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Emerging Therapies

Click now to listen to Regulatory Compliance Associates’ executive principal consultant, pharma and biologics, Steven J. Lynn, MS, shares his thoughts about emerging therapies, expanding cell and gene therapies on the horizon and how it will affect the industry.

 

 

 

Expanding the Emerging Therapeutic Horizon

Author: Jill Murphy, Editor for BioPharm International

 

 

Drug development is inherently costly and time-intensive, with potential attrition a persistent burden on companies’ finances (1). As companies gain a deeper understanding of cell and molecular biology and seek to develop more complex therapeutics for patient populations, they will also need to be more innovative to ensure commercially viable success is achieved (2).

 

An area that has witnessed significant breakthroughs over recent years has been that of cell and gene therapies. The market for these emerging therapies is projected to grow at a compound annual rate of 22.41% between 2022 and 2030 (3), driven by an expanding pipeline and increasing regulatory approvals.

 

Emerging Therapy Development

 

Despite the successes that have already been achieved with emerging therapy development and manufacturing, companies are still facing numerous challenges. Aspects such as demand for accelerated development timelines, advancing technologies, and the growing issue surrounding sustainability are monopolizing the priorities of bio/pharma companies.

 

However, through new opportunities, like allogeneic cell therapy, it is hoped that greater benefits to patients, particularly those in undertreated populations, will be achieved (4).

 

Continued investment in cell and gene therapies

 

Major players in the cell therapy and manufacturing industry are seeing a lot of changes that are heavily impacting the standard processes. The field continues to evolve, and it has been exciting to be a part of the new innovations in the industry, according to Daniel Palmacci, president of Cell & Gene at Lonza.

 

Cell and Gene Development

 

“While there has been a biotech funding slowdown, there remains a healthy pipeline for emerging therapies with nearly 3000 cell and gene products [currently] in development. Commercialization is high on the agenda as more products enter the market,” says Palmacci. “Cell and gene therapies are no longer on the fringe—they are now being used to treat several cancers and rare diseases.”

 

Breakthrough Treatment

 

Steven J. Lynn, MS, executive principal consultant, pharma and biologics at Regulatory Compliance Associates, expands on this and how there is still continued investment in the research and development area to further discover the next breakthrough treatment. “We’ve seen multiple clients either just starting out and needing some upfront advice to the late Phase II company looking to get ready for commercialization,” Lynn says.

 

Facility Automation

 

Tom Fletcher, scientific director at FUJIFILM Irvine Scientific, notes some examples of finding more cost effective, consistent ways to develop therapies, such as converting from adherent cell lines to suspension cell lines, or even finding new ways to use facilities to support automation and retain shipping flexibility.

 

Regulatory Compliance

 

In terms of regulatory and strategy expectations, certain companies are focusing on providing more information on cell and gene development and manufacturing. According to Shankar Iyer, alliance management lead at Pfizer CentreOne, companies feel it is important to reconsider when supply decisions must be made in this industry.

 

Supply Requirements

 

“It used to be that much of the supply of gene therapy products for late-stage clinical and commercial launches was decided at the early stage of clinical development. However, with advancements in biology, engineering, and data sciences, biotechs can establish or negotiate supply requirements in a more agile manner closer to the delivery of gene therapies to clinical subjects and patients,” says Iyer.

 

Addressing new short- and long-term challenges

 

Along with all the excitement that comes with innovations are the hurdles that developers and regulators are persistently working through. Topics such as cost reduction, manufacturing quality and efficiency, and increases in access are continuing to impact cell therapies in the short-term, according to Aaron Dulgar-Tulloch, PhD, technology leader for Genomic Medicine at Cytiva.

 

Proto Oncogenes

 

As for the long-term, however, Dulgar-Tulloch feels that there may be a completely shifted focus. “Long-term, I believe the most pressing challenge facing the cell therapy industry is demonstrating that it can move beyond blood-based cancers and into broader clinical utility in a way that will add differentiated value to the patients, relative to the continuing advancements that are expected from viral vector and nucleic-acid based gene therapies,” he says.

 

Emerging Therapy Commercialization

 

In addition to these points, Palmacci highlights how commercialization is the key challenge when looking from a developer standpoint. “Building specialist skills and regulatory know-how, investing in high-quality raw materials, establishing the right quality systems and analytical processes, and finding a partner with proven GMP [good manufacturing practice] commercialization experience are all critical,” he says.

 

Regulatory Guidance

 

“The ‘capacity crunch’ continues to draw headlines, but building capacity alone is not enough to serve this growing market.” Even with these challenges on the radar, Lynn notes that things are bound to continue changing, as regulators are still learning right along the side of the rest of the industry. However, staying up-to-date on the rapidly changing regulatory guidance across the globe is an ongoing challenge that he feels is never going to go away.

 

The benefits of utilizing allogeneic cell therapies

 

For years, almost all of the most recent cell therapies have used autologous therapies, which are when a patient’s own cells are used to make a therapy that is personalized for the patient. These therapies have been mostly positive for the long-term responses and can avoid issues that can stem from the immune response in patients.

 

Therapeutic Activities

 

A lot of recent developments in this area are focused on making more patient-centric therapies, with an overall outcome to better understand the patient for the most maximized therapeutic outcome. Some pharmaceutical companies have even developed the idea of involving patients in product design from an early stage, exploring their needs, and using their input into target product profiles (2).

 

Allogeneic Therapies

 

Allogeneic cell therapies have been on the rise and look promising, which is where the cells of other healthy donors are used to make a more therapeutic option for multiple individuals at a time. Lynn highlights that some of the benefits of using allogeneic therapies is how they contain cells that are readily available from young and healthy donors who are screened, because they are not coming from a patient who is already sick.

 

Batch Size

 

Usually, allogeneic therapies are grouped together as one, but according to Dan Strange, PhD, CTO at Cellular Origins, there are very notable segmentations. “For example, donor-derived allogeneic therapies are manufactured with processes that still look fairly similar to the manufacturing processes for autologous process (albeit using donor derived material), and with slightly larger batch sizes,” he explains.

 

Single Donor

 

“This approach eliminates a lot of the logistical complexity of the autologous approach, but there are still fundamental limits on how many doses you can make from a single donor—perhaps one batch makes one hundred doses. On the other hand, iPSC-derived allogeneic therapies offer a potentially unlimited supply of cells, but are less well characterized.”

 

Patient Population

 

According to Palmacci, these therapies are considered “off the shelf” models and have a lot of potential for patients. “As they use healthy donor stem cells as starting material, the viability of the cells in the end-product is improved,” he notes. “By enabling the development of many treatments from a single donor, a greater patient population can be treated—improving access and reducing costs.”

 

Autologous Models

 

Although autologous models have been the “safer” option for years for their positive results, Dulgar-Tulloch shares that they can be very complicated to keep up with in comparison to allogeneic models. “Autologous therapies can avoid many of the challenges around donor compatibility and immune rejection because they are created for a specific patient. Because you are developing and treating patients at an individual level, they are also often faster to develop and require less complex clinical trials,” he says.

 

Patient Access

 

“However, this personalized therapy approach is also very difficult to scale from a commercial perspective. It brings increased complexity in manufacturing due to differences in the starting material, higher costs because you can’t benefit from economic scaling, and logistical challenges in increasing patient access.”

 

Population Health

 

As for the future of allogeneic therapies, Lynn is hopeful to see many new approvals for these types of products that just a few years ago would have only been developed for a single patient via an autologous donation. One of the promises of allogeneic therapies is the ability to reach a wider patient population. “Cell and gene therapies can and have helped many patients eradicate their disease,” he says.

 

“If approved allogeneics can hit the market and serve a much bigger patient population, it could be a game changer for many public health issues.” Allogeneic therapies can also expand the access of breakthrough therapies on a worldwide scale by making them more affordable and easier to deliver off-the-shelf, according to Dulgar-Tulloch.

 

3D Manufacturing

 

Palmacci seconds being hopeful for the future for the ultimate benefit of the patients, with an end goal for cell therapies to become so mainstream that they will continue to transform lives. “Greater standardization would help to manage the risk of bringing new therapies to market.

 

Increased automation and digitalization would reduce reliance on manual lab-based manufacturing, and a widespread move from 2D to 3D manufacturing would boost efficiency,” he explains. “There also remains an important role for CDMOs [contract development manufacturing organizations] to help biotechs meet fluctuating demand.”

 

Industry players and allogeneic therapies

 

Some CDMOs look at autologous or allogeneic therapies as major opportunities for their business process. Lynn expands on how the use of allogeneic cells to make therapies does have multiple benefits to the manufacturer and ultimately the patient.

 

“In theory, because allogeneics can aid in getting more cells to produce products for the various therapies, it could be a benefit to CDMOs and CROs because they would be able to produce more product, which leads to less line downtime and more return on the investment,” he says.

 

CDMO and CRO

 

As for Dulgar-Tulloch, this topic is more complex due to the benefits of both kinds of therapies. “If you consider CDMOs and CROs, whose business model is built around service revenue for generating therapeutic doses, both autologous and allogeneic cell therapies are attractive opportunities,” Dulgar-Tulloch highlights.

 

“Autologous might even edge out allogeneic therapy as an opportunity given the sheer scale of manufacturing required to meet the potential patient need. If you look instead at pharmaceutical companies, allogeneic cell therapies are the clear winner from a business opportunity thanks to the increased scalability and decreased costs and logistics.”

