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The main regulatory standard for ensuring pharmaceutical quality is 21 Code of Federal Regulations (CFR) Parts 210 and 211, collectively referred to as the current good manufacturing practice (CGMPs) regulation for human pharmaceuticals. It’s not only the CGMP regulations that matter; the approaches biopharmaceutical companies take to interpret and embrace these regulations are of equal, if not more, importance. The remediation costs associated with CGMP non-compliance can be staggering to say the least.
CGMPs place emphasis on product quality and compliance with the regulations. So how do companies embrace, and even embody, quality and compliance with CGMPs? One way minimize remediation costs is to operate under a quality culture.
Quality Culture
A company should have a pharmaceutical quality system as described in FDA Guidance for Industry, Q10 Pharmaceutical Quality System. A quality culture is created when managers believe a company has a duty to create a mutually beneficial relationship between itself, its employees, and its customers.
Culture is the shared beliefs, values, attitudes, and behavior patterns that characterize a family, a community, or an organization. A healthy organizational culture is rooted in the understanding that quality is good for the company and its customers. Thus, its existence is a driving force behind how employees act and behave regardless of level, title, or decision-making authority.
FDA Form 483
In defining a set of Six Sigma values for a corporate culture, the core principles should include integrity, customer focus, and people. This type of quality culture begins with company leaders who believe in the necessity of serving customers in order for their organizations to succeed. Six Sigma is a widely accepted methodology to help reduce remediation costs.
FDA conducts several types of inspections to help protect consumers from unsafe products: pre-approval inspection, routine inspections of a registered facility, and “for-cause” inspections. After FDA completes an inspection, company management may receive an FDA Form 483 when an investigator(s) has observed any conditions that, in their judgment, may constitute violations of the Food Drug and Cosmetic (FD&C) Act, related acts, and applicable sections of 21 CFR 210 and 211.
FDA Warning Letter
Observations are made when, in the FDA investigator’s judgment, conditions or practices observed would indicate that product has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.
FDA Form 483 notifies the company’s management of objectionable conditions. Companies respond to the 483 in writing with their corrective action plan and implement schedule. The 483 is closed when the company receives their establishment inspection report (EIR). Unfortunately, there are companies that either do not follow through on their commitments or they do so too slowly. If circumstances merit, FDA can choose to escalate the potential for remediation costs by serving the company with a warning letter.
CAPA
Typically, FDA gives individuals and companies an opportunity to take voluntary and prompt corrective action before the agency initiates an enforcement action. The primary goal of a CAPA system is to introduce new procedure(s) that address requirements for the corrective actions that return an organization to compliance. Additionally, a FDA warning letter is the principal means of notifying regulated companies of violations and corrective actions needed.
The following factors are often used to determine whether to issue a warning letter:
The firm’s compliance history (e.g., a history of serious violations, past remediation costs or repeated failure to prevent the recurrence of violations)
The nature of the violation (e.g., a violation that the firm was aware of [was evident or discovered] but failed to correct
The product risk and the impact of the violations on such risk
The overall adequacy of the firm’s corrective action and whether the corrective action addresses the specific violations. Remediation costs also may include related violations, related products or facilities, and contains provisions for monitoring and review to ensure effectiveness and prevent recurrence
Whether documentation of the corrective action was provided to enable the agency to undertake an informed evaluation
Whether the timeframe for the corrective action is appropriate and whether actual progress has been made in accordance with the timeframe.
Consent Decree
When a company repeatedly violates cGMP requirements, FDA can force it, through legal channels, to make specific changes. Under this severe form of escalation by FDA, the objective is no longer a discussion about responses to 483s or warning letter observations, it’s about a forced company make-over. This process, known as consent decree, exposes all broken systems within a company.
FDA does not care about any efforts and expenses undertaken by the company to redesign and implement a robust quality management system; a common element of a consent decree is demonstrating sustainability. A company under consent decree who doesn’t demonstrate sustainability can lose future revenue in different ways. One way, which is particularly difficult to quantitate, is the price of “lost innovation”. The company is redirecting revenue into compliance, oversight, and remediation instead of reinvesting it into research and development of new products.
Consent Decree Definition
As previously mentioned, Sustainability is one of the primary drivers for defining an organization’s capacity to know when it is veering off course. The consent decree definition of the program is critical to making the correct decisions, taking appropriate actions, and maintaining a state of control without future external intervention.
Sustainability embraces the core quality culture values and expected behaviors of integrity, empowerment, and accountability. A consent decree mandates a series of annual inspections performed by a third-party to monitor sustainability. FDA recommends companies hire external experts and invest time and money to inspect and certify compliance, often for many years.
Operating under a consent decree is a dire situation for the company and one where there is no certain predictability of the outcome. To understand the full magnitude of a consent decree’s impact, one needs to take into consideration the many and various modes in which the negative consequences can be realized (see Figure 1).
Figure 1: Overview of different repercussions
to and reverberations from a pharma company
operating under consent decree. (Image courtesy of author)
Remediation Costs of Non-Compliance
This discussion focuses on three ways to look at the costs of non-compliance:
Quantifiable costs
Difficult-to-quantify costs
Invisible costs with hidden impacts
Quantifiable Costs
Quantifiable costs are those that can have a value assigned to them with a reasonable degree of accuracy. Quantifiable costs are usually more obvious, but they manifest in several ways as shown in Figure 1.
A major requisite term of a consent decree is for the company to retain, at its own expense, an independent third-party for ongoing certification and oversight of the implementation of agreed to corrective action. Another requirement may be a commitment to have every released batch certified to be CGMP.
At Will Employment
At Will Employment is defined as an indefinite period of time of employment that may be terminated either by employer or employee. It is not uncommon that firing an employee or/and replacement of multiple employees is a step associated with a consent decree. The training and retraining costs can often be difficult to quantify in the short term until compliance improves. This company action is meant to set the tone internally that the non-compliant way of doing business will no longer be tolerated.
