This requires the company to be deliberate in risk assessing how changes to any of the elements affects the other elements under the umbrella of the CCS.

The overall objective of the CCS is to describe what control elements are in place, why they are effective, and that potential contamination is controlled from the beginning to the end of the manufacturing process.

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 

Contamination Control Strategy Development in Pharmaceutical Manufacturing

When referring to this article, please cite it as Schniepp, S. Strategies for Contamination Control. 

A contamination control strategy should provide an overview of how contamination and containment practices work together to ensure product quality and patient safety, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates.