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FDA Consulting: Drug Shortages

A landmark FDA consulting article in Pharmaceutical Technology, “Linking Drug Shortages and Quality Metrics” provided information regarding the link between drug shortages including the enactment of the Food and Drug Administration Safety and Innovation Act,
 

FDA Drug Shortage List

 

FDA’s efforts to develop a common set of quality metrics for the pharmaceutical industry will help address the current drug shortage problem. Efforts from the industry to establish and maintain quality metrics capable of measuring the suitability of pharmaceutical products for the patient, and the capability of the manufacturer to consistently provide these products without delay will increase knowledge.
 
The Parenteral Drug Association (PDA) also published Technical Report No. 68 (TR68), “Risk-Based Approach for Prevention and Management of Drug Shortages,” which provides the bio/pharmaceutical industry with appropriate tools for preventing drug shortages.
 

FDA Drug Shortages

 

PDA technical reports, authored and peer-reviewed by PDA members, are intended to offer practical guidance on pertinent regulatory and scientific topics that affect the global pharmaceutical industry. Members with expertise in manufacturing and quality assurance for sterile biopharmaceutical and pharmaceutical products (the majority type of products subject to drug shortages) authored TR68.

 

Although PDA technical reports are not officially recognized guidance, they are often referenced by FDA consulting experts and regulators. Additionally, regulators may be involved in the writing or approving of the final report contents.

 

Product Shortages

 

TR68 addresses the drug shortage issue from a global perspective and offers relevant, proactive advice applicable to the global pharmaceutical industry. In addition, the paper recognizes several contributing factors potentially responsible for drug shortages: manufacturing issues, quality issues, and supply chain or distribution issues. This is important because TR68 recognizes that the issue of a potential drug shortage goes beyond the quality department within an organization.

 

Global Language for Global Issue

 

The document provides a common language for the industry to use when discussing drug shortages. It is this author’s opinion that it is always important when authoring potential global guidance to establish a common language for the readers. TR68 accomplishes this objective by placing a glossary at the beginning of the report and references, when possible, existing FDA consulting definitions from recognized, credible sources.

 

The definition for “harm” for example, is taken verbatim from the International Conference on Harmonization’s (ICH) Q9 guideline, Quality Risk Management. The definition of knowledge management is taken from ICH Q10 Pharmaceutical Quality Systems. Using previously established definitions helps the global users of TR68 understand the context and relationship of this document within the regulatory framework of the industry. 

 

FDA Shortage List

 

Once a common language is established, it is easier for a document user to relate the narrative portion of the document to the shortage list. The narrative of the technical report describes how the issue of drug shortages is global in nature and delineates current global regulatory and legal manufacturer reporting requirements when facing issues that may result in drug shortages. These issues are not limited to final product manufacturers but may involve suppliers of raw materials crucial for product formulation.

 

For example, TR68 describes how a supply-chain issue, a shortage of acetonitrile in 2008-2009, can prompt a drug shortage. The FDA consulting document discusses how multiple suppliers were unable to provide acetonitrile to the industry because of a series of unforeseen circumstances. This shortage impacted the ability of companies to manufacture APIs that then impacted the manufacture of the final drug product.

 

Drug Shortage List

 

The document is designed to guide bio/pharmaceutical companies in the assessment of the risk of experiencing a drug shortage. TR68 uses a risk triage model to collect and assess existing organizational information to determine drug-shortage risk. The model builds on the concepts of management responsibility, supply chain management, quality risk management, knowledge management, regulatory requirements and a company’s compliance history and treats them as integrated interrelated disciplines within an organization.

 

The examples included in the document provide templates to combine a company’s information into a comprehensive set of tools that not only measure the potential for a company to experience a drug shortage, but also delineate and identify gaps in organization structure that may exist in quality systems.

 

Medication Shortages

 

The document takes the aforementioned concepts and provides a framework for capturing the information in one inclusive document. This can help remedy issues with resolving medication shortages and patient wait times. The completed document can be used as a FDA consulting tool to share within an organization or with clients in determining potential process improvements or necessary resources required to address systemic process gaps.

 

TR68 can be used in part or in total by raw material and API suppliers, contract manufacturing organizations, and pharmaceutical companies to assess and manage organizational, manufacturing, and quality issues that could contribute to a drug shortage. The document provides tools to predict and hopefully prevent drug shortages in the future.

 

Article Details:

 

regulatory compliance

 

Pharmaceutical Technology
Vol. 39, Issue 3
Pages: 26–27 

 

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Metrics of Quality Culture

Susan Schniepp, Distinguished Fellow of Regulatory Compliance Associates® Inc., discusses how the FDA’s proposed guidance for the metrics of quality raises questions about quantifying the tangibles and intangibles of quality culture.