 

Cell and Gene Manufacturing

 

Even with the rapid growth of allogeneic cell therapies, Palmacci predicts that autologous cell therapy options will still be here to stay. “Allogeneic cell therapies are easily scalable and do not require multiple manufacturing sites or a decentralized model—one site can serve patients globally,” he shares.

 

“But whether allogeneic or autologous, any therapy that can significantly improve patient outcomes with high efficacy and safety standards is well positioned to generate interest and backing. Both allogeneic and autologous therapies have a role to play within patient treatment, and we do not expect allogeneic therapies to fully replace autologous ones any time soon.”

 

Other up-and-coming therapy developments

 

With the emergence of cell and gene therapy advancements comes other categories of therapeutic options for patients. For example, Palmacci mentions that the rollout of the messenger RNA COVID-19 vaccine has been a testament to the potential of emerging therapies and the speed at which they can transform the outcomes when there is a collective to support their development.

 

Antibody Drug Conjugates (ADCs)

 

Other categories include antibody-drug conjugates (ADCs), cancer vaccines, adoptive cellular therapies, and tumor-infiltrating lymphocytes therapy, according to Lynn, which are more targeted cancer therapies that focus on killing cancer cells. For Fletcher, his first thought in this space is the continued use of exosomes, which are extracellular vesicles that make a powerful vehicle for drug delivery and can be a great tool for addressing different diseases.

 

“Recently, we have learned more about how they operate naturally, which can help us utilize them more effectively,” he adds. Larger patient populations and more polygenic diseases have continued to offer advantages of scale to move therapies out of the lab, and more technology has been trending to leverage multiple or combination platforms, according to Iyer.

 

Mutated Cancer Cells

 

“For example, gene editing with hematopoietic stem cells, viral vector and ADCs as a CAR-T [chimeric antigen receptor T-cell] therapy, and viral and non-viral vector technologies for gene therapy,” he says. “Therapies are starting to move beyond blood-borne cancers and towards treating patients with solid tumors to treat a larger range of cancers.”

 

Strange hopes that both through a combination of manufacturing improvements and therapeutic developments, the industry can bring the cost of cell therapies down to a point where they can be delivered to patients affected by some of the most widespread and devastating diseases of our time.

 

Conclusion

 

Oncology continues to see exciting breakthroughs on the horizon. Dulgar-Tulloch emphasizes these new advancements and what to look forward to in the near future. “In cancer, we continue to see advances in immunotherapies and bispecific antibodies, often in combination with other therapies, with several approvals pending,” he states.

 

“We’re also poised to see two potential blockbuster drugs approved for Alzheimer’s Disease and a vaccine against RSV. With such promise on the horizon, it continues to be an exciting time to work in biotechnology.”

 

Article Details

 

 

BioPharm International
Volume 36, No.5
Pages 10-13, 20

 

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Quality Agreements and Out-of-Specification Investigations

regulatory complianceQ. I’m responsible for quality at a small, virtual startup company, and we contract out all of our activities. I’m working on documentation to contract out our product testing and was wondering what information there is regarding quality agreement and laboratory investigations.

 

A. The best place to start is to take a critical look at existing guidance documents and regulations that govern quality agreement and out-of-specification (OOS) investigations.

 

OOS Investigation

 

 

“The Food and Drug Administration is aware that many manufacturers of pharmaceutical products utilize extramural independent contract facilities, such as testing laboratories, contract packers or labelers, and custom grinders, and regards extramural facilities as an extension of the manufacturer’s own facility”. 

 

FDA Guidance

 

The next document to review for quality agreements is the FDA guideline titled Contract Manufacturing Arrangements for Drugs: Quality Agreements. Section B, Elements of a Quality Agreement, Part e. Laboratory controls states that a quality agreement should include:

 

“Designation of responsibility for investigating deviations, discrepancies, failures, out-of-specification results, and out-of-trend results in the laboratory, and for sharing reports of such investigations”.

 

EudraLex

 

This confirms that the responsibility for OOS investigations is shared and communication between the contract giver and contract provider is critical. The European Union also addresses the need for a relationship between you and your outsourced laboratory in EudraLex, Chapter 7 (7.15) on Outsourced Activities by stating:

 

“The Contract should describe clearly who undertakes each step of the outsourced activity, e.g. knowledge management, technology transfer, supply chain, subcontracting, quality and purchasing of materials, testing and releasing materials, undertaking production and quality controls (including in-process controls, sampling and analysis)”.

 

 

 

Good Manufacturing Practices

 

The above regulations establish the need for quality agreements that cover laboratory activities but doesn’t define what needs to be in an OOS procedure. The EU addresses the need to investigate OOSs in their good manufacturing practices. EudraLex Part 1, Section 6.35 states,

 

“Out-of-specification or significant atypical trends should be investigated. Any confirmed out of specification result, or significant negative trend, affecting product batches released on the market should be reported to the relevant competent authorities. The possible impact on batches on the market should be considered in accordance with Chapter 8 of the GMP Guide and in consultation with the relevant competent authorities”.

