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Pharmaceutical Regulatory Affairs

As the pharmaceutical market continues to expand globally, regulatory affairs in pharma is making an effort to harmonize global standards and to protect the complex supply chain. Pharma companies and regulatory consultants are also making an effort to stay compliant with worldwide guidelines in an ever-changing regulatory environment. 

 

There is a lot of effort on the part of drug companies to research and make sure they are compliant with the various worldwide manufacturing regulations. For the most part, GMP requirements are rather consistent worldwide.

 

The differences that exist can be managed by applying the strictest requirement to the products that would ensure its acceptance across the globe. Issues may arise when a standard applied to the technology is changed and the new requirement is stricter than its predecessor. Companies need to fully understand their product in the development stage to be able to address the ever-changing regulations.

 

Pharmaceutical Regulations

 

Regulators, government agencies, and standard-setting organizations can be the catalyst for the development of new and innovative therapies as a response to world health crises. There are a variety of ways a regulatory affairs consultant in pharma can get involved with these initiatives.

 

There are many trade organizations that offer workshops and conferences that address some of the unmet medical needs facing the global community. Companies should make sure they are on the mailing lists for these organizations so they can receive notice of upcoming conferences and choose the ones that seem most pertinent to their business. These conferences not only [provide] cutting-edge information, but they also offer an opportunity for people to network and discuss issues and potential solutions to them.

 

Manufacturers must navigate the regulatory science waters to ensure their products meet the proper requirements. In the following sections, industry experts give advice about regulatory affairs in pharma, standards development, and responding to regulators. 

 

Pharma Regulatory

 

Global regulatory affairs standards and monographs, such as the United States Pharmacopeia and the European Pharmacopoeia (Ph. Eur.), can help pharmaceutical manufacturers get their products approved by regulatory bodies and into patients’ hands. According to a US Pharmacopeial Convention (USP) spokesperson:

 

USP’s public standards can help facilitate the application process by establishing standards that sponsors reference in applications and licenses to demonstrate the quality, purity, and strength of their drug products.

 

International standard-setting organizations emphasize regulatory affairs in pharma and the importance of ongoing industry collaboration. USP encourages pharma companies to participate in the development of public standards. Susanne Keitel, director of the European Directorate for the Quality of Medicines and Healthcare (EDQM), which is in charge of the Ph. Eur., would like to see medical regulatory affairs from industry become more active in the development of pharmacopeia standards, such as nominating experts to participate in developing standards.

 

The knowledge and experience of experts from pharma companies is crucial to ensure robust, state-of-the art, validated, and affordable test methods and monographs, and relevant standards worldwide. For example, no pharmacopeia could do without the contributions and collaboration within industry when it comes to pharmaceutical packaging regulations. This cross-functional industry collaboration is both helpful and necessary.

 

USP’s Global Health Monographs program addresses treatments for major health concerns, such as malaria, or unmet needs in underserved communities outside of the United States. Pharmaceutical companies can help by donating specifications and materials. Any regulatory consulting firm working with clients on USP for pending monographs is another way industry expertise can be leveraged.

 

“These are monographs or monograph revisions for certain substances that have been submitted or are intended to be submitted to FDA for approval but have not yet received approval. By approaching USP early in the process, USP can more readily close the gap that otherwise might exist between FDA approval and the publication of an applicable USP monograph,” says a USP spokesperson.

 

Pharmaceutical Regulatory Affairs

 

The pharmaceutical regulatory affairs behind researching and developing a regulated product for distribution is a long and expensive process. By regulatory consultants working closely with regulators and pharma companies, it can make the product approval process smoother.

 

The approval process can be improved when sponsors work hand in hand with regulatory agencies during the approval process, answering reviewers’ questions as they arise, and providing timely information regarding manufacturing processes and quality control strategies.

 

“In my opinion, sponsors can be more open with FDA during the development process,” says Mukul  Agrawal, PhD, and member of the Bioequivalence Focus Group steering committee at the American Association of Pharmaceutical Scientists (AAPS).

 

“There are apprehensions about how FDA will perceive that and what if FDA asks for something unreasonable? To the contrary, FDA is helpful and appreciates the efforts of sponsors in doing things right and according to FDA’s expectations. While there is a need for balance in these interactions, it is better to maintain open communication with FDA. It is also possible to have a dialog with the FDA about their expectations, and if data can be provided to support justification for doing something differently, it should be discussed and agreed to with them.”

 

Pharmaceutical Regulatory Consulting

 

Not providing enough information about manufacturing and regulatory affairs in pharma can complicate FDA’s evaluation of a drug product.

 

Not providing information in the proper format (e.g., electronic common technical document [ECTD]) and providing insufficient or incomplete information …  not responding in a timely fashion to requests for additional information or answering questions posed by regulatory agencies [are mistakes companies make].

 

Using a pharmaceutical regulatory consulting firm can help the understanding of what’s expected by the regulatory body.

 

“The most frequent mistake in my opinion is that the companies find out too late in the process that some things were not done according to FDA expectations as described in the various guidance documents and then try to use a Band-Aid approach. It is important to have input from all departments within the company from the earliest stages of development to prevent mistakes,” says Agrawal.

 

FDA Pharmaceutical Regulations

 

One of the important tasks that most regulatory agencies worldwide perform is facility inspections. Companies that operate in the United States or import products into the US are inspected by FDA. An FDA spokesperson states:

 

“During an FDA inspection, investigators are seeking to verify that facilities are operating in a state of sufficient control according to current good manufacturing practice (CGMP) guidelines.” 

