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Remediation Costs of Non-Compliance

remediation costs

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).  

 

costs
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.

 

About the Article

 

 

Pharmaceutical Technology
Vol. 41, No. 11
Pages: 54–57

 

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Quality Risk Management Plan

A well-written and well-implemented quality risk management plan is an integral element of an effective quality system. During the development of your total quality strategy, the bottom line is that things can and will go wrong. Your QA management team and QMS system need to be designed with data quality management in mind. Your team should include employees from multiple functions who understand both risk and compliance. 

 

Quality Risk Management

 

regulatory complianceThe purpose of quality risk management is to help ensure continued compliance with regulatory requirements, such as good manufacturing practices. This is critical for risks analysis when events occur during manufacturing that can impact patient safety and product quality.

 

ICH Q9

 

The International Council for Harmonization (ICH) Q9 states;

 

“Two primary principles of quality risk management are: the evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and, the level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk”.

 

In developing your company’s plan, you will need to consider key risk indicators and how to mitigate risk. Managing your company’s risk with a well-defined plan may help reduce strategic risk associated with poor ISO 9001 Standards. Most importantly, reducing inefficiencies associated with the product and the process is critical to improving quality.

 

A reduction in deviations/investigations, FDA warning letters, customer complaints, and product yield all improve the culture of quality.

 

Risk Management Framework

 

A risk management framework is used to evaluate all aspects of the manufacturing process and identify areas of vulnerability. These vulnerabilities need to be assessed for their financial risk impact on the operation and the potential level of risk they pose. Risk management in healthcare requires a holistic viewpoint from multiple departments across the enterprise. 

 

Quality Risk Management Plan

 

A well-written quality risk management plan is an ongoing process requiring risk control documentation throughout the product lifecycle. It provides a solid risk management process for how to improve efficiency and minimize operational risk. Focus your operational risk management on the important activities to improve product quality rather than low-risk activities that have little impact. These are four key elements to consider when defining your risk mitigation strategies:

 

Element One: Gap Analysis

The first element is to perform an analysis of the identified risk associated with the operations. For example, consider project risk management if your product is being produced using an older manufacturing line. There is compliance risk that an out of date manufacturing process will experience breakdowns.

 

Element Two: Risk Evaluation

The second step is to evaluate the risk in terms of its impact on your ability to supply a quality product. In this case, frequent shutdowns can lead to product rejections, yield loss, and potential drug shortages. Search for risk management solutions that anticipate these types of supply chain risk in advance. 

 

Element Three: Identify Controls

Once the risk has been identified and the impact evaluated, risk controls can help mitigate. For example, cybersecurity risk is a growing problem where manufacturing automation needs to be reviewed. Some of the possible mitigation control strategies might include conducting threat modeling to identify your risk in security. Ensure your risk mitigation plan also qualifies cyber risk management and how a cyber secure manufacturing line holistically prevents outside hacking.

 

Element Four: Data Management

The last key element needed is data input and management. Any risk management tool should be able to indicate if and when you need to employ one of your risk control strategies. Simple risk identification includes if you see an increase in downtime on the line or a steady decrease in yield. This data could be indicators that the manufacturing line is headed for a catastrophic failure and steps need to be taken to prevent a drug shortage situation.

 

Security Risk Management

 

The above discussion is only an example of a risk assessment in one area of an operation. Other areas of the process need to be evaluated for potential vulnerabilities and risk. These areas include an evaluation of the reliability of raw material suppliers, stability, and contractual supplier compliance, age and reliability of laboratory test equipment, etc. Supplier compliance also includes partnering with contract manufacturing organizations and contract test organizations.

 

Integrated Risk Management

 

A dynamic quality risk management plan will integrate the overall organization and identify high risk vulnerabilities. It will be proactive in identifying strategies for mitigation of the high-risk vulnerabilities. Data will be leveraged to perform continuous monitoring of the vulnerabilities. And, of course, the plan will provide the appropriate documentation and rationale for risk management programs.

 

Risk Management Consultant

 

Implementing a quality risk management plan in an organization can also be challenging. A risk management consultant can provide all applicable function personnel involved in the operations additional feedback. These functions include finance, manufacturing, regulatory affairs, purchasing, auditing, and senior management. The plan should be dynamic and should be modified as situations change.