 

GMP Compliance

 

Part 2 of the EU GMP guide for APIs states in section 11.15 that:

 

“Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should require analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any re-sampling and/or retesting after OOS results should be performed according to a documented procedure”.

 

Out-of-Specification (OOS)

 

The best GMP compliance guidance, however, on conducting OOS investigations is the information provided in FDA’s Guidance for Industry, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production (6).

 

The responsibilities for the laboratory analyst and supervisor are clearly defined in this guidance and should be reflected in any laboratory OOS procedure. A well-written standard operating procedure (SOP) on OOSs should require investigations to be thorough, timely, unbiased, well documented, and scientifically sound.

 

GMP Regulations

 

Often, the procedure will contain a GMP regulations checklist that assists in identifying obvious laboratory errors. The checklist assesses the suitability of analyst qualification and training, use of correct procedure and specification, the calibration and performance of the equipment, correct preparation of test solutions and dilutions, use of proper reagents and standards, calculations, etc.

 

A thorough checklist and analyst documentation are critical in identifying true laboratory errors. The SOP should also discuss the sample retesting requirements when a true laboratory error is determined to be the cause of the OOS.

 

GMP Guidelines

 

The most important and critical element for OOS investigations is specifying the timeliness. These guidelines should be stipulated in the SOP and, in most cases, the investigation into the OOS, from the laboratory perspective, should be concluded in 24 hours or less.

 

The expectation of when the contract lab will inform you of any OOS obtained should be clearly defined in your quality agreement. The sooner a laboratory error can be ruled out as the cause of the OOS result, the sooner the full-blown manufacturing investigation can be started.

 

Quality Agreement

 

Taking the time to establish a quality agreement and investigate the details of their OOS procedure is the first step in establishing a good working relationship with your contract test laboratory. This working relationship will become invaluable when an OOS occurs.

 

The final product testing procedure for OOSs isn’t the only one you need to review, however. You should also look at the quality agreement and OOS procedure being used by your manufacturer for in-process test results, assuming they are different entities. The same information required in the final product OOS procedure should be the same for in-process testing.

 

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Article Details

Pharmaceutical Technology
Vol. 43, No. 6
Pages 50, 49

 

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QA Outsourcing

In today’s competitive business environment, life-science companies run lean, particularly in terms of personnel. The quality assurance (QA) function creates complexity for pharmaceutical companies because need and cost vary depending on both the quality & regulatory lifecycle.
 

Regulatory Affairs

 
An early-stage pharmaceutical manufacturer needs strategic regulatory affairs (RA) leadership as the new drug is registered and filed with regulatory agencies. Once the RA strategy and filings are in place, the company’s regulatory needs often transition. Priorities become ensuring the product is kept up-to-date with the regulatory expectations, new requirements, and changes in the manufacturing process. The quality function typically sees a similar pattern of heavy strategic needs followed by maintenance needs.
 
 

regulatory compliance

For a small- or mid-market company, this shift can create challenges for appropriate in-house staffing, particularly if the company has one or a limited number of products. It can mean an expensive hire early in the company’s lifecycle, followed by a period when the executive is too much horsepower for the maintenance needs of the company.
 

Quality Assurance

 
Outsourcing quality assurance can provide a better match to changing strategic needs through the company lifecycle. These are common options to consider:
 
  • Sole practitioner
  • Enterprise consulting firm
  • Dedicated QA consulting firm

 

Sole Practitioner Consultant

 

With corporate downsizing, many executives with quality and regulatory expertise are establishing small consulting practices. With their long and accomplished resumes, they easily attract pharmaceutical clients. Sometimes, the clients are former employers and colleagues, who value their expertise but can’t afford to have on the full-time payroll.
 
This arrangement enables the pharmaceutical company to hire RA/QA staffers as needed, while using the outsourced QA/RA executive on an as-needed basis for large strategy projects.
 
 

Subject Matter Expert

 

Problems can arise with this model when the pharmaceutical company changes scope or scale beyond the consultant’s capabilities. Additionally, when the sole practitioner finds a full-time job and decides a steady paycheck with benefits is better than pharmaceutical consulting.
 
So, while using the sole practitioner model, the pharmaceutical company may be best served by maintaining a rolodex of multiple subject-matter experts.
 

Enterprise Consulting Firm

 

Enterprise consulting firms offer services in more than one functional area, typically operations and financial areas. These firms can be ideal for early- and mid-market pharmaceutical companies because they represent one-stop shopping in multiple areas. Often these firms are large and can attract talent, which the life science company can access as needed.
 
Problems can arise with this model when the consulting firm lacks a deep stable of RA and QA talent, but rather brings in executives as needed. This arrangement can mean delays in getting help and also can mean a higher price tag when the firm adds a markup.
 