FDA Violation Penalties
FDA can levy significant violation penalties in the form of fines for not meeting action dates. Examples include $15,000 per day for missed dates, royalty payments up to 24.6% per product not revalidated on time, and costs for FDA inspections. Furthermore, the US Treasury can garnish profit from sales through fines. Such was the case for Wyeth, who agreed to a consent decree regarding its Marietta, PA and Pearl River, NY facilities. FDA inspections of these facilities found several GMP deviations that eventually resulted in warning letters.
One of the largest drug safety settlements occurred when generic-drug manufacturer, Ranbaxy USA Inc., a subsidiary of Indian generic-pharmaceutical manufacturer Ranbaxy Laboratories Limited, pleaded guilty to felony charges relating to the manufacture and distribution of certain adulterated drugs made at two of Ranbaxy’s manufacturing facilities in India (3). Ranbaxy paid a criminal fine and forfeiture totaling $150 million and settled civil claims under the False Claims Act and related state laws for $350 million.
Civil Monetary Penalties Law
Entering into consent decree can also expose a company to civil penalties. Depending on the circumstances, shareholders, patients, and sometimes even company employees may be able to sue for damages.
One such law suit arose from an unsuccessful effort by Baxter International to fix problems with its Colleague Infusion Pump. Westmoreland County Employee Retirement System (Westmoreland) alleged that Baxter’s directors and officers breached their fiduciary duties by “consciously disregarding their responsibility to bring Baxter into compliance with the 2006 consent decree and related health and safety laws”.
FDA Recall
The Baxter breach was alleged to have caused the organization to lose more than $550 million after FDA mandated a recall of the Colleague Infusion Pumps. Baxter invested time and money trying to fix the pumps, but the manufacturing problems persisted over time.
FDA invoked its power under the original consent decree by ordering Baxter to recall and destroy all Colleague Infusion Pumps then in use in the US. This is where invisible costs with hidden impacts turn into the customer reimbursement for the value of the recalled device. Invisible costs also included Baxter being required to assist in finding replacement devices for those customers impacted. The company’s stock price fell by more than 4% after the announcement and the company later recorded a pre-tax charge of $588 million to account for the estimated costs of the recall.
Drug Shortage
When a drug manufacturer subject to enforcement action is the sole supplier of an important medicine, drug shortages become a concern. Short-term solutions may include doctors substituting medications that may have lesser efficacy. Pharmaceutical companies with potential manufacturing capability may be incentivized by FDA to manufacture identical or equivalent drug products; however, medium-to-long lead times can delay product availability. When supplies dwindle, patients must pay higher prices for the same drug.
One illustration of this scenario is the FDA consent decree with Genzyme regarding repeated manufacturing issues at the company’s Allston, MA facility. The consent decree included an up-front disgorgement of past profits of $175 million and the requirement to move fill/finish operations out of the Allston plant by a specific date. Had Genzyme not met those deadlines, FDA could have required the company to disgorge 18.5% of revenue for the affected products.
Difficult-to-Quantify Costs
Other financial ramifications from consent decrees may be difficult to quantify. For example, some employees may lose their confidence in the commitment or ability of the company’s CEO and other executives to manage the situation.
Employee Attrition
Employee attrition is expected, but if the exodus includes long-tenured employees the company may be drained of valuable knowledge and talent. The longer the situation exists, the more difficult it becomes to retain the best employees.
Reputation Damage
A company under a consent decree is subject to reputation damage, which can be accentuated by the ease of publicly available negative media coverage about how the company operated. Negative media coverage can result in public fear. In the Ranbaxy case, an import ban had been in place for 30 drugs manufactured at two of its Indian manufacturing plants resulting from alleged data falsification. This type of information can result in public concerns that medicines could be adulterated.
Batch Release
Lost revenue due to the company’s inability to sell product can also be an issue. Companies under consent decree experience long delays in releasing product due to the intensive oversight required, when a batch fails release testing, and when a product is recalled. The cost for the logistics of product recall and destruction can be high, especially if the API is expensive or has a long lead time.
Group Purchasing Organizations
Another potential cost is the inability to sell a product. Group purchasing organizations (GPOs) use the power of collective purchasing to buy pharmaceuticals at discounts. An underlying premise is continuity of supply; if a pharmaceutical manufacturer is unable to deliver the product contracted, the GPO must obtain replacement product from the open market, often at a higher price. GPOs wary of a potential inability of the company to supply its products may consider other sources.
In one of the largest settlements to date, Ranbaxy pled guilty to felony charges. The charges were manufacturing and distributing adulterated drugs made at the Indian manufacturing sites. The criminal fine and forfeiture totaled $150 million and another $350 million in remediation costs to settle civil claims under the False Claims Act.
Invisible Costs and Hidden Impacts
If the remediation costs to bring a facility under consent decree into CGMP compliance is determined to exceed the company’s financial ability or it makes no financial sense to continue operations, the company’s management may decide to close the facility. Shuttering a facility, can have devastating impact on the local community, particularly in rural areas where the manufacturer is a primary employer. The community’s tax base will also suffer.
The company can lose its competitive edge because its busy focusing inside rather than externally. This can be a competitive advantage to your closest competition looking for a way in which to leverage your situation for their benefit. The potential opens for the company to become alienated and therefore lose rank compared to its direct competitors.
A company can also be denied approval of new drug while non-compliance exists (4). Because of its consent decree, approval of two new drugs by Eli Lilly was delayed. This was the result of CGMP issues being found during pre-approval inspection in the fall of 2001, which was six years after its consent decree.
Conclusion
The collective cost of remediation of non-compliance far exceeds the remediation cost to remain in compliance. The number of consent decrees issued per year has remained consistent during the past decade. However, companies have found it difficult to extricate themselves from the agreements.
As a result, the number of companies under consent decrees at any given time has increased. Generally, it takes many years for a company to demonstrate that it is in full compliance. Only one company that has received a decree in the past 10 years has met all requirements and had the decree lifted.
