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: 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. 

Articles

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.

Strategies for Contamination Control

Q: How much data do I need to support opening a corrective and preventive actions (CAPA)?

A: This is an interesting question because it raises the issue of whether a company is overusing or underusing the CAPA system. One data point is enough to open a CAPA depending on whether that data point is a significant occurrence. On the other hand, multiple similar deviations may be overlooked because they are deemed minor with little impact on operations. The most effective way to determine whether you should open a CAPA is to perform a risk assessment of the data.

A single significant deviation, such as putting the wrong label on the product, should justify opening a CAPA. This type of production error carries a high risk. If the mislabeled product is released with the incorrect label, it creates a serious risk to patient safety. The CAPA is necessary because it will enable the company to determine the appropriate actions needed to prevent the issue for recurring. In addition, the CAPA will prompt the company to review data across manufacturing lines and manufacturing facilities so the corrective solution to prevent recurrence can be implemented across the company. An example of a single data point that does not necessarily need a CAPA opened might be a field complaint of a bottle of tablets that contained 99 instead of 100 tablets. This occurrence should be investigated, but because it is low risk and more of an inconvenience to the patient, it may not require a CAPA. Opening a CAPA for this one event could be considered overusing the CAPA system. That being said, if the complaint department tracks these data and finds a significant upward trend of short count bottles over a short period of time, a CAPA may be warranted.

Underusing the CAPA system is also a concern. Not opening a CAPA when faced with data that suggests there is multiple occurrences of the same/similar deviation prevents the company from continuously improving processes. Let’s suppose that in reviewing deviations you notice that a few manufacturing employees have multiple deviations for the same minor issue in the same batch record over a short period of time and that the deviation has been determined to be human error and only retraining of the operators was performed. In this scenario, it would be prudent to open a CAPA for several reasons. First, human error is rarely the cause of a deviation. Second, obviously the retraining to prevent the error is not effective because the error keeps occurring. Third, the data are telling you that you may have an issue in how effective your process for investigating deviations is being implemented.

Data generated from quality systems can also be used to prevent an event from occurring. A preventive action is used to correct potential problems, and try to address them before they happen. In the example above, based on the data collected, you can review other batch records to determine if the operator deviations have the potential to occur with other product batch records and then implement the appropriate corrections to those batch records.

There is no hard and fast rule on how much data you need to open a CAPA. It could be one data point or several data points. The best tools to use to determine whether a CAPA is needed is a risk assessment of the data and common sense.

Susan J. Schniepp is distinguished fellow Regulatory Compliance Associates.

When referring to this article, please cite it as Schniepp, S.J. The Relationship Between CAPAs and Data: What’s the Right Balance? 

A risk assessment should be performed as part of the CAPA process, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. 

The Relationship Between CAPAs and Data: What’s the Right Balance?

Susan J. Schniepp, distinguished fellow for Regulatory Compliance Associates, and Shiri Hechter, senior lab operations manager for Nelson Laboratories, provide a simple approach to validating analytical methods.

Q. How can an analytical method be validated?

A. When using an analytical method published in a pharmacopeia, the method is considered validated and it just needs to be verified under actual conditions of use (1). However, when using analytical methods for routine testing that are not published in the pharmacopeias, it is expected that the method would be validated.

The United States Pharmacopeia defines validation of an analytical procedure as “the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications” (2). The European Directorate for the Quality of Medicines and HealthCare (EDQM), which publishes the European Pharmacopoeia (Ph. Eur.), takes a similar approach stating, “This chapter defines the different analytical situations (categories) which might occur in an OMCL [official medicines control laboratories] and the corresponding validation characteristics which should be considered. Refer to the current version of the ICH [International Council for Harmonisation] guideline on ‘Validation of Analytical Procedures: Text and Methodology (Q2)’ ” (3).

The following examples of industry guidelines provide rationale and approach when validating analytical methods:

The United States Pharmacopeia–National Formulary (USP–NF) general chapter <1225> Validation of Compendial Procedures (2)

PA/PH/OMCL (13) 82 R5, Validation/Verification of Analytical Procedures revised in July 2020 (3)

FDA’s Analytical Procedures and Methods Validation for Drugs and Biologics, Guidance for Industry, July 2015 (4)

ICH guideline Q2(R2) on validation of analytical procedures (currently under public consultation) published March 31, 2022 (5).

These documents are inter-connected because they reference each other and the approach they define is based on defining “Typical analytical performance characteristics that should be considered in the validation of the types of procedures …” (2). In USP General Chapter <1225>, some typical performance characteristics referred to are accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. These characteristics should all be considered when determining the validation approach for any analytical procedure.