 

Companies that operate worldwide should be aware of pharma regulatory compliance and what international inspectors look for during an inspection.

 

Although there is a common approach for regulatory inspections by all agencies that are members of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) in the US, European Union, and Asia, their focus and expectations may differ. For example, some agencies might look more closely at pest control, whereas others may be more concerned with adherence to local pharmacopeias. In addition, agencies such as the US FDA will investigate potential criminal conduct, while other agencies verify compliance with the regulations.

 

Pharmaceutical Regulatory Compliance

 

Facility compliance inspections may cause pharma regulations anxiety for leadership, but being prepared can make the process pain free.

 

The best way to prepare for an inspection, whether it is in the US, EU, or Asia, is to know your operations. Regulations for pharmaceutical companies are fairly clear when it comes to understanding your quality system, completing past investigations, and following standard operating procedures (SOPs). Personnel should be prepared and relaxed and employees should not change their behavior to accommodate the regulators.

 

An FDA spokesperson concurs:

 

To prepare for an FDA inspection, facilities should review the CGMP guidelines and assure they are in compliance with those guidelines. FDA offers several resources to help facilities better understand and adhere to CGMP guidelines, such as public outreach through presentations at national and international meetings and conferences to explain the CGMP requirements and latest policy documents.

 

Working with a Pharmaceutical Regulator

 

There are a variety of things pharma companies can do when inspections must comply with regulations, including having good controls, compliance processes, training, and systems up front.

 

There is less preparation effort if the company is in a good compliance state. Making sure everything is done correctly day in and day out will always help meet the expectations of your pharmaceutical regulatory. Make sure that the SOP system covers all the activities needed to undertake the type of ongoing manufacturing operations at the site.

 

EU Pharmaceutical Regulation

 

Global experts in pharmaceutical manufacturing regulations often suggest performing internal audits prior to an inspection by regulators can help based on EU pharmaceutical regulation changes.

 

Internal audits … may be helpful in identifying areas that may pose problems during the inspection. Practice audits can challenge logistics and allow personnel to go through an ‘inspection’ without the pressure of an official EU regulatory inspection. You want [personnel] comfortable and unflustered when the regulators are viewing them performing their jobs or asking them questions about their job functions.

 

During the actual EU pharmaceutical investigation, the best way to make the impact on your employees pain free is to make sure you talk to them before they enter into the inspection room or before they are to be observed by the EU inspectors. This is not to coach them on what to say but rather to calm them down before they are observed or questioned by the inspector so they can interact in a positive way with the inspector. Companies should also identify and address any potential pharmaceutical regulatory compliance risks prior to inspections.

 

Knowing your risks allows you to better prepare for inspection questions.  You also need to be seen as addressing the risks that you have found.

 

cGMP Regulations for Pharmaceutical

 

Companies should plan the logistics of an inspection including the location for the inspection, personnel escorts and contacts, and preparing any communications or documents the inspectors might require. Pharmaceutical regulatory consulting companies like RCA conduct assessments as if an inspector may want to see:

 

A copy of the current organizational chart, a copy of the titles of your SOPs, a list of your corrective actions and preventive actions (CAPA)/investigations, and a list of your complaints. The rule of thumb is to go back approximately two years for the CAPA/investigations and complaints.

 

Addressing findings from previous inspections is also imperative.

 

Inspectors review previous inspection reports and expect that prior commitments have been completed. Most importantly, any documents the inspectors ask for should be provided in a timely manner. Bottom line, the sooner you get the regulators the information they want, the sooner they will be able to wrap up the inspection. If you are organized and forthcoming in your information your inspection will go much smoother.

 

Companies may benefit from providing a quality assurance consultant with an overview of their facilities. This can increase the success of training programs and process revisions before an inspection takes place.

 

Recognize that the inspector is dropping into your environment with little context. By providing them with the context they will be better able to understand what you do and ask better questions. It is recommended to use storyboards to describe processes, situations, or decisions. Storyboards can be useful in meeting pharma regulations because they help the inspector understand the situation rather than forcing the pull information from one or more documents.

 

While preparation may be key, there are obvious things companies should avoid to meet pharmaceutical regulatory compliance during an inspection, such as lying, being evasive, or arguing with inspectors.

 

“The inspector will want direct answers to direct questions and to talk to the people doing the job, not management,” says Lerner. The regulatory investigator is there to ensure GMPs are being followed, and avoiding the inevitable may make things worse. “Sometimes companies try to hide situations from investigators or provide misleading answers.  A good investigator usually asks the same question in different ways and in multiple areas and will uncover misleading or untrue answers,” says Madsen.

 

Medical Affairs in Pharmaceutical Industry

 

Responding to violations observed during an inspection is equally important across the entire Medical Affairs team.

 

Respond quickly but thoughtfully.  For a 483, point out any situations that the investigator may not have fully understood.  It’s best to clarify and resolve these during the inspection, if possible, before they are put in writing.

 

Regulatory affairs in pharma should take FDA 483 observations seriously, but be careful not to overcommit.

 

When the inspector returns, they expect the commitments to be completed and could escalate actions if not completed. Systemic corrections should be put in place. Companies should make sure to address how you are going to maintain a compliant status once the change has been implemented and have a plan for any violations that cannot be immediately fixed. 

 

Addressing root causes of observed violations is key. It is often the most critical element of the assessment a quality control consultant would provide to you about lingering NCR’s:

 

The agency really wants to see that you are addressing the root cause and that you are addressing this issue across the organization. As an example, if the inspector found that a particular non-conformance (NCR) was not investigated fully, it is equally important to both explain what happened in that instance (and why you made specific decisions) and what you are doing to prevent future insufficient NCR investigations.