Considering the fines and the payments to the third-party consultants, the remediation costs associated with a consent decree can become very high and have a significant effect on a company’s profit. It is estimated that the costs incurred by Warner-Lambert for a consent decree–in terms of product terminations, delays in approvals, and bringing facilities and systems into compliance–was nearly $1 billion. The Warner Lambert fine was only $10 million, a small percentage of the total cost. Schering-Plough’s initial fine was $500 million. Abbott Laboratories has spent almost $1 billion resulting from a consent decree issued, including a fine of approximately $100 million.
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.
When it comes to pharmaceutical manufacturing, ensuring a strong quality culture is one way to avoid recurring GMP issues, such as data integrity. Susan Schniepp, Distinguished Fellow at Regulatory Compliance Associates, and 2022 PDA Board of Directors Chair outlined the evolution of current quality culture initiatives and showcased some tools to help organizations build quality culture into GMP manufacturing operations during the Nov. 11, 2021, Redica Systems Quality Week webinar, “Past, Present, and Future of Quality Culture.”
“I think that is what we see sometimes in our industry,” she said. “We do not remember how we got some of the regulations that exist today, and we repeat our past mistakes.”
From Quality Metrics to Quality Culture
Schniepp began her presentation with a look at how quality culture evolved from the early 2010s discussion on quality metrics. Key points included the following:
On Oct. 5, 2005, CDER Director Janet Woodcock directed pharma manufacturers to build “a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight.” This set in motion CDER’s emphasis on quality in manufacturing.
Then, in 2012, the U.S. Congress passed the FDA Safety and Innovation Act (FDASIA). Title VII of the Act allows for risk-based inspection of manufacturing sites, including requesting records in advance, or in lieu of an inspection. Additionally, the Act requires the FDA to provide Congress with an annual report on the state of drug shortages.
Around the same time that FDASIA became effective, drug shortages became a critical concern for the agency. Schniepp pointed to aging facilities as one reason for shortages. “Tangential to metrics and quality culture, we had aging facilities, i.e., facilities producing many of the drugs showing up on the drug shortage list were degrading and not being maintained.” Quality issues at these sites had become apparent and potentially causing shortages.
In 2014, FDA proposed implementation of a quality metrics system to encourage adoption of quality-supporting practices.
GMP Manufacturing & Measuring Quality Culture
The quality metrics push resulted in a series of conferences by ISPE, PDA, and the Brookings Institution (Figure 1 below).
“One of the elements that came out of all of these discussions was the fact that you could request any metrics that you wanted. What FDA proposed initially was rejection rate on batches, CAPA rates, etc., but the conversation became that without the culture of the organization being assessed, you could not really count on the data. So, that is how [quality metrics and quality culture] tie together,” Schniepp explained.
Quality Metrics
“You needed to have a functioning, efficient, quality metric system that gives you reliable data. And you have to count on the integrity of the culture of an organization in order to have confidence in the data that it sends you. Off of that, the discussion turned to, ‘well, how do you measure quality culture?’”
GMP Manufacturing & Quality Culture Behavior
Schniepp was part of a PDA team studying the relationship between quality culture behavior and mature quality attributes to see if there was a set of mature quality attributes that could serve as a surrogate for quality culture behaviors (ISPE has also done work in this area).
“’Mature quality attribute’” refers to “those things in your quality management system (QMS) such as your CAPA program, your change control, your investigations procedures, how you report deviations, how you record batch rejection rates, i.e., all of those things are in your quality culture or in your QMS.”
Quality Attributes
But her team wanted to know if mature quality attributes related to the behaviors of employees and management correlated with company culture, such as do people feel comfortable speaking up, do they talk to management about their concerns, do they understand their jobs, etc. The team’s research resulted in what Schniepp refers to as “the Culture Equation” (Figure 2).
Figure 2
“The foundation of this is quality attributes that are quantifiable and easily measured, provided they equal quality behaviors,” she said. “In other words, you have attributes reflected in your behaviors that then define your quality culture. So, if quality cultures equal quality behaviors equals quality culture, your quality attributes equal quality behaviors equal quality culture. If you can measure your quality attributes, you can define your quality culture.”
Operational Excellence
By surveying PDA’s membership, her team gathered enough data to conduct statistical analysis and was able to determine there is a relationship between quality culture behavior and quality attributes. They then worked with another team from the University of Saint Gallen’s operational excellence program. That team also found a correlation confirming “quality attributes equal quality behaviors equal quality culture.”
The PDA and St. Gallen research resulted in the PDA Quality Culture Guided Assessment Tool, addressing five key areas in which companies should focus in order to build quality culture: Employee Ownership and Engagement, Continuous Improvement, Technical Excellence, Leadership Commitment, and Communication and Collaboration. This tool is currently under development as a PDA standard.
Quality Metrics, Data Integrity & Quality Culture
Figure 1
Data integrity is increasingly connected with quality culture. In the PIC/S guidance, Good Practices For Data Management And Integrity in Regulated GMP/GDP Environments, “they have defined quality culture, and they have given us a little bit of information about how management can create a work environment—a culture—that is transparent and open.”
Schniepp also pointed to three other documents:
UK MHRA GxP Data Integrity Definitions and Guidance for Industry
WHO Guidance on Good Data and Record Management Practices
FDA guidance Data Integrity and Compliance With Drug CGMP Questions and Answers
“In their regulations, regulators are starting to define and link culture to data integrity violations,” she explained.
Data Integrity
She then provided a real-life example of a data integrity violation caused by a company’s culture.
“This one is kind of an interesting one because it was really an attempt by management to encourage employees to do a good job, but what they did created integrity violations.”
A contract manufacturing organization (CMO) set a GMP manufacturing goal to release batch records to clients within 30 days of manufacturing the product. To encourage this, management dangled the carrot of a pizza party at the end of the year if this goal was met. In order to meet this goal, employees released batch records to clients even if investigations had not uncovered the root cause. Investigations would be prematurely closed and then reopened after the batch record had been sent to the client.