 

Single-Source Vendor Risk

 

Let’s say you produce a product and you have a single-source supplier for one of your excipients. You have audited the supplier and have identified some significant gaps in their quality system. You identify this vulnerability in your quality risk management plan as a high-risk item because of the lack of vendor compliance.

 

One of your mitigation strategies might be to qualify an alternate supplier for the excipient. Once you have qualified that alternate supplier, you need to update your plan to downgrade the risk because you have taken the appropriate steps to mitigate it and eliminate the identified vulnerability.

 

Qualifying a Secondary Supplier

 

When qualifying a secondary supplier you may want to consider choosing a supplier in a different geographic location. There may be geographical situations or circumstances that could affect the ability of the original supplier to supply materials in a timely manner. This concept could also be applied not only to secondary suppliers of a raw material but also to suppliers of the final pharmaceutical product.

 

When choosing a new supplier in a different geographical location it will be important to understand the capabilities of the new region. The following Table demonstrates some of the information you will want to assess.

 

The chart identifies the Regulatory Agency in charge of the region you might be considering. It identifies the estimated number of employees currently in the industry and results of 2019 drug quality inspections (NAI, VAI, and OIA). Issues on Data Integrity are also tied to warning letter citations.

 

Geographic Risk Management

 

The decision to qualify a new location is a difficult one but with the proper information, it can be done.  Quality risk management plans are important because they help improve a company’s ability to provide a quality product to patients. They are contingency plans with identified actions that help to ensure a continuous supply of product to the market. Further, the risk management plan is designed to accelerate products that are safe, effective, and available.

 

They are dynamic documents that require integration into and data inputs from all departments in order to be successfully implemented at a company, require integration into and data inputs from all departments in order to be successfully implemented at a company.

regulatory compliance

 

 

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Compendial Requirements

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

 

Q: Do I need to comply with all aspects of the various pharmacopeias? (e.g., United States Pharmacopeia–National Formulary [USP–NF], European Pharmacopoeia [Ph.Eur.],Japanese Pharmacopoeia, etc.)?

 

A: This would seem like a straightforward answer, but as with most issues related to the pharmaceutical industry, it is a bit complicated. Each pharmacopeia has various sections the industry must comply with including monographs, defining the test methods and purification for excipients, APIs, and drug products. These specific monographs often refer to general test procedures (loss on drying, pH, residue on ignition) that are consistently performed respective of the materials.

 

Compendial Testing

The conditions for performing compendial testing are included in the monograph, while the details of how to perform the tests are included in the general chapter. Individual monographs will specify the use of a certified reference standard that serves as the measure to which your specific item should be compared to in determining its suitability for use. It is acceptable to use in-house reference standards as long as the company has mapped its in-house standard to the official standard. The important detail to remember is to requalify your in-house standard when the lot number of the official standard changes.

 

Not all information in the pharmacopeias needs to be complied with. The USP–NF has a section called general information chapters, which are basic guidance advice for performing various operations such as environmental monitoring. Although these chapters are not legally enforceable, users should take notes and document their process when it conflicts with pharmacopeia’s advice. Like the USP–NF, there are some sections in the Ph.Eur. that are not legally binding. These would be general method analysis of substances used in the manufacture of medicines if they are not referenced in a monogram.

 

Compendial Standards

The pharmacopeias allow for alternative methods to be used providing they are validated and the results generated from the alternative method yields comparable results to the compendium method. All the pharmacopeias have a process for updating their contents. It is up to the users of the pharmacopeias to make sure they are using the current version published by the governing authority for the specific pharmacopeia. If you follow this simple advice, you should have no trouble maintaining compliance to the compendia requirements.

 

About the article

 

 

 

Article details

BioPharm International
Vol. 36, No. 10
Page: 34

 

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FDA Inspections: Hope is Not a Strategy

Subject matter experts from Regulatory Compliance Associates® Inc. discuss how too many organizations scramble when an FDA inspection occurs because they fail to be adequately prepared. True inspection preparedness, however, supplements internal audits with a practiced inspection process and focused behavioral training.

 

 

Internal Audit

 

While internal audits are a key component of inspection preparedness, they tend to be informal, less intense, and more focused on auditing than inspecting. True inspection preparedness supplements internal audits with a practiced inspection process and focused behavioral training for key personnel.

 

Before a FDA inspection occurs, organizations should have an inspection process in place and conduct mock inspections. Like any process, inspection readiness needs a plan that is executed, assessed, and continuously improved upon. 