 

Properly addressing violations cited by investigators on a FDA 483 form may help companies avoid receiving a warning letter from FDA. When FDA does send a warning letter, companies should take their response seriously.

 

The warning letter itself is an indication that the company has been out of compliance for some time and has been unsuccessful in solving their compliance issues. Probably the most conservative response to a warning letter is to outline your plans to improve your quality system and commit to bringing in an unbiased third party (consultant) to review and make sure your plans are executed appropriately and will eliminate your systemic quality problems. If you are at the warning letter stage, it means you have been unable to solve your problems and you need help. Make sure you communicate this in your response.

 

This advice rings true. In recent warning letters, the agency has often suggested a company obtain outside consultation in resolving GMP violations.

 

Government Regulations on Pharmaceutical Companies

 

Ensuring the safety and efficacy of medicines doesn’t stop when the drug is approved by regulators and distributed to the public. Inefficient manufacturing practices, GMP violations, negligence by ingredients or service suppliers, and other complex issues can all have an impact on the safety of a drug product. Both industry and regulators have a continued responsibility to ensure the safety of patients.

 

One aspect of pharma’s part of this responsibility is keeping regulators informed of any adverse events associated with a drug product. An FDA spokesperson states that pharmaceutical companies that “market prescription and nonprescription drug and biological products in the US must review all adverse event information they obtain or otherwise receive from any source, and report adverse events to the FDA’s Center for Drug Evaluation and Research as described under the regulation or section of the Food, Drug, and Cosmetic Act that is applicable to the type of product they market.”

 

“Adverse event reporting is a serious matter and should not be taken lightly,” says Schniepp. A well-managed and properly staffed pharmacovigilance unit is key, according to Moreton. “[The unit should have] clearly defined responsibilities and report in to the senior management (not sales and marketing),” says Moreton.

 

Pharmaceutical Regulatory Intelligence

 

Companies should report pharmaceutical regulatory intelligence behind adverse events via the regulatory affairs in pharma established by notified bodies. When in doubt, it is better to be conservative and report by the earlier of multiple deadlines. Providing complete information required by FDA pharma regulations is just as important as is maintaining accurate records. It is best to initiate the process for adverse event reporting as soon as regulatory affairs in pharma companies become aware of of the event to prevent any delays in filing.

 

A very common mistake made by regulatory affairs in pharma is waiting too long to report the event. Many companies are tempted to wait until they have completed the investigation into the event before reporting its occurrence. By contrast, regulatory bodies like the FDA are clear on adverse event reporting.

 

“These entities must ensure that the adverse event reports they submit to FDA are transmitted in an electronic format the FDA can process, review, and archive.  In addition, these entities must have written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse event to FDA as well keep records of all known adverse event information,” states an FDA spokesperson.

 

Conclusion

 

Regulatory affairs in pharma should be used as a tool to help manufacturers develop and market their products and that regulators and their regulations should not be feared or avoided. Being mindful of regulatory requirements, especially European regulations for pharmaceutical industry, can make the regulatory approval process much smoother. Maintaining GMPs and having well-trained personnel will ease the stress of regulatory inspections. 

 

It is clear that both industry and regulators have the same ultimate goal: provide safe and effective treatments to people who need them. Understanding and nurturing the industry-regulator relationship fosters innovation in regulatory affairs in pharma and ensures patient safety worldwide.  

 

Article Details

RCA

 

Pharmaceutical Technology
Vol. 40, No. 12
Pages: 20-24

 

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Medicine Manufacturing: Crisis Guidelines

Products must be manufactured by following guidelines and in accordance with appropriate medicine manufacturing regulatory requirements, even during a pandemic and crisis management, says Susan J. Schniepp, Distinguished Fellow, Regulatory Compliance Associates.

 

Q. I am in the quality department and am responsible for investigations, and I have been working from home due to the COVID-19 pandemic. The investigation standard operating procedure (SOP) requires me to perform face-to-face interviews with people and to complete the investigation within 90 days. Working remotely to conduct the interviews is taking much longer, and I am afraid I’ll miss my deadlines. Could I eliminate the interview requirement until I am able to return to the facility?

 

A. I certainly understand the challenges of trying to conduct remote face-to-face interviews and the need to try and streamline processes during times of crisis, but now is not the time to take unnecessary, undocumented shortcuts with any of your medicine manufacturing procedures.

 

medicine manufacturing

My recommendation is that you step back from your frustration with the situation. Focus on the elements you need to conduct a thorough pharmaceutical manufacturing investigation and look at finding alternative means to fulfill the SOP requirements as defined in your contingency plan. If you do not have a contingency plan in place, you should immediately develop one and include appropriate risk-based information.

 

The European Medicines Agency has a guidance on the format for a risk management plan that might help you get started on this activity.

 

To determine how you might make your operations more efficient during crisis times, I further suggest you review the FDA’s guidance titled, Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products.

 

The guidance document states “this guidance is intended to encourage manufacturers of medically necessary drug products (MNPs) and any components of those products to develop contingency production plans to use during emergencies that result in high absenteeism at production facilities” … “The guidance provides considerations for the development and implementation of a plan for production of MNPs during a crisis, including specific elements that should be included in the plan.” 

 

The medicine manufacturing contingency plan you develop should include information regarding the company’s prevention and risk mitigation processes.