“That, in and of itself, is a data integrity nightmare,” Schniepp said. “Can you imagine explaining in an audit by a regulator, ‘well, we wanted a pizza party?’”
GMP Manufacturing & Organizational Culture
Regarding deviation investigations, she told another story of a company for whom she worked that involved repeat observations. When reviewing deviations, she found that one operator had 30 deviations tied to him involving a specific product. This operator failed to sign the batch record during a specific point in time in manufacturing. His managers kept retraining him.
[Author’s Note: Additional information about deviation investigations can be found in the articles, “GMP Inspection Case Study Focuses on Inadequate Deviation Investigations” and “How to Avoid Three Common Deviation Investigation Pitfalls.”]
Batch Records
In talking with the operator, Schniepp learned that in order for the operator to sign the batch record (according to GMP regulations at that particular point in manufacturing), the operator had to leave the product alone in the equipment, de-gown, sign the batch record, re-gown, and return, all the while hoping the product was okay. Out of concern for the product, the operator chose to stay behind and try to remember to sign the batch record once he was done.
“It was a poorly designed batch record process,” she said. But the operator did not feel listened to when he brought his concerns to management.
GMP Labeling
Schniepp then pointed out that other employees worked on the product under the same cGMP constraints. So, what were these other employees doing? How many other data integrity violations occurred? Was GMP labelling reviewed accurately?
“Nobody else was bringing it up. If you do not have that open culture, if you are not encouraging people to speak up and you are not listening to them, you do not have a good quality culture.”
The Future is GMP Manufacturing Quality
For further evidence of the importance of GMP certification and quality culture, Schniepp reviewed a 483 observation issued in 2019 with numerous examples of data mismanagement. The company in question then responded to FDA with a letter promising to ensure a robust quality culture going forward. [Author’s Note: For more about this GMP compliance incident, read the first case study in the article, “Data Integrity Concerns Discovered in Gene Therapy Product Submissions,” by Jerry Chapman.]
FDA 483
Schniepp believes this 483 observation shows FDA’s intent to heavily focus more on good manufacturing practices in future inspections. This means companies must develop or enhance their quality culture when thinking about how to prepare for upcoming inspections.
“I believe we will see more of this,” she said. “More companies will be looking at their GMP manufacturing and trying to improve the Quality Culture.”
Otherwise, as she explained at the beginning of her presentation, companies who remain in the past when it comes to cGMP certified practices that lead to quality culture face the prospect of 483 observations, Warning Letters, and other negative outcomes.
Regulatory Compliance Associates (RCA) has helped thousands of pharmaceutical companies meet regulatory, compliance, quality assurance, and remediation challenges. With more than 20 years of experience with FDA, Health Canada, EU and global regulatory agencies worldwide, Regulatory Compliance Associates® offers leading pharmaceutical consultants. We’re one of the few pharma consulting companies that can help you navigate the challenges associated with industry regulations.
Our pharmaceutical consulting firm includes over 500 seasoned FDA, Health Canada & EU compliance consultants and regulatory affairs experts who understand industry complexities. It’s a pharma consultancy founded by regulatory compliance executives from the pharmaceutical industry. Every pharmaceutical industry consultant on the Regulatory Compliance Associates team knows the unique inner workings of the regulatory process.
Client Solutions
Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, Regulatory Compliance Associates will guide you through every pharmaceutical consulting step of the regulatory process and create a customized approach depending on your product and your pharma company’s individual needs. Our regulatory compliance clients include:
Companies new to FDA, Health Canada or EU regulations and regulatory compliance
Start-up organizations with novel submissions to 510(k) submissions from multi-national corporations
Investment firms seeking private equity due diligence for pre-acquisition and post-deal research
Law firms seeking pharmaceutical consulting firm expertise in the remediation of warning letters, consent decrees, 483’s or import bans
Regulatory affairs is Regulatory Compliance Associates backbone. We exceed other pharma consulting companies with industry experts experienced in complexities of the pharmaceutical and biopharmaceutical industries. Our pharma consulting expertise spans all facets and levels of Regulatory Affairs, from Regulatory Support for New Products to Life Cycle Management, to other services like Outsourced Regulatory Affairs, Submissions, Training, and more.
As your partner, we can negotiate the potential assessment minefield of regulatory compliance services with insight, hindsight, and the clear advantage of our breadth and depth of knowledge and regulatory compliance consulting. We offer the following pharma consulting regulatory affairs services for pharmaceutical companies.
The regulations process surrounding pharmaceutical companies can be tricky for even the most experienced industry veteran to understand. Just one misstep could mean significant and lasting consequences for your business. At Regulatory Compliance Associates, we offer the pharma consulting experience and pharma consultants necessary to guide you through the quality compliance process.
Regulatory Compliance Associates Quality consulting includes assessments, strategy, implementations, staff augmentations, and identification of quality metrics to ensure continuous improvement. Our pharma consultants understand the strategic thinking needed to align your business needs and goals. Regulatory Compliance Associates quality assurance services include quality experts with experience spanning major corporations and start-ups. Our pharmaceutical consulting firm knows firsthand how to achieve, maintain, and improve quality, and we excel in transferring pharma consulting knowledge to your organization.
Regulatory Compliance Associates has a proven remediation services approach to managing FDA Warning Letters, Consent Decrees, Remediation and other serious regulatory situations. Our pharma consultants know how to partner with executive, legal, and communication teams. Each RCA pharma consulting Expert will develop a response that will be accepted by the regulatory agency and be realistic to execute.
Regulatory Compliance Associates pharma regulatory consultants will develop a comprehensive proof book of documented evidence demonstrating the corrective action taken to remediate non-compliant issues. In addition, each Regulatory Compliance Associates pharma consulting Expert understands compliance enforcement. We’ll prepare a comprehensive pharma consulting strategy to assist in your remediation efforts, drive continuous improvement, and maintain regulatory compliance with the regulations.