Therefore, the pharmaceutical company may be best served by validating the talent they receive, and by communicating their QA/RA needs well in advance to their enterprise consultants.
 

Quality Assurance & Regulatory Affairs Consulting Firm

 

The focused Quality Assurance & Regulatory Affairs consulting firm is a blended solution. Because quality and regulation is their only business, these firms generally provide good talent at a fair price. They can offer a variety of QA consultant or RA consultant options and should be able to scale or change direction quickly.
 
Problems can arise in identifying and vetting the QA RA firm because there are few large players with a national reputation. The pharmaceutical company may be best served by establishing a due diligence process that matches their needs to the consulting firm’s strengths.
 
The following cases illustrate several approaches that provide QA RA expertise while saving money.
 

Outsourced QA RA Insights

 
One established pharmaceutical company evaluated its product lifecycle and decided to implement a series of changes surrounding the API. Retiring the old API, transitioning to the new API, and the related activities were simply beyond the bandwidth of the quality and regulatory team in place.
 
The pharmaceutical company recognized there would be economies of scale by using the same team of outside experts over the course of multiple projects. Additionally, the pharmaceutical company found that having local experts also saved on travel costs. This allowed the consulting firm to become part of the team, adding value to ad hoc meetings and integrating into their quality and regulatory functions without being on the payroll.
 

New Product Development

 
A Fortune-500 company was planning a new drug/device product development using disruptive technology. Recognizing that risk management and speed-to-market would be crucial for early adoption and success, the company decided to create a new subsidiary to develop and launch the product.
 
The seasoned QA and RA management stay with the Fortune 500 enterprise instead of joining the subsidiary, whereas some of the early- and mid-careerists were attracted to the startup venture. The subsidiary realized they had staff to implement but lacked QA RA leadership and deep expertise.
 

Quality Management System

 
The QA RA consulting firm was brought in to complete product development, direct regulatory filings and compliance activities, and to set up a quality-management system (QMS). The subsidiary had originally planned to adopt the QMS of the parent company but the consulting firm pointed out the need to right-size the legacy QMS for the new start-up subsidiary.
 
With ongoing outsourced QA RA expertise and their implementation staff, the subsidiary was able to launch the product, comply with all regulations, and implement their QMS systems without hiring expensive executives. Additionally, some of their staff used the consulting firm as their mentors and used this opportunity to step up. Over time, there were some internal promotions within the QA/RA team because the subsidiary had created a culture of promoting from within.
 

Benefits For Early-Stage Companies

 

Example one

 
A biotech startup was in a Phase II clinical trial and struggling with its cash-burn rate. They had a four-person quality team in place in anticipation of future needs.
 
Their QA/RA consulting firm recommended managing work more efficiently, scaling back to two analyst-level personnel and augmenting with occasional consultation by outsourced quality experts. This model was possible because the quality systems were already in place but didn’t need such heavy staffing.
 
By transferring expenses away from the quality function, they were able to deploy additional resources to the scientific and product development area, their greatest need.
 

Example two

 
Another early-stage company engaged a consulting firm because the owners were not familiar with the regulations surrounding their medical device. The team had a business plan in place, a solid IP platform, and a distribution plan, but the company lacked a regulatory pathway.
 
A consulting firm provided the company with an overview of the RA and QA requirements. Because the leadership team was bootstrapping the company, they decided to purchase off-the-shelf quality documents and asked the consultants to fill the gaps.
 
The consulting firm began a steady process of backfilling where the firm needed help, such as matching the purchased standard operating procedures with the business needs and remediating the product development in accordance with the developing QMS. As the launch date for the new product approached, the consulting firm helped the company implement corrective and preventive actions and a complaint system, along with an internal audit plan.
 
The consulting firm performed all this QA RA oversight and backfilled the firm’s gaps while working within a fixed monthly fee, helping the firm’s cash flow requirements. The product has since launched and is a commercial success.
 
As the company continues to grow and scale, the consulting firm continues to provide ongoing support as the outsourced QA RA manager, working hand-in-hand to augment the firm’s capabilities, while keeping their expenses to a manageable level.
 

Conclusion

 
Outsourcing quality and regulatory expertise can bring needed experience while saving costs. As companies grow and scale, they need flexible models for meeting their evolving compliance needs, and outsourcing can provide value.
 

 

regulatory compliance

 

Complete article published in BioPharm International.

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

Audit Trail: Risk-Based Approach to Compliance

With the rapid evolution of technology, more and more companies in regulated industries have transitioned to an electronic medical device audit trail. This was the impetus for the U.S. Food and Drug Administration’s (FDA) 21 CFR Part 11 regulation, which states that electronic records and signatures are equivalent to paper record and handwritten signature.

 

Compliance with the regulation requires that a digital signature be assigned to a specific individual, include a signature type (i.e., review, approval, author), and be traceable from the document back to the signer.