 

The guidance states “these preventative measures can include steps to prepare personnel such as:

 

  • “Educating employees on topics such as, in the case of a pandemic, personal hygiene (hand washing and coughing and sneezing etiquette), social distancing, and appropriate use of sick leave
  • “Encouraging employees to get immunized as appropriate by providing information on local vaccination services or by offering on-site vaccination services, if reasonable
  • “Providing information for and encouraging employees to develop family emergency preparedness plans
  • “Reviewing CGMP [current good manufacturing practice] regulations regarding appropriate sanitation practices and restriction of ill or sick employees from production areas (see 21 CFR [Code of Federal Regulations] 211.28)”.

 

The final guideline also recommends “that manufacturers, when evaluating activities that might be reduced in frequency, delayed, or substituted by a suitable alternative, first identify and consider activities that are intended by the CGMP regulations to provide controls not connected with the manufacturing of any specific batch. Examples include:

 

    • “Production equipment routine maintenance
    • “Utility system performance checks and maintenance (e.g., air temperature, lighting, compressed air)
    • “Environmental monitoring of facilities such as cell culture, harvesting, and purification rooms during production
    • “Stability testing for certain drug products and components
    • “Periodic examinations of data and of reserve samples”.

 

In addition, the guideline also recommends that:

 

“If the demand for MNPs cannot be met by the measures described above, manufacturers can consider reducing activities that are more directly connected with batch manufacturing or a product accept/reject decision provided that they have a documented rationale or risk assessment to show that the proposed changes will not unacceptably reduce assurance of product quality. Examples include:

 

  • “Not requiring second-person verification of activities for less critical steps (though we recommend a self-check of work)
  • “Reducing the number of samples for labor-intensive laboratory testing
  • “Forgoing an in-process test to assure adequacy of mix, particularly when making successive batches, where the risk is judged to be low in terms of drug safety and efficacy
  • “Delaying completion of deviation investigations of minor events.
  • “CDER [the Center for Drug Evaluation and Research] recommends that in taking such measures, firms plan to carefully monitor indicators of product quality to note any unfavorable trends or shifts as a result of the implementation of the Plan. CDER also recommends that firms retain samples for testing at a later date in cases where testing is reduced or omitted because of lack of resources”.

 

While it is important to act quickly and efficiently during a medicine manufacturing crisis, the process and product must still be manufactured in accordance with appropriate regulatory requirements. Before you make any drastic changes to SOPs or eliminate process steps you need to read the FDA guidance document, prepare a proper risk assessment, and justify why the removal of the requirement from the SOP does not impact patient safety and product quality.

 

The documentation you provide and the assessments you perform to address some of the extraordinary situations facing you and your colleagues. In the effort to produce necessary medical drugs, preparation should give you confidence that you have acted appropriately and within the regulations to fulfill patient needs.

 

 

medicine manufacturing

 
Susan J. Schniepp
Pharmaceutical Technology
Volume 44, Issue 6, pg 62, 60
 

 

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Quality Metrics

Susan Schniepp, Distinguished Fellow at Regulatory Compliance Associates®, discusses the quality metrics journey in determining the suitability of pharmaceutical products.

 

quality metrics

 

One of the most discussed and debated topics on today’s pharmaceutical landscape is the issue of quality metrics. Establishing, maintaining, and interpreting quality metrics to determine the suitability of pharmaceutical products has become a high priority for the FDA. To understand the issue of quality metrics it is important to start at the beginning.

 

FDASIA

 

The first stop on this journey took place in 2012 when Congress passed the Food Drug Administration Safety and Innovation Act (FDASIA) which enhanced FDA’s capability to proactively react to, prevent, and alleviate drug shortages. This direction is embedded in the language contained in Title VII—Drug Supply Chain and Title X—Drug Shortages.

 

Specifically, Title VII Section 705 of the Act states FDA:

 

“…shall inspect establishments described in paragraph that are engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs (referred to in this subsection as ‘drug establishments’) in accordance with a risk-based schedule established by the Secretary”.

 

QA Risk Factors

 

This section also describes the risk factors considered in establishing the inspection schedule. One of the risk factors listed in this section is:

 

“Any other criteria deemed necessary and appropriate by the Secretary for purposes of allocating inspection resources.”

 

Section 706 of the same act authorizes FDA to request certain company information in advance of or in lieu of inspections by stating

 

“Any records or other information that the Secretary may inspect under this section from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug shall, upon the request of the Secretary, be provided to the Secretary by such person, in advance of or in lieu of an inspection…”

 

In addition, Title X section 506C-1 (Annual Reporting on Drug Shortages). Title X section 506C-1 requires FDA to annually provide Congress “a report on drug shortages…”

 

Quality Metrics Examples

 

The second part of the journey occurred in the Federal Register Notice. In that notice, FDA asked the industry to:

 

“assist the Food and Drug Administration in drafting a strategic plan on drug shortages as required by the Food and Drug Administration Safety and Innovation Act…”

 

This notice asked a series of thought-provoking questions about more specific quality metrics including:

 

“What metrics do manufacturers currently use to monitor production quality?” and “How frequently would such metrics need to be updated to be meaningful?”.

 

The industry reaction to this information was varied. Many trade organizations responded to the questions in the Federal Register. Some prepared white papers while others held meetings to discuss the issue with their members. The general consensus was that industry needed to seriously engage with FDA to define which quality metrics would provide information to the agency supporting efforts to eliminate drug shortages and to be used in establishing a risk-based approach to inspections.

 

FDA Quality Metrics

 

The third leg of the journey was the issuance of a draft guidance titled Request for Quality Metrics. In between the issuance of the Federal Register and the release of this original draft guidance there were many industry comments submitted to the agency suggesting various metrics that might be employed by the agency.