USP <1225> aims at compendial procedures that include routine tests on raw materials and finished products. The FDA guidance covers new drug applications, abbreviated new drug applications, biologics license applications, and supplements to these applications. Definitions, data elements, and acceptance levels are well documented in these publications. Depending on the objectives of the method, data elements could vary. For example, USP <1225> defines four categories for consideration. For example, the chapter indicates that Category I–Assay, does not need to have detection limit, whereas Category II–Limit Tests, requires detection limit. The full data elements required for validation are detailed in Table 2 in USP <1225>. Similar instructions can be found in ICH guideline Q2(R2) table. The OMCL (3) document also provides reference tables that discusses the source of the method (i.e., Ph. Eur. method, validated method form a manufacturer, etc.) and the validation requirements needed to ensure it is an appropriate method for its intended use.

In summary, when performing analytical method validation, validation parameters and elements are determined based on the analytical test method and the intended analytical application.

Schniepp, S.J. and Lynn, S.J. Verifying Compendial Methods. 

USP. <1225> Validation Of Compendial Procedures. 

General European OMCL Network (GEON), PA/PH/OMCL (13) 82 R5, July 2022.

Analytical Procedures and Methods Validation for Drugs and Biologics–Guidance for Industry 

 Q2(R2) Analytical Procedure Development and Revison of Q2 (R1) Analytical Validation

. Currently under public consultation (ICH, March 31, 2022).

When referring to this article, please cite it as Schniepp, S.J. and Hechter, S. Considerations for Method Validation. 

Considerations for Method Validation

A.The MBR is the controlling document for product manufacturing. It contains the instructions and specific manufacturing processes needed to produce a particular product. The MBR ensures the ingredients needed to produce a product are correct; added in the correct order; and the mixing, stirring, or other activities used to produce the product are conducted in the correct sequence. For example, the MBR would list an ideal ingredient amount for the product, while the completed batch record would indicate the actual amount used for the individual batch. Batch records are a requirement of 21 

) 211.188, Batch Production and Control Records.

Q. Who is responsible for issuing the batch record to production?

A. Most companies have a document control department that is responsible for issuing the MBR to production. This department may or may not report to the quality department. The most important item to remember about releasing the batch record to manufacturing is that it needs to be tied to an actual production run. The link that ties the MBR to the completed batch record is the lot number assigned to the product being manufactured. Each manufacturing run must have a different lot number for traceability and recall purposes.

Q. Can I release a batch record that has open investigations/deviations associated with it?

 211.22(a), states, “There shall be a quality control unit that shall have the responsibility and authority to approve or reject … drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated” (1). The errors referred to include errors that occur during the manufacturing process. If you are releasing a product that has a batch record associated with an open deviation/investigation then, in my opinion, the “error” has not been thoroughly investigated. The bottom line is, I would not recommend this practice. In my opinion, there is too much risk associated with releasing a product to the field with open investigations or deviations because, if the investigation result indicates the product has not achieved the specified quality attributes, by releasing it you have not only risked patient safety but you are facing a recall situation.

Q. In what order should I review batch record information?

A. I think we need to be clear on what we are discussing when releasing the batch record. It includes a review of the incoming raw materials that include the active ingredient(s), excipients, primary packaging, and labeling. The batch record process should verify these items were properly received, sampled, and put into quarantine until the incoming quality group established their suitability for use. This includes testing of the water that might be used in manufacturing the product. The review should confirm that all the materials used were appropriately discharged using calibrated equipment in a suitable environment and that the manufacturing rooms were properly cleaned and cleared before the start of the batch. The main focus of the picture should be the details of the batch manufacturing itself. Attention needs to be paid to make sure that any deviations during this phase of production have been resolved. It is also important to make sure that operators signed (this could be electronically) in the appropriate places indicating they performed the work. If required, there should also be an indication that another employee or a supervisor witnessed the work. This is particularly important when verifying the right ingredients were discharged to the line to make the right product with the right dosage amount. Many companies use a checklist to make sure all the elements of the master batch record are included in the product batch record. This is an acceptable practice and, when coupled with a thorough review of the contents of those elements, you should confidence in releasing product batches.

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

When referring to this article, please cite it as S.J. Schniepp, “Frequently Asked Questions about Batch Records,” 

Susan J. Schniepp, distinguished fellow for Regulatory Compliance Associates, provides simple answers to frequently asked questions regarding batch records.