 

 

To ensure the transparency, trustworthiness, and reliability of records, regulatory oversight of a company’s data and records management includes examining timestamped audit trails. GxP Lifeline recently met with Seyed Khorashahi, executive vice president of medical devices and CTO at Regulatory Compliance Associates (RCA) — a worldwide consulting firm that assists pharmaceutical, biologic, sterile compounding, biotechnology, and medical device companies with resolving compliance and regulatory challenges. Khorashahi shares some valuable insight on the anatomy of a medical device audit and advises companies on how to comply with this critical component of Part 11.

 

Medical Device Audit

 

Bottom line, an audit trail is the who, what, when, and why of a company’s data. It’s a log containing metadata that essentially allows you to reconstruct all user actions and events. As a result, the accuracy of the data will show who made a change and what was changed. And when it was changed. And, more importantly, why.

 

Part 11 includes the predicate rules, which apply to record retention throughout the product’s life cycle — from cradle to grave. An audit trail ensures the ongoing completeness, accuracy, integrity, and security of data and records. It’s also necessary to provide transparency of the actions people take with the data. This all needs to be available to auditors during an inspection.

 

Audit Tracking

 

Manufacturing regulated products calls keeping a close eye on tracking product data — especially when it can impact on patient safety. This can be tricky in the day-to-day gathering, storage, tracking, usage, etc. of data.

 

Good Documentation Practices (GDP) mandate that you document everything in regulated product development. This help provide supporting evidence during audit tracking that employees are following procedures. An important component in a medical device audit is data needs to be timestamped. Therefore, data needs to be in electronic form. Companies still using paper records need to digitize documents in order to file and track them electronically.

 

Document Scanning

 

When scanning materials, clarity is critical to field audit tracking. Text-only documents can be simple enough, but images are more difficult. You need the ability to capture everything to ensure it’s a true copy that is acceptable under GxP regulations.

 

Beyond that, scanning stacks of documents is prone to its own set of challenges. Not only is it extremely time-consuming, all scanned documents need to be reviewed. This ensures there are no errors or missing pages at the end of the medical device audit. Then the same Part 11 signature guidelines need to apply.

 

Another challenge is the audit trail software that companies use for managing quality processes and data are configurable. This means they might not have a way to limit access to specific users or revise permission access. Above all, leadership employees should employ controls for the inadvertent deletion of data. This directly puts data integrity at risk.

 

Medical Device Cybersecurity

 

Also, if they’re using an open system (connected to the network), it becomes a cybersecurity concern because open systems have a wider cyberattack surface. Hackers continuously employ various human and computer-generated measures to gain access to a company’s data. Once data is breached, it’s no longer compliant with data integrity requirements.

 

There are also situations where employees undermine medical device audit trails by sharing login credentials. This has actually been noted in both warning letters and the audit trail report. Community system access may be a common workaround to keep production going when key personnel are away.

 

However, going back to the who, what, when, and why concept, when an entire department uses the same username and password, there is no way to accurately trace actions to specific individuals or verify electronic signatures.

 

Audit Trail Compliance

 

As I mentioned earlier, at the end of the day, data stewardship is all about keeping track of who, what, when, and why. Companies are collecting and handling more data these days. This means there is a lot more information to keep an eye on. Data has a certain life cycle based on the type of product.

You need to make sure you have a validated system and processes in place to ensure it remains intact, secure, and readily accessible for audits.

 

  • Electronic signatures – Are electronic signatures unique to the individual? Ensure that signatures cannot be copied or transferred.
  • User credentials – Is user access tightly controlled based on each person’s role and job responsibility? For example, people who access and modify data should not be able to turn off or modify the audit trail. Having too many users with read and write access to data increases the risk of intentional or inadvertent data changes or loss.
  • Audit trail reviews – Are audit trails getting reviewed often enough and by the right people? Part 11 guidelines specify the audit trail review requirements regarding who and how frequently they need to be reviewed. This is necessary to ensure records are accurate, free of gaps and errors, and that the information provided to auditors matches what is in the system.
  • Escalation – Are only authorized personnel reviewing and approving records? There are occasions when an approver is unavailable. There should always be another person who is authorized to approve and sign records. The system needs to include the functionality and procedures to allow the escalation of document reviews and approvals to other authorized individuals. These situations also need to be logged and documented.
  • Security – Are there system vulnerabilities that could lead to a security breach? I touched on security earlier, but I can’t emphasize enough the importance of system and data security. Even before COVID-19 dispatched employees to work remotely, many companies were incorporating mobile devices. This increases security vulnerabilities. Using an integrated QMS that has security measures such as role-based authentication and access controls can effectively augment data protection processes.