 

In addition, industry trade organizations held conferences and seminars to discuss the issue with the stakeholders and agency representatives. A number of these trade organizations published white papers based on the proceedings from these conferences and put forth the position that the need to submit metrics to the agency was redundant because of the requirement to submit annual product reviews. The agency listened to industry and some of the feedback was incorporated into the guidance.

 

Quality Performance Indicators

 

The quality performance indicators that were chosen as metrics for the updated guidance include:

 

  • Lot Acceptance Rate
  • Product Quality Complaint Rate
  • Invalidated OOS Rate
  • Annual Product Review
  • Product Quality Review
  • On Time Rate

 

The guidance also contained three optional metrics intended to measure quality culture:

 

  • Measuring Senior Management Engagement
  • CAPA Effectiveness
  • Process Capability/Performance

 

This version of the quality metrics guidance generated 83 comments from industry submitted to the docket. A number of these comments focused on the practicality of submitting the requested metrics. In response to this concern the agency issued the Quality Metrics Technical Conformance Guide: Technical Specifications Document that explained how companies would be expected to submit the data to the agency.

 

Quality Management

 

The fourth part of our journey came when the second version of the guidance, titled Submission of Quality Metrics Data Guidance for Industry was released for comment. The docket for commenting on this most recent version of the guidance closed. There were 25 comments submitted. 12 from trade associations, 10 from individual firms, one from a hospital group, one from an academic institution and one from a private citizen.

 

The guidance clearly stated the

 

“…metrics can be also useful to FDA: to help develop compliance and inspection policies and practices…. improve the agency’s ability to predict, and therefore, possibly mitigate future drug shortages; and to encourage the pharmaceutical industry to implement state-of-the-art, innovative quality management systems for pharmaceutical manufacturing.”

 

Quality Metrics

 

The FDA also clarified the goal of the metrics program by stating

 

“As described in this guidance, FDA is initiating a voluntary reporting phase of the FDA quality metrics reporting program.”

 

This current version of the document requires companies to report on only three metrics:

 

  • Lot Acceptance Rate
  • Product Quality Complaint Rate
  • Invalidated OOS Rate

 

The optional metrics intended to measure quality culture were removed.

 

Total Quality Management

 

These proposed metrics are not new to the pharmaceutical industry. Many of them are currently being used by companies to measure their total quality management performance. In order to be successful, companies need to review and analyze the information the FDA is asking for, as well as other metrics they are collecting, and identify potential problem signals. Quality leadership teams should look to solve issues and self-correct before regulatory inspections occur.

 

The problem with the proposed metrics, however, is that they are lagging indicators of performance. There is no set requirement on which metrics a company should track to measure their overall performance. Each company should determine which metrics to track based on their operations, number of facilities they operate and where they are located, what types of products they manufacture, and what type of culture exists in their places of business. Any metrics chosen must be meaningful and written to provide a clear analysis of ongoing activities.

 

Quality Assurance Management

 

It is important for operations and quality to agree on any type of quality assurance metrics. Additionally, how to report the results to management is as important as the results themselves. The interpretation of the data is a crucial element because it may include a root-cause analysis of its own and may help to promote continuous process improvements.

 

When choosing a metric, it is important that the architects of the QA metric are aware of consequences that may inadvertently drive negative behavior. Management attempting to incentivize achievement of the goal such as offering a financial award if the goal is achieved may lead to inappropriate behaviors that do not address the real issue. In these cases, it is generally not the metric that will drive the behavior but rather use of behavioral rewards. Reward for achievement rather than analysis of the real underlying causes will not lead to sustainable positive change.

 

Quality Control Management 

 

When managed properly, metrics are an important tool to drive positive design controls and process improvements. Regardless of what metrics a company chooses to measure their performance, achieving a quality culture is important in assuring reported quality control metrics are accurate and reliable. A quality culture requires management and employees to establish an environment where responsibility, accountability, and reliability are paramount. This helps each person deliver a high-quality product to the customer and sustained performance over time.

 

Management must educate employees and provide the tools and environment where they can perform their functions in an atmosphere that encourages excellence and continuous improvement. Continuous improvement programs are, in fact, reliable indicators of the presence of a quality culture. Where the industry’s and the agency’s destination on this journey ends is yet to be seen. What is evident is that companies must have a robust quality metrics program so they may continue to supply quality products without interruptions to patients.

 

Planning Quality Management

 

Companies need to keep in mind that when planning a quality management program, they should evaluate numerous data input points. This would include, but not limited to:

 

  • Product-quality attributes
  • Manufacturing site performance
  • People metrics
  • Quality-system metrics

 

For product-quality metrics, companies should consider reporting on batch-specific data such as trending drug product, drug substance, and stability test results against customer complaint rates.

 

Internal Audit

 

Indirect product-quality metrics could include environmental monitoring, water trend results, and yield rates. When establishing site metrics, the company could look at inspection history including internal audit findings and maintenance history such as equipment age versus defect-failure rates.

 

People metrics should consider ongoing job-specific training and education, skills and experience assessments, and employee turnover rate by job function and site.

 

Root Cause

 

Quality systems metrics might look at change control, investigation root-cause trends, and release-testing cycle times. Companies that can successfully establish a robust metrics program that helps them continuously improve should have no trouble meeting the FDA metrics requirements.

 

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Risk Management for Machine Learning in Medical Devices

regulatory compliance

 

The quest is on for machine learning (ML) to turn raw data into useful medical devices that improve outcomes and reduce burden on the healthcare system. Supporting, and someday emulating, human thought processes enables ML devices to improve the decision-making process for patients and clinicians. Software designed to continually learn and improve poses both challenges and opportunities.