 

FDA’s proposed guidance for quality metrics raises questions about quantifying the tangibles and intangibles of quality culture.

 
metrics of quality
 

The long awaited, anxiously anticipated FDA guidance on quality metrics was finally distributed for comment on July 28, 2015. The official title of this guidance for industry is Request for Quality Metrics, Guidance for Industry (1) and its potential release has been looming on the horizon since 2012.

 

Drug Establishments

 

The intent of FDA to establish quality metrics first emerged in 2012 when Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA) enhancing FDA’s capability to proactively react to, prevent, and alleviate drug shortages. Specifically, Title VII Section 705 of the Act states FDA

 

“shall inspect establishments described in paragraph [1] that are engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs (referred to in this subsection as ‘drug establishments’) in accordance with a risk-based schedule established by the Secretary.”

 

Section 706 of the same act allows FDA to request certain information from companies in advance of or in lieu of inspections by stating,

 

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

 

In the Feb. 12, 2013 Federal Register Notice (3), FDA asked the industry to

 

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

 

This notice asked a series of thought-provoking questions including “What metrics do manufacturers currently use to monitor production quality?” and “How frequently would such metrics need to be updated to be meaningful?”. After a few years of actively engaging and listening to industry in a variety of venues, this new guideline has finally been released.

 

FDA Guidelines

 

The metrics proposed in the guideline are not new to the pharma industry. Many of them are currently being used by companies to internally measure performance. In some cases, the specified metrics are also reported to the agency via the annual report or are contained in the annual product review. The bio/pharma industry needs to review these metrics and ensure they will provide meaningful data while avoiding unintended consequences.

 

Quality Culture

The underlying and understated tenet used to determine a company’s well-being is a measure of their quality culture. The culture of a company dictates the veracity of their metrics. The best way to ensure the data reported has merit is to assess the quality culture of the submitting organization.

 

It is in this area that the new guidance lacks clarity. The guidance leaves the opportunity open to establish quality-culture metrics by stating,

 

“these metrics are not intended to be an all-inclusive set of the quality metrics that FDA could consider useful to assess a product and manufacturer’s state of quality. For example, senior management commitment to quality is an important factor in evaluating the overall health of the PQS [pharmaceutical quality system] and quality culture”

 

and

 

“…the Agency is committed to a dialog with industry to consider benchmarks and standards that could provide acceptable metrics that specifically demonstrate senior management’s commitment to a culture of quality …”

 

This commitment to establishing quality culture metrics is further evidenced by the section in the guideline titled “Optional Metrics Related to Quality Culture and Process Capability/Performance”. In this section, FDA states,

 

“acknowledges the importance of quality culture to the overall state of quality of the product, process, and commitment to quality”

 

Quality Metrics

 

FDA proposes three voluntary metrics to try to get at the elusive quality culture. The first optional metric proposed is intended to measure senior management engagement by assessing whether the head of the quality unit and the head of the operations unit have signed the annual product review (APR) or product quality review (PQR).

 

CAPA

 

The second optional metric proposed is corrective action and preventive action (CAPA) effectiveness. The measurement for this metric is to indicate the percentage of corrective actions that required retraining of personnel, the assumption being that the root cause of the original deviation (real or due to insufficient analysis) was determined to be insufficient or ineffectual training.

 

Process Improvement

 

The third proposed metric is intended to measure a firm’s process capabilities through a series of three questions. The real question should be if these three optional metrics, taken together, shed any light on the quality culture.

 

Management Engagement

 

Achieving a quality culture requires management and employees to establish an environment where responsibility, accountability, and reliability are paramount, and to understand the role each person performs in delivering a high-quality product to the customer and sustaining that performance on a continual basis.

 

Management must educate employees and provide the tools and environment where they can perform their functions in an atmosphere that encourages excellence and continuous improvement.

 

Product Quality Review (PDR)

 

Assigning the head of quality and the head of operations the task of signing the APR or the PQR does not ensure management engagement nor does it mean that the quality culture is lacking. It is up to an organization to establish the appropriate level of responsibility and signing authority for APR and PQRs.

 

It is up to senior management to provide the people charged with these activities the necessary resources to complete the task in a timely manner with the expectation that they will be held accountable for the contents.

 

Retraining Personnel

 

The second optional quality culture metric is specific to CAPA. The proposed metric is to report the percentages of corrective actions involving the retraining of personnel. Without context supporting the retraining of personnel, this metric does not offer insight into the true culture of an organization.