Regulatory Action
Regulatory Compliance
Regulatory Enforcement
Warning Letter
483 Observation
Oversight Services
Risk Management Plan
About Regulatory Compliance Associates
Regulatory Compliance Associates® (RCA) provides pharmaceutical consulting to the following industries for resolution of life science challenges:
We understand the complexities of running a life science business and possess areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. We are used to working on the front lines and thriving in the scrutiny of FDA, Health Canada, MHRA and globally-regulated companies.
As your partners, we can negotiate the potential minefield of regulatory compliance and regulatory due diligence with insight, hindsight, and the clear advantage of our unique expertise and experience.
Founded in 2000
Headquartered in Wisconsin (USA)
Expertise backed by over 500 industry subject matter experts
The name Sotera Health was inspired by Soteria, the Greek goddess of safety, and reflects the Company’s unwavering commitment to its mission, Safeguarding Global Health®.
Sotera Health Company, along with its three best-in-class businesses – Sterigenics®, Nordion® and Nelson Labs®, is a leading global provider of mission-critical end-to-end sterilization solutions and lab testing and advisory services for the healthcare industry. With a combined tenure across our businesses of nearly 200 years and our industry-recognized scientific and technological expertise, we help to ensure the safety of over 190 million patients and healthcare practitioners around the world every year.
We are a trusted partner to 5,800+ customers in over 50 countries, including 40 of the top 50 medical device companies and 9 of the top 10 pharmaceutical companies.
Commitment to Quality
Our Certificate of Registration demonstrates that our Quality Management System meets the requirements of ISO 9001:2015, an internationally recognized standard of quality.
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.
Click to learn more about best practices and techniques for investigating deviations & improving pharmaceutical quality.
The pandemic created a backlog of delayed inspections in its wake, and regulatory bodies are prepared to hire additional employees and significantly increase the rate of inspections. That means an increased likelihood of your organization facing an audit, and increased importance in having an effective strategy for quality deviation audits & investigations.
MasterControl has partnered with regulatory experts Regulatory Compliance Associates (RCA) for an exclusive virtual event exploring best practices for investigating quality deviations. Join Sue Schniepp – RCA Distinguished Fellow for an informative event designed to help you manage quality events and effectively manage any audits that come your way.
We’ll explore strategies for:
Audit management and how to define root cause early.
Why centralized workspaces are interconnected with quality.
CAPA processes and quality event forms.
Answering interview questions about standardization.
Organizing source documents for audit reporting
Quality deviation inspection best practices
About MasterControl
MasterControl Inc. is a leading provider of cloud-based quality and compliance software for life sciences and other regulated industries. Our mission is the same as that of our customers – to bring life-changing products to more people sooner. The MasterControl Platform helps organisations digitise, automate and connect quality and compliance processes across the regulated product development life cycle. Over 1,000 companies worldwide rely on MasterControl solutions to achieve new levels of operational excellence across product development, clinical trials, regulatory affairs, quality management, supply chain, manufacturing and postmarket surveillance. For more information, visit www.mastercontrol.com.
Regulatory Compliance Associates (RCA) has helped thousands of pharmaceutical companies meet regulatory, compliance, quality assurance, and remediation challenges. With more than 20 years of experience with FDA, Health Canada, EU and global regulatory agencies worldwide, Regulatory Compliance Associates® offers leading pharmaceutical consultants. We’re one of the few pharma consulting companies that can help you navigate the challenges associated with industry regulations.
Our pharmaceutical consulting firm includes over 500 seasoned FDA, Health Canada & EU compliance consultants and regulatory affairs experts who understand industry complexities. It’s a pharma consultancy founded by regulatory compliance executives from the pharmaceutical industry. Every pharmaceutical industry consultant on the Regulatory Compliance Associates team knows the unique inner workings of the regulatory process.
Client Solutions
Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, Regulatory Compliance Associates will guide you through every pharmaceutical consulting step of the regulatory process. Our pharmaceutical consulting Experts will create a customized approach depending on your product and company’s individual needs. Our regulatory compliance clients include:
Companies new to FDA, Health Canada or EU regulations and regulatory compliance
Start-up organizations with novel submissions to 510(k) submissions from multi-national corporations
Investment firms seeking private equity due diligence for pre-acquisition and post-deal research
Law firms seeking pharmaceutical consulting firm expertise in the remediation of warning letters, consent decrees, 483’s or import bans
Regulatory affairs is Regulatory Compliance Associates backbone. We exceed other pharma consulting companies with industry experts experienced in complexities of the pharmaceutical and biopharmaceutical industries. Our pharma consulting expertise spans all facets and levels of Regulatory Affairs. Additionally, we specialize in Regulatory Support for New Products to Life Cycle Management, Outsourced Regulatory Affairs, Submissions, Training, and more.
As your partner, we can negotiate the potential assessment minefield of regulatory compliance services with insight, hindsight, and the clear advantage of our breadth and depth of knowledge and regulatory compliance consulting. We offer the following pharma consulting regulatory affairs services for pharmaceutical companies.
The regulations process surrounding pharmaceutical companies can be tricky for even the most experienced industry veteran to understand. Just one misstep could mean significant and lasting consequences for your business. At Regulatory Compliance Associates, we offer the pharma consulting experience and pharma consultants necessary to guide you through the quality compliance process.
Regulatory Compliance Associates Quality consulting includes assessments, strategy, implementations, staff augmentations, and identification of quality metrics to ensure continuous improvement. Our pharma consultants understand the strategic thinking needed to align your business needs and goals. Regulatory Compliance Associates quality assurance services include quality experts with experience spanning major corporations and start-ups. Our pharmaceutical consulting firm knows firsthand how to achieve, maintain, and improve quality. Finally, our regulatory compliance services team excels in transferring continuous improvement knowledge to your organization.
Regulatory Compliance Associates has significant experience and a proven remediation services approach to managing FDA Warning Letters, Consent Decrees, Remediation and other serious regulatory situations. Our pharma consultants know how to partner with executive, legal, and communication teams. Each RCA pharma consulting Expert will develop a response that will be accepted by the regulatory agency and be realistic to execute.
