Archives: Published Articles

Quality Considerations for Using AI in Bio/Pharma

In the second episode of the Ask the Expert video series, Susan J. Schneipp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice-president, Technical, at Parexel, discuss the quality requirements needed when incorporating AI in bio/pharmaceutical development and manufacturing.

 

External link to the Video Page

 

The use of artificial intelligence (AI) is seeing a surge in a variety of industries. But does the regulated nature of bio/pharmaceutical development, manufacturing, and commercialization serve up unique challenges for incorporating AI into processes? According to Siegfried Schmitt, vice-president, Technical, at Parexel, using new technology will most likely require the assistance of experts in that technology. And if you’re contracting a third party for that help, you need to do an assessment of that vendor.

 

“[T]he thing with AI, it being a computer-based technology, there is sometimes the issue of, do you have sufficient or good documentation practices applied? It’s all too easy to play around with computer code and settings and so on, but you do need to have appropriate documentation, and because you’re applying it to process development … It is something that can get inspected, so be ready for an inspection,” Schmitt cautions.

 

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, stresses that a robust quality management system and document control are necessary when adding AI to a process. “I also worry about if there’s the expertise to interpret what the data [are] telling you. You’re going to be collecting a lot more data than you’ve collected before, and data that’s new, and how it impacts your organization. And the data you’re collecting may prompt you to want to make a change in the coding, [but] you need to follow that stream through your quality management system,” Schniepp says.

 

Click the video above to watch Sue and Siegfried answer the question: “My company is researching the possibility of using AI in the formulation of a new product. Are there any quality considerations we should be aware of?”

 

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

The Future of Biotech Quality

Experts share insights on what the future may hold regarding biotech quality, regulatory requirements and quality standards for biotechnology industry.

 
Quality StandardThe biotech industry has experienced significant growth in recent years. These complex therapies have evolved, and with this evolution comes new challenges in ensuring the quality of these products and the safety of the patients that use them. Quality regulations, and industry, may have to continually adapt to address these challenges.
 
 
To gain perspective on what the future quality standard holds for biopharmaceuticals and how the industry and regulators will address quality going forward, BioPharm International spoke with Anthony Newcombe with PAREXEL and Susan Schniepp at Regulatory Compliance Associates (RCA).
 

Quality Standards 

 

BioPharm: With the fast development of the biopharmaceutical industry over the past 30 years, how have quality regulations adapted to address the complex nature of biologics?

 

Newcombe: Over the past 50 years, the industry has grown, especially due to advances in areas such as recombinant DNA and hybridoma technology, and more recently gene and cell therapies. As these advancements have occurred, new quality regulations have been developed to address the complex nature of biologics with specific quality requirements associated with viral safety, expression constructs, product characterization, and comparability.

 

Regulatory & Regulation

 

BioPharm: Are there regulatory guidelines in development for ensuring the quality of biologics in the future?

 

Newcombe: There is no indication that the current, published quality guidelines would not ensure the quality of biologics in the future, but it’s likely that regulatory guidance documents will continue to be revised and updated over time to adopt industry best practices and new technologies, for example the draft International Council for Harmonization (ICH) Q12 and the revised EudraLex Annex 1.

 

Biotech Consultants

 

BioPharm: Do Biotech consultants foresee science outpacing quality regulations?

 

Schniepp (RCA): I think science has already outpaced quality regulations. An example is the applicability of pharmacopeial methods for product testing. Many monographs utilize traditional high-performance liquid chromatography (HPLC) for testing.

 

Companies have migrated to ultra-high-pressure liquid chromatography (UHPLC) and other sophisticated methodology, thereby rendering compendial monographs obsolete. By the time updates are made to the pharmacopeias to capture the current technological advancements, more sophisticated equipment and methodologies are being introduced.

 

The industry seems to be moving toward a continuous monitoring where results regarding product quality can be achieved in real-time. The current processes used to update procedures, systems, and filings may not be able to keep pace with the rapid introduction of technological advances. I don’t think this is new.

 

Science has always outpaced quality regulations. When dissolution testing was introduced, it took a while for that technology to be widely accepted. I think this phenomenon is more of an issue today than in the past because science innovations are occurring at a much more rapid pace and affecting all aspects of the drug product lifecycle than 20 years ago. This rapid advancement of technology makes it harder for the quality regulation to catch up.

 

Newcombe: Quality regulations ensure that biopharmaceuticals are safe and effective, and in my opinion, are generally not driven by the pace of scientific advances. However, new quality regulations are likely to be required to keep up with the development of new advanced therapies, including gene and cell therapy and tissue engineering.

 

Some of these are autologous products using a patient’s own blood components and personalized medicines can present additional manufacturing, compliance, and regulatory challenges.

 

Quality Control 

 

BioPharm: How do you see the role of the quality control (QC) unit changing versus the current quality standard?

 

Newcombe: I would not anticipate any significant changes to the role of the QC unit in the coming years. QC laboratories currently undertaking release testing for approved biologics using validated methods are unlikely to change their existing role significantly. There may also be a general reluctance to implement new analytical technologies used for testing of approved products due to potential regulatory impact with a continued reliance on established analytical methods.

 

Schniepp (RCA): I think the quality unit will evolve to be a more hands-on review of the product attributes. The quality unit will need to be equal partners with manufacturing to be able to release product quickly and solve deviations and investigations in a timelier manner than we are experiencing today. Complete investigations will still need to be performed. They will just need to be done quicker depending on the nature of the product.

 

Traditionally, the quality unit has reviewed the results of the manufacturing process after the work has been completed and the batch has been packaged. To keep pace with the new quality standard of products being developed by biopharma, the quality unit may need to be releasing product, performing investigations, and initiating changes in real time. This requires agile and flexible processes and systems that can keep pace with advancements.

 

The quality professional of the future may need to have a solid basis in science to be able to meet the demands of manufacturing. They will need to be able to quickly ascertain how a proposed change or deviation could affect the functionality and quality of a product, which will require an intimate understanding of the manufacturing and science associated with the product. To keep pace with the future, quality must be imbedded in the process and not just as the final approver for product release.

 

Biotech Manufacturing

 

BioPharm: What quality control challenges do you see developing for biopharmaceutical manufacturing

 

Schniepp (RCA): Quality control to me is the testing that is associated with determining if the product meets critical parameters throughout the manufacturing process and at release. The question is: Do we have the correct equipment, tests, and sensitivity to accurately assess the quality of products being developed today, and how will we deal with these intricacies as we advance more and more toward personalized medicines?

 

This concept should extend beyond the product testing and be assessed for the environmental support testing as well. Determining the proper tests and environmental controls as the industry moves forward will require new and novel thinking.

 

Newcombe: Recent data integrity requirements and guidelines have had an impact on data management within QC laboratories. This may present challenges for some organizations associated with the collection, processing, reviewing, and reporting of data and ensuring the accuracy and consistency of analytical results. The access and management of data stored on electronic systems within the QC laboratory is also likely to present continued challenges.

 

Article Details

 

regulatory compliance

 

BioPharm International
Vol. 31, No. 7
Pages: 16-20

 

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

 

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

 

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

 

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

 

 

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

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

 

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

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. 

 

Published by:

 

 

 

Medical Device and Diagnostic Industry.

 

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