 

It could be argued that any CAPA that results in a reduction or elimination of a recurring deviation would require an element of training personnel. In fact, retraining of personnel on the CAPA issue, how it was solved, and how to implement the necessary change is evidence of management engagement. It should be expected that a majority of CAPAs involve some retraining of personnel.

 

Critical Quality Attributes (CQA)

 

The third quality-culture optional metrics involves trying to use critical quality attributes (CQA) as a key indicator of a quality culture. Of the three optional metrics proposed, this one does provide some measurement of the existence of a quality culture.

 

On the surface, the questions just seem to be a regurgitation of information contained in the APR or PQR. Upon closer evaluation, however, it is clear that FDA is trying to measure whether a company drives for continuous improvement through their review and assessment of threshold levels established with CQAs.

 

Corrective Action

 

Companies that establish corrective actions to CQAs and link them to a requirement to issue a CAPA when they exceed the established threshold levels demonstrate a commitment to continuous improvement. Continuous improvement programs are, in fact, reliable indicators of the presence of a quality culture.

 

Measuring Intangibles

The establishment of simple quality metrics that not only measure the quality of the product but also reflect the quality culture of an organization is required to assist FDA in establishing a risk-based audit program. The problem is that it is difficult to measure something as intangible as culture with cold, hard data. The remaining question is: If taken together, are the three proposed optional metrics indicative of a quality culture? The answer is, maybe.

 

Careful thought and consideration should be exercised when determining what to measure, how often to measure, how to interpret and communicate the data, and what the expectation is for using the data to drive positive change. Management needs to be cognizant of the fact that whatever metrics are reported, they must be developed, evolved, and adjusted over time to maximize their impact on driving positive change.

 

Root Problem

 

When choosing a metric, it is important that leadership is aware of unintended consequences that may inadvertently drive negative behavior instead of the root problem. Management attempting to incentivize achievement of the goal such as offering a financial award if the goal is achieved, may lead to inappropriate behaviors that do not address the real issue.

 

In these cases, it is generally not the metric that will drive the behavior but rather use of behavioral rewards. Reward for achievement rather than analysis of the real underlying causes will not lead to sustainable positive change. When managed properly, metrics are an important tool to help drive positive change and quality process improvements.

 

Quality Compliance

 

Upon observation, an unhealthy quality culture is easy to identify. People in a poor culture do not understand their job and its importance to the business. They often appear stressed, and they hide their mistakes or blame others for their errors. There is no evidence of teamwork.

 

People work in silos and rarely, if ever, seek input or advice from others. Metrics that could potentially be used to measure a poor culture include a large employee turnover, an overabundance of deviations attributed to human error, and lack of pride in the performance of employees’ jobs.

 

Product Validation

 

In contrast, a robust, healthy quality culture can be evidenced by alignment of goals between quality and operations. Product validation is a collaboration between self-sustained work teams that focus on continual improvement, and employees who incorporate quality into their daily jobs.

 

They are not afraid to speak up and offer suggestions for improvement to their colleagues. People understand the importance of their jobs and respect each other and their management. This culture welcomes inspections and views these inspections as another tool to use in their continual improvement initiatives. Metrics that could potentially be used to measure a healthy quality culture include a small employee turnover, deviations that identify a root cause other than human error, and pride in the performance of their jobs.

 

Conclusion

When establishing a metrics program, companies should evaluate numerous data input points including, but not limited to, product-quality attributes, manufacturing site performance, people metrics, and quality-system metrics. For product-quality metrics, companies should consider reporting on batch-specific data such as trending drug product, drug substance, and stability test results against customer complaint rates.

 

Indirect product-quality metrics could include environmental monitoring, water trend results, and yield rates. When establishing site metrics, the company could look at inspection history including internal audit findings and maintenance history such as equipment age versus defect-failure rates. People metrics should consider ongoing job-specific training and education, skills and experience assessments, and employee turnover rate by job function and site. Quality systems metrics might look at change control, investigation root-cause trends, and release-testing cycle times.

 

There is no set requirement on which metrics a company should track to measure their overall performance. Each company should determine which metrics to track based on their operations, number of facilities they operate and where they are located, what types of products they manufacture, and what type of culture exists in their places of business.

 

The metrics chosen must be meaningful and written to provide a clear analysis of ongoing activities. It is important for operations and quality to agree on the metrics and how to report them to management to avoid overreaction to the data. It is not sufficient to simply report the data. The interpretation of the data is of crucial importance because it may include a root-cause analysis of its own.