I recommend using a risk-based approach with audit trails. Your quality management system (QMS) and processes can identify and resolve the risks to data integrity. Here are a few items to consider when doing a risk assessment and being compliant with Part 11:

 

Digitization is the direction things are going. You need to be able to effectively control and rely on your data. And legacy and hybrid systems won’t always be compatible with the evolving regulatory landscape. Companies in regulated environments need to make sure their data and metadata are compliant with data integrity requirements. Data access should be transparent and accessible to future medical device audit team members, including in a readable format for the extent of the data’s life cycle.

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

Crafting Standard Operating Procedure

Susan Schniepp, distinguished fellow, and Andrew Harrison, chief regulatory affairs officer and general counsel, both of Regulatory Compliance Associates, discuss how to write standard operating procedure that holds up to audits.

 

Q. I work for a contract manufacturer and am in charge of the standard operating procedures (SOPs). During customer and regulatory audits, we keep being cited for inadequate SOPs. Can you give me some advice on what constitutes a well-written SOP?

 

regulatory compliance

 

A. You are not alone. In 2014, “inadequate standard operating procedures” was one of the top five most-frequently-cited FDA 483 observations. SOPs are one of the first items auditors review during inspections. SOPs need to reflect your operations and should not be written for regulators. SOPs should be written for your personnel to conduct operations with consistency and quality thus assuring regulatory compliance. Do not write SOPs because you think the regulations require them or for a process, procedure, or operation listed in the regulations that you do not perform. This will continue to lead to audit observations.

 

Effective SOPs

 

So what are the characteristics of a good SOP? Effective SOPs are tailored to an organization’s regulatory compliance design and needs and contain sufficient detail to allow personnel to conduct operations as management wants. If you have an experienced work force, you may need less detail. SOPs take into account who has the authority to make decisions and clearly define accountability (i.e., who per forms what actions). SOPs also provide guidance on what to do when things don’t go right; they delineate decision points and actions to take for each decision. SOPs define the outputs from each process (documentation, product), who owns the process, and identify other stakeholders for the process, which helps determine who requires training on the SOP. The SOPs also specify who needs to ensure the process is working and who initiates quality metrics changes when needed.

 

So what do you need to consider to write a clear, concise SOP with the right amount of information accurately reflecting your established processes? Keep your mind open to different various communication types. SOPs may use various presentation styles as a means of communicating the details of the SOP.

 

Presentation style

 

The following are examples of presentation styles that you may want to consider using when writing your SOPs:

 

  • Playscript (operator does “a” now and “b” next)
  • General description-paragraph form
  • Flow chart
  • Pictorial
  • Any combination of the above as long as personnel can follow the instructions.

 

Determine the type of style and level of detail that is most effective for your personnel. Also, consider the predominant primary language (it may not be English) and general understanding level of your organization when writing SOPs. Depending on the make-up of the workforce, you may need to consider having dual-language SOPs, which might require translation expertise.

 

Recommended elements

 

Certain recommended elements should be included in SOPs. Remember, the format and content of SOPs are not defined by the regulations. Each company must establish the SOP format and content that accurately reflects their operations. The seven basic elements for any SOP are:

 

  • A unique title that corresponds to a unique document number: This combination should be specific enough so that the document referred to can’t be confused with other documents in your document collection. The unique reference number is often an alpha/numeric combination that specifies the functional department that employs the SOP. This unique identifier often includes the version of the SOP for easy reference and to ensure the current version is being used.

 

  • The date that the SOP is considered operational and should be followed by employees: Dictating one date format versus another creates unnecessary/irrelevant deviations. The focus of dates should be their legibility.

 

  • A purpose and a scope that describes why the company has this SOP (what process or procedure is being described) and who in the company needs to adhere to the contents of the SOP: The purpose and scope of an SOP are interrelated. The purpose describes why the SOP is needed, and the scope defines the boundaries of the SOP.

 

  • Roles and responsibilities: The roles and responsibilities should not be a reiteration of the procedure but should describe the parties responsible for ensuring proper execution of the SOP (who may or may not be the individuals performing the step-by-step procedure).

 

  • Change control history of the document: The change control history is important because it establishes the history of the document from initiation to obsoletion. In some cases, it is important for the company to know what sections of an SOP were changed and why they were changed. This valuable information is captured through the change control history and should be included in the change control request.

 

  • Who can sign and vouch for the contents of the document: The SOP is not complete until the official required signatures are applied to the document. The official signatures required for any document may vary from department to department and indicate that the changes to the SOP are: consistent with company policy, ensure the operation continues to be executed in a predictable manner, do not affect the validation status or quality of the product, and that the step-by-step instructions represent the repetitive actions to be performed to ensure the predicated and expected outcome defined by the SOP.

 

  • The step-by-step instructions: The step-by-step instructions represent the repetitive actions to be performed to ensure the predicated and expected outcome defined by the SOP. There is no rule that SOPs need to be written words. If the operation in the SOP can be described easily with a flow diagram, there is no reason not to use this type of informational display. The instructions should not be too long. The longer the SOP is, the poorer the retention of the information. The general rule is SOPs should not exceed 10 pages. If your SOP exceeds 10 pages, you might want to consider breaking it into smaller operations, if possible.