Regulatory Compliance Associates pharma regulatory consultants will develop a comprehensive proof book of documented evidence demonstrating the corrective action taken to remediate non-compliant issues. In addition, each Regulatory Compliance Associates pharma consulting Expert understands compliance enforcement. We’ll prepare a comprehensive pharma consulting strategy to assist in your remediation efforts, drive continuous improvement, and maintain regulatory compliance with the regulations.
Regulatory Action
Regulatory Compliance
Regulatory Enforcement
Warning Letter
483 Observation
Oversight Services
Risk Management Plan
About Regulatory Compliance Associates
Regulatory Compliance Associates® (RCA) provides pharmaceutical consulting to the following industries for resolution of life science challenges:
We understand the complexities of running a life science business and possess areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. We are used to working on the front lines and thriving in the scrutiny of FDA, Health Canada, MHRA and globally-regulated companies.
As your partners, we can negotiate the potential minefield of regulatory compliance and regulatory due diligence with insight, hindsight, and the clear advantage of our unique expertise and experience.
Founded in 2000
Headquartered in Wisconsin (USA)
Expertise backed by over 500 industry subject matter experts
The name Sotera Health was inspired by Soteria, the Greek goddess of safety, and reflects the Company’s unwavering commitment to its mission, Safeguarding Global Health®.
Sotera Health Company, along with its three best-in-class businesses – Sterigenics®, Nordion® and Nelson Labs®, is a leading global provider of mission-critical end-to-end sterilization solutions and lab testing and advisory services for the healthcare industry. With a combined tenure across our businesses of nearly 200 years and our industry-recognized scientific and technological expertise, we help to ensure the safety of over 190 million patients and healthcare practitioners around the world every year.
We are a trusted partner to 5,800+ customers in over 50 countries, including 40 of the top 50 medical device companies and 9 of the top 10 pharmaceutical companies.
Commitment to Quality
Our Certificate of Registration demonstrates that our Quality Management System meets the requirements of ISO 9001:2015, an internationally recognized standard of quality.
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.
Life science companies are feeling the pressure of greater scrutiny by regulators and responding by developing sustainable compliance strategies. Whether it’s preparing for an audit or developing a response to an FDA finding, Regulatory Compliance Associates (RCA®) team of compliance assurance consultants can help.
Every regulatory body takes its responsibility seriously to ensure the products consumers rely on meet a rigorous set of legal standards for quality, safety and effectiveness. RCA’s business consultant Experts are internationally known in the regulatory compliance industry for Safeguarding Global Health® with every new product approved.
Pharmaceutical Consulting Services
Regulatory Compliance Associates (RCA) has helped thousands of pharmaceutical companies meet regulatory, compliance, quality assurance, and remediation challenges. With more than 20 years of experience with FDA, Health Canada, EU and global regulatory agencies worldwide, Regulatory Compliance Associates® offers leading pharmaceutical consultants. We’re one of the few pharma consulting companies that can help you navigate the challenges associated with industry regulations.
Our pharmaceutical consulting firm includes over 500 seasoned FDA, Health Canada & EU compliance consultants and regulatory affairs experts who understand industry complexities. It’s a pharma consultancy founded by regulatory compliance executives from the pharmaceutical industry. Every pharmaceutical industry consultant on the Regulatory Compliance Associates team knows the unique inner workings of the regulatory process.
Client Solutions
Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, Regulatory Compliance Associates will guide you through every pharmaceutical consulting step of the regulatory process. Our pharmaceutical consulting Experts will create a customized approach depending on your product and company’s individual needs. Our regulatory compliance clients include:
Companies new to FDA, Health Canada or EU regulations and regulatory compliance
Start-up organizations with novel submissions to 510(k) submissions from multi-national corporations
Investment firms seeking private equity due diligence for pre-acquisition and post-deal research
Law firms seeking pharmaceutical consulting firm expertise in the remediation of warning letters, consent decrees, 483’s or import bans
Regulatory affairs is Regulatory Compliance Associates backbone. We exceed other pharma consulting companies with industry experts experienced in complexities of the pharmaceutical and biopharmaceutical industries. Our pharma consulting expertise spans all facets and levels of Regulatory Affairs. Additionally, we specialize in Regulatory Support for New Products to Life Cycle Management, Outsourced Regulatory Affairs, Submissions, Training, and more.
As your partner, we can negotiate the potential assessment minefield of regulatory compliance services with insight, hindsight, and the clear advantage of our breadth and depth of knowledge and regulatory compliance consulting. We offer the following pharma consulting regulatory affairs services for pharmaceutical companies.
The regulations process surrounding pharmaceutical companies can be tricky for even the most experienced industry veteran to understand. Just one misstep could mean significant and lasting consequences for your business. At Regulatory Compliance Associates, we offer the pharma consulting experience and pharma consultants necessary to guide you through the quality compliance process.
Regulatory Compliance Associates Quality consulting includes assessments, strategy, implementations, staff augmentations, and identification of quality metrics to ensure continuous improvement. Our pharma consultants understand the strategic thinking needed to align your business needs and goals. Regulatory Compliance Associates quality assurance services include quality experts with experience spanning major corporations and start-ups. Our pharmaceutical consulting firm knows firsthand how to achieve, maintain, and improve quality. Finally, our regulatory compliance services team excels in transferring continuous improvement knowledge to your organization.
Regulatory Compliance Associates has a proven remediation services approach to managing FDA Warning Letters, Consent Decrees, Remediation and other serious regulatory situations. Our pharma consultants know how to partner with executive, legal, and communication teams. Each RCA pharma consulting Expert will develop a response that will be accepted by the regulatory agency and be realistic to execute.
Regulatory Compliance Associates pharma regulatory consultants will develop a comprehensive proof book of documented evidence demonstrating the corrective action taken to remediate non-compliant issues. In addition, each Regulatory Compliance Associates pharma consulting Expert understands compliance enforcement. We’ll prepare a comprehensive pharma consulting strategy to assist in your remediation efforts, drive continuous improvement, and maintain regulatory compliance with the regulations.