 

Article Details

Pharmaceutical Technology
Vol. 39, No. 9
Pages: 22–25

 

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CAPA Quality

A risk assessment should be performed as part of the CAPA quality process, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates.

 

Q: How much data do I need to support opening a corrective and preventive actions (CAPA)?

 

A: This is an interesting question because it raises the issue of whether a company is overusing or underusing the CAPA system. One data point is enough to open a CAPA depending on whether that data point is a significant occurrence. On the other hand, multiple similar deviations may be overlooked because they are deemed minor with little impact on operations. The most effective way to determine whether you should open a CAPA is to perform a risk assessment of the data.

 

Preventive Action

 

A single significant deviation, such as putting the wrong label on the product, should justify opening a CAPA. This type of production error carries a high risk. If the mislabeled product is released with the incorrect label, it creates a serious risk to patient safety. The CAPA is necessary because it enables users to determine preventative action needed to ensure the issue doesn’t recur.

 

CAPA Manufacturing

 

In addition, the CAPA will prompt the company to review data across manufacturing lines and manufacturing facilities so the corrective solution to prevent recurrence can be implemented across the company. An example of a CAPA manufacturing data point that does not necessarily need a CAPA opened might be a field complaint of a bottle of tablets that contained 99 instead of 100 tablets.

 

CAPA Audit

 

This occurrence should be investigated, but because it is low risk and more of an inconvenience to the patient, it may not require a CAPA. Opening a CAPA audit for this one event could be considered overusing the CAPA system.

 

CAPA Quality Assurance

 

However, if the complaint department tracks these data and finds a significant upward trend of short count bottles over a short period of time, a CAPA may be warranted. Underusing the CAPA system is also a concern. Not opening a CAPA when faced with data that suggests there is multiple occurrences of the same/similar deviation prevents the company from continuously improving processes.

 

CAPA Deviation

 

Let’s suppose that in reviewing deviations you notice that a few manufacturing employees have multiple deviations for the same minor issue in the same batch record over a short period of time. Assume the deviation has been determined to be human error and only retraining of the operators was performed.

 

CAPA Action

 

In this scenario, it would be prudent to open a CAPA for several reasons. First, human error is rarely the cause of a deviation. Second, obviously the retraining to prevent the error is not effective because the error keeps occurring. Third, the data is telling you about effectiveness issues with your process for investigating deviations & how it is implemented.

 

 

Data generated from quality systems (QMS) is often used to prevent an event from occurring. For example, a preventive action is used to correct potential problems, and try to address them before they happen. In the example above, you can review other batch records to determine if the operator deviations have the potential to reoccur. Finally, you can implement appropriate QMS corrections to those batch records once other product batch records are reviewed.

 

Conclusion

 

There is no hard and fast rule on how much data you need to open a CAPA. It could be one data point or several data points. The best tools to use to determine whether a CAPA is needed is a risk assessment of the data and common sense.

 

About the Article

RCA

 

 

 

 

 

Pharmaceutical Technology
Vol. 47, No. 4
Page: 50

 

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Considerations for Method Validation

Susan J. Schniepp, distinguished fellow for Regulatory Compliance Associates, and Shiri Hechter, senior lab operations manager for Nelson Laboratories, provide a simple approach to method validation and validating analytical methods.

 

Q. How can an analytical method be validated?

 

method validationA. When using an analytical method published in a pharmacopeia, the method is considered validated and it just needs to be verified under actual conditions of use. However, when using analytical methods for routine testing that are not published in the pharmacopeias, it is expected that the method would be validated.

 

United States Pharmacopeia

 

The United States Pharmacopeia defines validation of an analytical procedure as

 

“the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications”.

 

The European Directorate for the Quality of Medicines and HealthCare (EDQM), which publishes the European Pharmacopoeia (Ph. Eur.), takes a similar approach stating,

 

“This chapter defines the different analytical situations (categories) which might occur in an OMCL [official medicines control laboratories] and the corresponding validation characteristics which should be considered. Refer to the current version of the ICH [International Council for Harmonisation] guideline on ‘Validation of Analytical Procedures: Text and Methodology (Q2)’ ”.

 

Analytical Method Validation

 

The following examples of industry guidelines provide rationale and approach when validating analytical methods:

 

  • The United States Pharmacopeia–National Formulary (USP–NF) general chapter <1225> Validation of Compendial Procedures
  • PA/PH/OMCL (13) 82 R5, Validation/Verification of Analytical Procedures revised in July 2020
  • FDA’s Analytical Procedures and Methods Validation for Drugs and Biologics, Guidance for Industry, July 2015
  • ICH guideline Q2(R2) on validation of analytical procedures (currently under public consultation) published March 31, 2022.