 

If you keep these points in mind when writing your SOPs, you should stop receiving the ‘inadequate SOPs’ citation.

 

Pharmaceutical Technology
Volume 39, Issue 12
Pages: 53–54

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

Pharmacovigilance: Complaints to Quality

Q. I am a quality assurance professional working for a small start-up company. I am setting up their quality management system, but I have little experience with complaint handling or Pharmacovigilance. Can you provide some basic advice on setting up a system to handle customer complaints?

 

A. A Pharmacovigilance customer complaints process is a critical quality function that needs to be designed in conjunction with your quality management system (QMS). The requirements for complaint handling are well documented in the regulations (1–3). The importance of the complaint system and its relationship to other functions is often underappreciated by companies when setting up a QMS.

 

Quality Management System

 

The complaint system should be one of the first systems to be established by a company because the information gleaned from complaints feeds directly into the deviations, investigations, and corrective actions and preventive actions (CAPA) functions. Whether your product is a prescription drug (small or large molecule), over-the-counter medication, medical device, or combination product, the process for addressing customer complaints falls under regulatory scrutiny (4). 

 

The first element of a robust complaint system is to establish a standard operating procedure (SOP) for complaint handling. The SOP should indicate the communication vehicle used to collect customer complaint information. These communication avenues can include, but are not limited to, use of a dedicated telephone number and/or an Internet link where customers can report the problem they are having with your product.

 

Risk Analysis

 

It may seem archaic to recommend a phone number during a risk analysis, but it is necessary because not everyone taking your medication is comfortable with or has access to the Internet. These individuals may be more at ease leaving a message on an answering machine. Needless to say, this is an element of the complaint handling system that might be outsourced. If you decide to outsource this activity, you should specify this in your SOP and have a quality agreement with the company that is performing this service for you.

 

Standard Operating Procedure (SOP)

 

Once the basic communication elements are determined and established, they need to be monitored on a routine frequency. The monitoring frequency should be established in the SOP for the handling of complaints. The phone line and the weblink should be monitored at a minimum once a day. It would be ideal if the communication lines could be continuously monitored, but this may be impractical for a small company. If this activity has been outsourced, the information collected on a daily basis by the service provider should be collected and reviewed on a daily basis by the company.

 

Root Problem

 

The next element needed for effective Pharmacovigilance is determining the minimum information that you need from the customer. To effectively help conduct a root cause analysis, you will want to know:

 

  • Name and contact information
  • Age and sex
  • The name of the product
  • The dosage strength, if applicable
  • The name of the store where the purchase was made

 

A detailed description of the problem/issue associated with the product. Again, if you are outsourcing this function, you will need to make sure this information is being collected by your service provider.

 

Root Cause Tree

 

Once you have established the communication avenues and the information requirements, completing the root cause tree is a crutical step in the process. Determining the complaint categories can help describe the factors that need corrective action.

 

There are several complaint categories that a customer might want to report to a company including medical conditions, product quality problems, preventable mistakes, and therapeutic failures. Any type of medical complaint is serious and needs to be assessed and addressed in a timely manner, because these types of complaints often have regulatory reporting timelines associated with them.

 

Root Cause Analysis

 

Once your Pharmacovigilance categories help compete the root cause tree, defining the severity can assist in the risk management analysis. Medical complaints can range from mild (e.g., headache, rash, tiredness, etc.) to serious reactions (e.g., hospitalization, suicidal thoughts, death, etc.). The more serious the medical complaint, the more aggressive the company needs to be in pursuing the investigation into the complaint. The regulatory reporting requirements for medical complaints should be specified in the SOP.

 

Non-medical complaints do not need to be reported to the regulatory authorities, but they should be documented and investigated. These types of complaints (e.g., smashed bottle, smashed carton, incorrect tablet count, etc.) do not need to be reported to regulatory agencies, but they still need to be investigated as they could indicate deficiencies in the manufacturing and packaging operations.

 

Safety Risk Assessment

 

There are other considerations to consider when establishing a complaint handling function, such as whether or not the company wants to try and have the product returned for examination. The design of your safety risk assessment should clearly outline how the product will be handled if it is procured. Keep in mind, however, that all complaints are available for regulatory review during an inspection.

 

Establishing a robust and well-documented Pharmacovigilance process is a significant and an important element of a strong quality system. Thought and consideration on how complaints will be communicated to the rest of the organization and how complaint resolutions will be investigated, documented, and reported are critical elements to having a complaint function that serves the organization, the customers, and the regulatory authorities.

 

Published By:

 

Pharmacovigilance

 

Pharmaceutical Technology
Volume 43, No. 4
Pages: 70, 69

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].