 

For example, in the not-so-distant future, patients may experience medical devices such as an intelligent insulin pump that more effectively manages patient needs in anticipation of a dessert about to be consumed. As ML matures, the possibilities to improve patient care are endless while the challenges are many.

 

ML Device Development

 

As device developers seek to harness ML for next generation products, it’s important to address the unique ML challenges in the pre-commercial stage, including:

 

  1. The research phase, where selecting the ML algorithm drives subsequent risk mitigation considerations
  2. The building phase, which addresses verification, validation, and risk management concerns specific to ML
  3. Regulatory processes and the nuances of working with regulatory bodies and novel technology

 

ML Algorithms

 

ML typically uses supervised or unsupervised algorithms to discover a data pattern and generate actions. In supervised learning, the developer guides the teaching process of the algorithm. This requires a known data set with inputs and outputs to train the machine to make predictions. The developer corrects the machine’s predictions in this learning cycle, and the system learns from the corrections.

 

Natural language processing is an example of this. The developer enters a sentence, asks the machine what it means and over time, the machine learns the pattern and consequently makes smarter outputs.

 

Unsupervised Learning

 

The other type is unsupervised learning, where the developer does not provide teaching guidance along the way. Instead, the machine extracts general rules from the data using mathematical optimization and other techniques. An example involves the condition of peritonitis, a swelling of the peritoneal cavity. The machine takes pictures of the patient cavity and determines if infection is suggested based on its analysis of prior data.

 

Choosing to use either a supervised or unsupervised ML algorithm typically depends on factors. These include the structure and volume of the data, and the use case at hand of the medical device. The developer can introduce errors in the model if the underlying assumptions are untrue. For example, a machine could learn how to visually differentiate between a criminal and civilian if given a set of photographs. However, the resulting algorithm would be incorrect when applied to future photos because appearance doesn’t predict criminal behavior.

 

ML Validation and Verification

 

Besides choosing the best algorithm at the onset of new product development, the R&D professional needs to choose the right amount of data to validate the model. Mislabeled data, too little data, and too much data introduces risk into the machine. The risks are based on the type of algorithm in ML.

 

In supervised learning, the decision tree or statistics are used to teach the machine. It’s validated by using fault tree analysis that pairs with the decision tree to understand if the machine takes the wrong path based on input data. The challenge in validation is mathematically proving the error margin falls within the tolerance originally specified. The math requires an adequate data set where data points can be allocated between the learning the validation samples.

 

In Vitro Diagnostics

 

ML can make it difficult to determine appropriate data sizes due to the lack of standards and potential introduction of creative approaches. A developer, for example, might compare previous clinical studies to suggest sample sizes. In-vitro diagnostics (IVD) validation might require some 450,000 patient data sets for algorithm development and validation to ensure the sample size in the fault tree analysis.

 

Artificial Intelligence

 

In another example, IBM Watson allows developers to choose various AI algorithms. A developer searching for cancer tumors in a biopsy might choose a neural network, which can be difficult to understand and challenging to develop and validate.

 

The neural network is trained using sets of data like a list of blood test results that indicate the patient has a certain number of cancer cells. Or, the algorithm can be trained by supplying it with images of healthy cells and those afflicted with cancer. In this example, the algorithm can be validated by comparing the training data set to a reasonable clinical study, which compares blood test results to correct diagnoses, the developer asserts that the algorithm has been adequately trained.

 

Algorithms, which are developed by using a pre-developed AI model, can be validated by leveraging the recommendation of the original creator on the amount of data needed to test to meet the desired margin of error. Another way to determine sample size involves leveraging domain experts such as clinicians, who understand the frequency of all paths in the decision tree based on their knowledge of each tree node and its associated risks.

 

Cybersecurity 

 

Developers understand the need for security and privacy in healthcare applications. In ML, a new security risk involves the malicious introduction of bad data into the machine, which can lead to invalid and harmful outputs. Use of ethical hackers, however, can help mitigate the risk of bad data in supervised learning. These hackers specialize in simulating malicious acts that lead to limitations or boundaries on system learning, which ultimately protect against bad data.

 

Mitigation Tactics

 

The risk of bad data in unsupervised ML can be reduced by buying an established algorithm with embedded mitigation tactics (mathematical, programmatic, etc). However, a thorough review of the algorithm mitigations is necessary by cybersecurity specialists who understand medical devices and unsupervised machine learning algorithms.

 

Developers have long been wary of privacy issues related to protected health information in cloud applications. Since many ML platforms leverage cloud storage and therefore introduce new risks to the process, it’s important for ML developers to understand how their data is collated with other data sets. This shared data about the patient condition could be combined to violate privacy through a technique called inference by malicious entities.

 

Inference

 

Inference is an approach that combines different innocuous and non-sensitive data to gain sensitive information. Consider the aggregated data for an automobile accident patient. It’s possible an attorney might slice the data and discover information about the victim’s diabetes to blame the patient for the mishap due to a potential diabetic coma.

 

The use of polyinstantiation can mitigate these types of risks by slicing the data into sets for collation, and designing data silos so only the developer knows which piece goes into the algorithm, thereby preventing the disclosure of the entire patient database.

 

Regulation in ML Technologies

 

Experienced medical device developers understand the well-established process for working with regulators and developing submissions. The challenge in ML surrounds the lack of precedence.