 

Roles & Responsibilities 

 

The Inspection Room (Front Room) 
While inspectors often walk the facility, the inspection room provides a meeting space to review documentation and answer questions from the inspectors. In this “front room,” system owners or subject matter experts (SMEs) review and present materials to the FDA inspector. 

 

The Control Room (Back Room) 
The control room provides the documentation, interviewees, and preparation that is needed to support the inspection process. This “back room” team processes requests for information, retrieves documents from electronic systems, and also triages documents as needed. The control room is staffed with quality and technical personnel who log requests for information and alert department heads within the organization. 

Control room personnel should always:

  • Conduct a minimum of two reviews of every document prior to sending it to the inspection room:
  • Quality Review:
    • Make sure it points to valid SOPs and Work Instructions, etc.
  • Technical Review:
    • Make sure the SMEs have reviewed and are prepared to speak to the process with the inspector
  • Have back-up printers, toner, copiers and paper on hand

Some organizations appoint runners to take the data back and forth between the control room and inspection room. There are technology solutions to operationalize the inspection process as well. 

 

Behavioral Training

 

In the past, employees were often trained to give curt answers to FDA inspectors to avoid inadvertent revelations to the agency. This approach created fear and mistrust among employees, and set up adversarial relationships with FDA staff. In order to create the most beneficial inspection process environment, however, both the agency and the company need to form a partnership. Key behavioral tips for success include:

 

  • Empower the inspection and control room teams.
  • Bring SMEs into the control room to help gather data, review documents, and consult on the answer before they are summoned to the inspection room.
  • Help SMEs understand their role in the bigger picture of the inspection. Prep them on related questions that have already been asked.
  • Don’t allow an SME to bring in notes or an uncontrolled document.
  • Use the control room to debrief SMEs after meetings with the inspector.
  • Anticipate and prepare. The language used in inspector requests can provide insights. Anticipate next questions, proactively pull documents, and understand related metrics. For example, if the inspector asks about CAPA, review related documents such as open CAPAs, high-risk CAPAs, the average length of time for CAPAs, and the longest time for open CAPAs. Be prepared to answer the inspector’s next questions.

Practicing the inspection process, however, can be one of the best ways to help employees learn appropriate behaviors and response techniques. Train employees to:

 

  • Focus on the question asked; restate the question when unsure of what’s being asked.
  • Readily admit to not knowing an answer, but provide a date and time when the answer will be provided.
  • Create an environment that reinforces the positive but recognizes weaknesses, such as “we understand this is an area for improvement,” rather than “this has been a problem for a long time.”
  • Recognize the need for training across the organization on inspection readiness. Consider off-site locations as well. The FDA inspection process starts when the FDA inspector pulls up into the parking lot and interfaces with reception and security personnel. Don’t limit inspection training to just inspection and SME personnel.

 

Mock Inspections

 

Many companies conduct internal audits as part of their inspection readiness strategies. Mock inspections, however, take the next step and allow companies to actually practice the inspection room, the control room, and inspector interaction. 

 

During mock inspections, organizations set up inspection rooms and control rooms to help teams learn how to readily access documentation that would potentially be requested during an inspection. Additionally, these practice sessions give employees an opportunity to demonstrate proper behavior and interviewing techniques when working with the regulatory agency. 

 

A mock inspection can also be used to probe further on issues uncovered during internal audits. The mock Inspection team should bring in SMEs and other personnel as needed for this activity. This approach helps the organization fully understand areas needing improvement, and gives them a platform to take corrective action before the agency actually arrives.

 

Being properly prepared for inspection ensures that the inspection process will run smoother, decreases the likelihood of observations, and helps groom the organization and individuals for higher levels of future performance. 

 

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Medical Device and Diagnostic Industry.

 

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GMP Manufacturing

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).

 

regulatory compliance
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

 

regulatory compliance

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.

 

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Aseptic Processing 101

Susan J. Schniepp, Distinguished Fellow at Regulatory Compliance Associates, answers some commonly asked questions about aseptic processing and environmental controls.

 

Q. What is aseptic processing?

 

A. Aseptic processing is a manufacturing method that can produce product that is absent of bacteria without subjecting the product to terminal sterilization processes.

 

Aseptic Manufacturing

 

Many products degrade and become ineffective when subjected to the harsh conditions of terminal sterilization. Aseptic manufacturing allows these products to be produced in a sterile environment, allowing them to maintain their effectiveness while being safe to inject into patients.