Regulatory Action
Regulatory Compliance
Regulatory Enforcement
Warning Letter
483 Observation
Oversight Services
Risk Management Plan
About Regulatory Compliance Associates
Regulatory Compliance Associates® (RCA) provides pharmaceutical consulting to the following industries for resolution of life science challenges:
We understand the complexities of running a life science business and possess areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. We are used to working on the front lines and thriving in the scrutiny of FDA, Health Canada, MHRA and globally-regulated companies.
As your partners, Regulatory Compliance Associates can negotiate the potential minefield of regulatory compliance and regulatory due diligence with insight, hindsight, and the clear advantage of our unique expertise and experience.
Founded in 2000
Headquartered in Wisconsin (USA)
Expertise backed by over 500 industry subject matter experts
The name Sotera Health was inspired by Soteria, the Greek goddess of safety, and reflects the Company’s unwavering commitment to its mission, Safeguarding Global Health®.
Sotera Health Company, along with its three best-in-class businesses – Sterigenics®, Nordion® and Nelson Labs®, is a leading global provider of mission-critical end-to-end sterilization solutions and lab testing and advisory services for the healthcare industry. With a combined tenure across our businesses of nearly 200 years and our industry-recognized scientific and technological expertise, we help to ensure the safety of over 190 million patients and healthcare practitioners around the world every year.
We are a trusted partner to 5,800+ customers in over 50 countries, including 40 of the top 50 medical device companies and 9 of the top 10 pharmaceutical companies.
Commitment to Quality
Our Certificate of Registration demonstrates that our Quality Management System meets the requirements of ISO 9001:2015, an internationally recognized standard of quality.
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.
Q. I have been hearing that regulatory authorities are beginning to audit companies regarding their ‘quality’ culture’s relationship to data integrity tools. Can you give me a little background on this issue?
A. The regulatory authorities have always been interested in data integrity tools. Recently, however, the specific culture of an organization is being connected to the veracity and accuracy of the data generated to support the quality of manufactured products. The theory is the more mature an organization is the more reliable the product support data are. To understand this concept thoroughly, we should start with a brief review of FDA’s quality metrics initiative.
Data Integrity Guidance
When FDA posted the first draft guidance, Request for Quality Metrics, the metrics chosen were lot acceptance rate, product quality complaint rate, invalidated out-of-specification (OOS) rate, and annual product review or product quality review on time rate. The guidance also contained three optional metrics intended to measure quality culture: measuring senior management engagement, corrective actions and preventive actions (CAPA) effectiveness, and process capability/performance.
Although the optional data integrity tools intended to measure quality culture were removed from the current version of the guideline, it is the first indication that regulators felt there was a correlation between culture and data integrity. At the same time the issue of quality metrics was being discussed, there was a resurgence of data integrity problems in the industry evidenced by the number of citations that reference this issue.
Data Integrity Issue
Between 2005 and 2016, approximately 225 FDA warning letters were issued with observations for data integrity. These observations included repeat human error deviations, insufficient training, system failures, inappropriate qualification or configuration of systems, poor procedures or not following procedures, and intentional acts of falsification.
The increase in data integrity observations prompted regulatory authorities to address the issue by releasing a series of guidelines that reemphasize the importance of data integrity. FDA, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, the World Health Organization (WHO), and the Pharmaceutical Inspection Co-operation Scheme (PIC/S) have all released documents to reeducate the industry on data integrity concepts and expectations. In addition to the regulatory guidelines, the Parenteral Drug Association (PDA) released a free document titled Elements of a Code of Conduct for Data Integrity to help address the problem.
Quality Culture
One common theme permeating through these documents is that of quality culture. Regulators have linked the reliability of data to the existence of a quality culture as exemplified by statements taken directly from the guidance.
The PIC/S guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (5) states, ‘Management should aim to create a work environment (i.e., quality culture) that is transparent and open, one in which personnel are encouraged to freely communicate failures and mistakes. Organizational reporting structure should permit the information flow between personnel at all levels’.
MHRA Guidance
The MHRA guidance (2) titled ‘GXP’ Data Integrity Guidance and Definitions discusses organizational culture, stating:
‘The organization needs to take responsibility for the systems used and the data they generate. The organizational culture should ensure data [are] complete, consistent, and accurate in all its forms (i.e., paper and electronic)’ … ‘The impact of organizational culture, the behavior driven by performance indicators, objectives, and senior management behavior on the success of data governance measures should not be underestimated. The data governance policy (or equivalent) should be endorsed at the highest levels of the organization.’
WHO Guidance
WHO deals with the concept of quality culture in their document Guidance on Good Data and Record Management Practices by stating,
Adoption of a quality culture within the company that encourages personnel to be transparent about failures so that management has an accurate understanding of risks and can then provide the necessary resources to achieve expectations and meet data quality standards.
This same document states:
Management, with the support of the quality unit, should establish and maintain a working environment that minimizes the risk of non-compliant records and erroneous records and data. An essential element of the quality culture is the transparent and open reporting of deviations, errors, omissions and aberrant results at all levels of the organization, irrespective of hierarchy.
Regulatory Leadership
Based on the language used in data integrity guidance documents, it is clear that regulatory authorities consider quality culture an important element in establishing the veracity and integrity of the data being generated by companies that support the products they manufacture.
The trouble with quality culture is determining how to measure it. PDA has developed a culture assessment tool that links organizational attributes to specific behaviors.
PDA Guidance
Attributes were defined as elements of a quality system such as, but not limited to, deviations reporting, change control, CAPA, complaints, and environmental monitoring programs or systems. Behaviors were defined as intangibles such as, but not limited to, robust communication and transparency, rewards and recognition, employee engagement, and cross functional vision.
The theory was if quality attributes equaled quality behaviors, which then equaled quality culture, then if the quality attributes of a company could be measured, they would reflect the maturity of the quality culture of an organization. The PDA tool involves several steps that include training employees on the use of the tool, an onsite assessment, an all-staff survey, and finally analysis and action on the results.