 

Regulators are used to working with established frameworks where a consistent set of inputs generates a reliable set of outputs, but in ML, the outputs are continuously evolving. Thus, device developers must help regulatory agencies establish ways to assess the safety and effectiveness of products. Some suggested tactics include:

 

  • Build a regulatory affairs team with experience in ML and multidisciplinary functions.
  • Conduct early and frequent meetings with regulatory authorities so both sides can learn from each other.
  • Find clinical and regulatory information throughout the world that is supportive of the desired goal. If negative information is uncovered, address it rather than ignore it.
  • Do not submit a “black box.” Develop ways to communicate how and why a particular result occurred.
  • Seek related credible sources, publications, guidance documents and subject matter experts, reference them, and utilize them.
  • Recognize that regulators are used to understanding the device’s Mechanism of Action. In ML and other novel technologies, it is difficult to describe how the device works, so seek alternatives such as Safety Assurance Cases to help effectively communicate risks and risk management activities.

 

Safety Assurance

 

When developing new medical device technologies, regulation compliance, risk identification, and risk management are all equally important. Safety assurance cases are an effective way of helping demonstrate device safety.
 
 
Assurance cases have been used successfully by other industries such as avionics to efficiently minimize product risk and expedite government reviews. The assurance case helps reviewers better understand risk management in a regulatory submission and recognize how the sponsor both mitigates risks and reduces the likelihood of a device harming end users.
 
 
Safety assurance cases can streamline processes for U.S. Food and Drug Administration (FDA) reviewers by improving their understanding of claims and supporting information, and elucidating the evidence supporting product safety and efficacy. This system is markedly different than the traditional method, which entails presenting FDA reviewers with supporting evidence sans guidance and rationale.
 
Such an approach, however,  can be problematic for regulators dealing with new technologies because there may not yet be any applicable review standards in place. The safety assurance case process enables reviewers to follow a structured map that focuses on specific evidence of safety claims, possibly resulting in faster submission evaluations.
 
 
Safety assurance cases are similar to legal cases, as they authorize product safety and serving as the logical glue for various parts of the regulatory submission. It is an overarching document that:
 
  1. Presents all claims that can be easily linked with supporting evidence to demonstrate the validity of safety claims
  2. Is a formal method used to demonstrate the validity of a claim. It is presented as a clear, understandable argument supported by scientific evidence
  3. Contains arguments based on statistical measurements of the system’s reliability and are grounded in risk-based and scientific methods to help discuss and draw conclusions

 

For regulators, safety assurance cases:

  1. Help to connect the dots in a structured way
  2. Helps them to see both claims and supporting evidence
  3. Helps them understand the “big picture”

 

For medical device manufacturers, safety assurance cases:

  1. Align medical device product development with FDA expectations.
  2. Help gain faster regulatory approvals. Medical device companies that move toward best practices by leveraging safety assurance case principles can clearly demonstrate product safety in a single document, making it easier for the FDA to review.

 

The three elements of an assurance case are claims, evidence, and arguments.

  1. The claim is a statement about a property of the system—typically, contained and/or driven by a requirements specification
  2. The evidence should provide information demonstrating the validity of the claim. This evidence may include verification and/or validation results including, but not limited to, test data, experiment results, and analysis. The evidence should also address the relevance to the claim, whether the evidence directly supports the claim, and whether it is providing sufficient coverage of the claim
  3. Arguments should link evidence to the claim and provide a detailed description of what is being proven. The arguments also should identify specific evidence that supports the claim
 
There are numerous examples, published by the FDA, industry, and academia that explain the reasoning for constructing an effective safety assurance case. It is important that companies understand the importance of a well-structured medical device product development process executed by experienced professionals, as well as the diligence and effective communication strategies that provide regulators, payers and medical professionals with the evidence and confidence needed to bring these new technologies to market.
 

Risk Management

 

Companies considering integrating ML into their products can boost their probability of success by developing a complete ML strategy (as opposed to a piecemeal or single-product approach). Working with experienced ML professionals helps, along with a multidisciplinary ML mindset incorporating R&D, regulatory, software, and cybersecurity expertise.
 
It also is wise to take a studied approach in selecting the ML algorithm, and develop a robust risk management plan that addresses the unique challenges in ML validation and cybersecurity. Most of all, companies should prepare themselves for the challenges surrounding safety and efficacy. This will be important during the regulatory submission process. Developers should be open to novel approaches such as safety assurance cases.

 
Incorporating ML into medical devices offers life sciences companies unparalleled opportunities to impact health and create sustainable differentiation from competitors. As with any emerging technology, there are risks along the product lifecycle during the R&D, regulatory, and validation processes. A prudent approach involves careful planning combined with a solid risk management strategy that brings in seasoned experts to augment internal capabilities.
 
 

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Conducting an Internal Audit

The internal audit function of life science companies is one cornerstone of an effective and efficient quality management system. There are several types of audits that comprise a robust internal control program including supplier audits, internal audits, and regulatory audits.

 

Compliance Audit

 

Compliance audit documents to be reviewed include the quality manual, list of standard operating procedures, open deviations, and corrective and preventive actions. Any additional supporting evidence an ISO audit team may choose to review will help the certified auditor team assess and decide the final facility compliance status.

 

Forensic Audit

 

Preparing for a forensic audit or regulatory audit typically consists of the regulatory inspector providing the facility being audit agenda. This listing would include any areas of the audit mentioned in a FDA 483 and audit trail documents. The audit report will focus on life science departments to be inspected. This can include incoming raw materials, quality control, chemistry and microbiology laboratories and manufacturing. 

 

IT Audit

 

Conducting an IT audit is also critical in times like these of high cybersecurity concerns. Internal audits are performed by the company as a self-assessment for the purpose of identifying areas/issues that might affect their IT compliance status. This specific audit committee may include employees from across the company to intentionally examine IT process and quality from a cross-functional perspective. 