 

Q. What is the difference between aseptic processing and terminal sterilization?

 

A. The major difference between aseptic processing and terminal sterilization is when the sterilization step occurs in the process. In terminal sterilization, the sterilization is performed after the API, excipients, containers, and stoppers have been assembled.

 

Sterilization

 

The final assembled product is then subjected to high heat and/or radiation that renders the product sterile. Terminal sterilization processes are harsh and can have negative effects on product efficacy.

 

Aseptic Container

 

For products that can’t withstand terminal sterilization, drug manufacturers employ aseptic manufacturing. The aseptic manufacturing process requires the drug product and any excipients, the container, and the stoppers to be individually sterilized.

 

Aseptic Clean Room

 

All must be done before being introduced into the cleanroom or sterile manufacturing core where the final product is manufactured. Additionally, this highly controlled environment is constantly monitored for air quality and potential microbial ingress.

 

Q. Why must manufacturers establish environmental controls for aseptic processes?

 

A. Let’s be clear, all drug manufacturing, including solid oral dosage form and terminal sterilization manufacturing are required to have established environmental controls.

 

Proper Aseptic Technique

 

This requirement is addressed in global current good manufacturing practices (cGMPs). The purpose of these controls is to prevent product contamination due to unsanitary conditions.

 

Environmental Controls

 

The environmental controls to be monitored include, but are not necessarily limited to, air quality including particulate matter, ventilation, temperature, humidity, air pressure, and microbial contamination.

 

The environment controls have, as expected, stricter limits for aseptic processing manufacturers due to the nature of their business.

 

Q. What does PUPSIT stand for, and why is it required?

 

A. PUPSIT is a term used in aseptic processing operations, and it stands for pre-use post-sterilization integrity testing. This testing is performed on the sterilizing filter after it is installed before product manufacturing. Follow up testing occurs again after the product manufacturing is completed.

 

Filtration Sterilization

 

The purpose of the pre-test is to ensure that the sterilization and installation process has not damaged your filter prior to the filtration of your product. The purpose of the post-test is to demonstrate that the filter remained intact and undamaged during actual product filtration.

 

An article published by the Parenteral Drug Association (PDA) states:

 

“Since 1998, the EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use, Annex 1 (Manufacture of Sterile Medicinal Products) or ‘Annex 1’ has contained the requirement for verifying the integrity of a sterilizing grade filter before use and after its sterilization.

 

The requirement remained in the 2008 revision and in the 2017 draft revision to Annex 1. While not a requirement by the U.S. FDA, EMA inspectors and some PIC/S inspectors have been increasingly expressing expectations for companies to employ this testing procedure”.

 

The article goes on to explain the concerns that led to the PUPSIT requirement:

 

“Concerns have been raised that a sterilizing filter could develop certain flaws that would allow microbiological contamination to pass during filtration. The key is that flaws may be blocked or clogged by fluid contaminants or components during the filtration process and remain undiscovered during post-use integrity test. This phenomenon is sometimes referred to as ‘filter flaw masking’”.

Additionally, the article explores the rationale for not employing PUPSIT because of:

 

“the contamination/product deterioration risk associated with performing PUPSIT may greatly outweigh the risk of product contamination as a result of the masking effect.”

 

Sterile Filtration

 

To test a filter during sterile filtration, the sterile filtrate side must be under atmospheric pressure. This requires a fluid pathway to remove any wetting agent.

 

“The exposure of the downstream portions of the sterile product transport line poses a risk to maintaining the sterility of the filtered product. This, along with other risks, is greater than the remote likelihood of microbiological contamination from a flaw which can be masked during use of the filter that is not detected afterwards.”

 

PUPSIT

 

Further, the PUPSIT concept is still actively being debated. The best way to address the use/non-use of PUPSIT in your organization is to make sure you have an appropriate risk assessment in place defending your position.

 

Q. What makes aseptic drug manufacturing so challenging?

 

A. Aseptic manufacturing requires highly trained and experienced people to carry out the operations. Even when not in use, special equipment and cleaning procedures must be part of the constant environmental monitoring. Finally, the risk to the product and patients is significant when the aseptic process is compromised.

 

Article Details

 

regulatory compliance

 

Pharmaceutical Technology
Volume 45, Number 10
Pages: 58, 57

 

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