ALCOA Data Integrity
There are, of course, other tools available to measure the culture of an organization. The real point is whatever tool your company uses to measure culture, it will be an important element in determining your data integrity risks and remediating them before an inspection.
Auditing a company to determine if their culture is conducive to generating data that meets the attributable, legible, contemporaneous, original, and accurate (ALCOA) concepts is on the horizon and may become a part of routine audits performed by regulators or industry auditors when evaluating the suitability of a manufacturer, potential partner, or service provider.
Regulatory Compliance Associates (RCA) has helped thousands of pharmaceutical companies meet regulatory, compliance, quality assurance, and remediation challenges. With more than 20 years of experience with FDA, Health Canada, EU and global regulatory agencies worldwide, Regulatory Compliance Associates® offers leading pharmaceutical consultants. We’re one of the few pharma consulting companies that can help you navigate the challenges associated with industry regulations.
Our pharmaceutical consulting firm includes over 500 seasoned FDA, Health Canada & EU compliance consultants and regulatory affairs experts who understand industry complexities. It’s a pharma consultancy founded by regulatory compliance executives from the pharmaceutical industry. Every pharmaceutical industry consultant on the Regulatory Compliance Associates team knows the unique inner workings of the regulatory process.
Client Solutions
Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, Regulatory Compliance Associates will guide you through every pharmaceutical consulting step of the regulatory process and create a customized approach depending on your product and your pharma company’s individual needs. Our regulatory compliance clients include:
Companies new to FDA, Health Canada or EU regulations and regulatory compliance
Start-up organizations with novel submissions to 510(k) submissions from multi-national corporations
Investment firms seeking private equity due diligence for pre-acquisition and post-deal research
Law firms seeking pharmaceutical consulting firm expertise in the remediation of warning letters, consent decrees, 483’s or import bans
Regulatory affairs is Regulatory Compliance Associates backbone. We exceed other pharma consulting companies with industry experts experienced in complexities of the pharmaceutical and biopharmaceutical industries. Our pharma consulting expertise spans all facets and levels of Regulatory Affairs, from Regulatory Support for New Products to Life Cycle Management, to other services like Outsourced Regulatory Affairs, Submissions, Training, and more.
As your partner, we can negotiate the potential assessment minefield of regulatory compliance services with insight, hindsight, and the clear advantage of our breadth and depth of knowledge and regulatory compliance consulting. We offer the following pharma consulting regulatory affairs services for pharmaceutical companies.
The regulations process surrounding pharmaceutical companies can be tricky for even the most experienced industry veteran to understand. Just one misstep could mean significant and lasting consequences for your business. At Regulatory Compliance Associates, we offer the pharma consulting experience and pharma consultants necessary to guide you through the quality compliance process.
Regulatory Compliance Associates Quality consulting includes assessments, strategy, implementations, staff augmentations, and identification of quality metrics to ensure continuous improvement. Our pharma consultants understand the strategic thinking needed to align your business needs and goals. Regulatory Compliance Associates quality assurance services include quality experts with experience spanning major corporations and start-ups. Our pharmaceutical consulting firm knows firsthand how to achieve, maintain, and improve quality, and we excel in transferring pharma consulting knowledge to your organization.
Regulatory Compliance Associates has a proven remediation services approach to managing FDA Warning Letters, Consent Decrees, Remediation and other serious regulatory situations. Our pharma consultants know how to partner with executive, legal, and communication teams. Each RCA pharma consulting Expert will develop a response that will be accepted by the regulatory agency and be realistic to execute.
Regulatory Compliance Associates pharma regulatory consultants will develop a comprehensive proof book of documented evidence demonstrating the corrective action taken to remediate non-compliant issues. In addition, each Regulatory Compliance Associates pharma consulting Expert understands compliance enforcement. We’ll prepare a comprehensive pharma consulting strategy to assist in your remediation efforts, drive continuous improvement, and maintain regulatory compliance with the regulations.
Regulatory Action
Regulatory Compliance
Regulatory Enforcement
Warning Letter
483 Observation
Oversight Services
Risk Management Plan
About Regulatory Compliance Associates
Regulatory Compliance Associates® (RCA) provides pharmaceutical consulting to the following industries for resolution of life science challenges:
We understand the complexities of running a life science business and possess areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. We are used to working on the front lines and thriving in the scrutiny of FDA, Health Canada, MHRA and globally-regulated companies.
As your partners, we can negotiate the potential minefield of regulatory compliance and regulatory due diligence with insight, hindsight, and the clear advantage of our unique expertise and experience.
Founded in 2000
Headquartered in Wisconsin (USA)
Expertise backed by over 500 industry subject matter experts
The name Sotera Health was inspired by Soteria, the Greek goddess of safety, and reflects the Company’s unwavering commitment to its mission, Safeguarding Global Health®.
Sotera Health Company, along with its three best-in-class businesses – Sterigenics®, Nordion® and Nelson Labs®, is a leading global provider of mission-critical end-to-end sterilization solutions and lab testing and advisory services for the healthcare industry. With a combined tenure across our businesses of nearly 200 years and our industry-recognized scientific and technological expertise, we help to ensure the safety of over 190 million patients and healthcare practitioners around the world every year.
We are a trusted partner to 5,800+ customers in over 50 countries, including 40 of the top 50 medical device companies and 9 of the top 10 pharmaceutical companies.
Commitment to Quality
Our Certificate of Registration demonstrates that our Quality Management System meets the requirements of ISO 9001:2015, an internationally recognized standard of quality.
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.
Regulatory Compliance Associates® (
A. The regulatory authorities have always been interested in data integrity tools. Recently, however, the specific culture of an organization is being connected to the veracity and accuracy of the data generated to support the quality of manufactured products. The theory is the more mature an organization is the more reliable the product support data are. To understand this concept thoroughly, we should start with a brief review of FDA’s quality metrics initiative.