 

Audit Committees

 

Preparing for an internal audit requires the same discipline as preparing for supplier and regulatory audits. This includes audit committees and the number of employees involved in the process. During the COVID-19 pandemic, many companies reduced the number of employees allowed at an audit site. Many of the other audit committee who helped conduct the audit were allowed to work remotely. It is important to consider where employees are globally and the role they each play during an internal audit. 

 

Internal audits are part of management team responsibilities. Conducting an internal audit is different from the other audit types, whether it is pre-, during, or post-pandemic. If designed and implemented appropriately, there is great value in the internal audit. It allows the company to find vulnerabilities in their systems and remediate before they are discovered by an external auditor.

 

Audit Procedures

 

Internal audits can provide valuable information that can be used to prevent issues before they become compliance concerns. Audit procedures often help develop a remediation plan to take action to mitigate compliance problems. Having corrective actions in place before others identify the issue may lessen the impact of the observation. Most importantly, show there is a process in place for continuous improvement. In addition, the internal audit can be used for training staff and communicating valuable information to the organization.

 

Audit Schedule

 

The ideal tone for an internal audit should be a collaborative team-oriented activity that is instructive, informative, open, honest, and inclusive. There are several factors that help contribute to establishing this tone. The most successful is hiring a certified information system auditor to help guide the process. 

 

Another way to set the proper tone is to publish the audit schedule or agenda in advance. This makes sure the functional areas personnel are informed of the time schedule. During a pandemic, the agenda takes on another level of importance because it ensures the proper documents are ready to go. Teams should upload all data either before or during the audit. Prior planning precludes poor performance in this area.

 

Audit Office

 

Each of these specific audits requires preparation to make sure the forensic audit is productive and accomplishes its intended purpose. In the manufacturing world, the goal of the audit office is to ensure facilities are manufacturing fit-for-use products in full adherence. This includes meeting current good manufacturing practice (CGMP) requirements.

 

Audit Trail

 

Supplier audits are performed to confirm the audit trail of raw materials, packaging, labeling components, etc.. An effective audit trail should provide documentation of a continuous, uninterrupted supply of materials that are compliant with CGMPs. Regulatory authorities perform inspections to determine if the manufacturing company is providing materials that comply to CGMPs.

 

Audit Risk

 

An operations audit conducted requires documents be shared electronically to the auditor using secure electronic systems. This electronic exchange helps reduce audit risk by increasing the efficiency between independent auditor and a facility being audited. The quality audit documentation can be reviewed by the auditor, and questions can be communicated to the audit manager via email, conference calls or virtual technology. While this may not be ideal, because it eliminates the audit planning in-person interaction, it is still an effective way to conduct a system audit.

 

Facility Audit Tour

 

internal audit

Touring the facility is challenging when a virtual audit or external audit is conducted. These challenges can be overcome with some flexibility and ingenuity. Live video feed could be streamed to the auditor while the company’s audit manager and/or subject matter experts are available. This can help answer questions that might arise during the live videoconference.

 

Audit Video Recording

 

Additionally, the operational audit could be recorded, and that recording could be provided to the auditor. The understanding would include the audit manager being available to answer any questions upon the review of the video. The recorded version of the tour has both positives and negatives. For example, a certified auditor needs to see things in as real time as much as possible. However, it does allow for the auditor to pause and go back to review audit control processes in more detail if warranted.

 

Audit Issues

 

The auditors should work with the functional area and talk with as many employees as possible to identify the issues of concern. Individuals who are responsible for performing the day-to-day activities often have the best insight. Questions would include what is currently working and what needs to be improved.

 

Excluding them from participating in the audit process might result in overlooking a serious issue. As a result, this could come up or inadvertently lead the auditor to think the site is hiding something. To be able to get the most valuable information about the potential compliance issues facing the organization, internal audits should not be judgmental or antagonistic. 

 

Audit Questions

 

Auditors should be direct and avoid asking questions designed to intentionally stump people. Another important behavior is the ability of the auditor to listen to the answers and refrain from judging. The exact same behavior defined for the auditor should also be the behavior displayed by the auditees.

 

Auditees should be direct and avoid deflecting or obfuscating answers. They should take the time to explain why they do things the way they do them. Performance audit answers should be proactive, point out things of concern and seek advice on how to remediate them. Both parties need to remember they are not enemies, rather they are the partners in improving the organization.

 

Conclusion

 

Conducting these types of each technical audit presents a multitude of challenges. Today’s audit risk model has allowed the life science industry to creatively utilize technology-based applications to communicate and perform an effective system audit. The documentation and supporting evidence review can be conducted remotely, and confidentiality can be maintained. After reviewing the documentation and supporting evidence, the auditor can request interviews with various personnel.

 

Integrated audit interviews can then be scheduled via Zoom or online video conferencing. With appropriate planning and the proper use of technology, remote auditing can have the same audit quality as in-person auditing. 

 

 

BioPharm International

Vol. 34, No. 2

Pages: 44-45

 

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Quality Inspection: Making the Most of Your Processes

Quality inspection results should be included as part of the batch release documentation, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates.

 

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 a quality 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.

 

Quality Inspection

 

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.

 

Quality Control Inspection

 

When evaluating quality control 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 leading 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. The line operators need 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.

 

Quality Assurance Inspection

 

The last quality assurance stage 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 , 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 quality checks in manufacturing and batch release process will be.

 

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Pharmaceutical Technology
Vol. 47, No. 12
Page: 34

 

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