 

These documents are inter-connected because they reference each other and the approach they define is based on defining “Typical analytical performance characteristics that should be considered in the validation of the types of procedures …”.

 

USP 1225

 

In USP General Chapter <1225>, some typical performance characteristics referred to are accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. These characteristics should all be considered when determining the validation approach for any analytical procedure.

 

Analytical Validation

 

USP <1225> aims at compendial procedures that include routine tests on raw materials and finished products. The FDA guidance covers new drug applications, abbreviated new drug applications, biologics license applications, and supplements to these applications. Definitions, data elements, and acceptance levels are well documented in these publications. Depending on the objectives of the analytical validation method, data elements could vary.

 

Method Qualification

 

For example, USP <1225> defines four categories for consideration. The chapter indicates that Category I–Assay, does not need to have detection limit, whereas Category II–Limit Tests, requires detection limit. The full data elements required for method qualification and validation are detailed in Table 2 in USP <1225>.

 

Validation Parameters

 

Similar instructions can be found in ICH guideline Q2(R2) table. The OMCL document also provides reference tables that discusses the source of the method (i.e., Ph. Eur. method, validated method form a manufacturer, etc.) and the validation parameters needed to ensure it is an appropriate method for its intended use.

 

In summary, when performing analytical method validation, validation parameters and elements are determined based on the analytical test method and the intended analytical application.

 

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Pharmaceutical Technology
Vol. 47, No. 2

 

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Name Changes and Re-Registration Navigation

Consider these common FDA registration scenarios: an acquisition or carve-out occurs, and a medical device has a new manufacturer, or a manufacturer decides to change its name as a result of restructuring. Both occurrences are common in today’s rapidly changing business environment.

 

After the dust settles when a name changes, it’s often up to company executives to complete the implementation plan and move the new business forward, often with little time or often with fewer resources. However, a manufacturer change or product name change requires modifications to the product labeling and regulatory re-registrations, which are increasingly complex. This article covers key steps required for successful reregistration and labeling changes while presenting strategies to avoid common pitfalls.

 

Name Change Requirements

 

fda registrationMost developed countries require a device to be registered, clearly displaying the legal manufacturer’s name. Abroad, outside the European Union (EU) and United States, about 40% of countries require a CE certificate to register the product. Roughly 20% of these countries require a certificate to foreign government (CFG) or certificate of free sale from the country of manufacture in order to register the product.

 

In the event of a company name change in the United States, FDA requires an update to the registration per 21 CFR 807.26 and 21 CFR 807.30. In the event of a name change for devices sold in the EU, an updated CE certificate is required based on the MDR 2017/745 classification of the medical device. All countries that have regulations concerning the marketing of medical devices require some sort of notification in the event of a company name change, which can range from a simple notification to a full reregistration.

 

Product Labeling

 

A changed company name also triggers the need to update the product labeling. In the United States, FDA requires registration within 30 days of commercial distribution of the device per 21 CFR 807. FDA 21 CFR 801 requires the name of the manufacturer to be conspicuously displayed on the product labeling. For product sold in the EU, the label must bear the name or trade name and address of the manufacturer per MDR 2017/745. This requirement applies to all countries that have regulations concerning medical devices.

 

Product labeling is a broad category covering areas including the actual product label, instructions for use, product inserts, packaging, and collateral such as brochures, catalogs, and other promotional vehicles.

 

FDA does not require updated labeling to be submitted in order to change the company name, but clearly expects that the company will be making a good faith effort to update the label copy in a timely manner.

 

Requirements Beyond U.S. Borders

 

For products sold to international markets, the requirements for each country must be researched and understood. In order to export the product, correct labeling and FDA registration is needed to obtain Certificates to Foreign Government (CFG).

 

While no blanket rules apply to requirements for all export countries, all countries require the label to match what is listed in the registration. For example, in the EU based on the latest 2021 MDR regulatory updates, the manufacturer information on the label must match the manufacturer information listed on the CE certificate and the Declaration of Conformity.

 

Outside of the EU, it’s not uncommon for CE and ISO certificates to be required as supporting documentation for registration. Each country has its own requirements, so it’s necessary to develop an individualized approach to gathering requirements and developing an implementation plan (see Table I).

 

Risks and Pitfalls: Revenue Delays

 

During the merger or acquisition process, the deal makers might not fully appreciate the reregistration workload or timeframe. This task typically falls upon technical executives after the deal is signed. All too often, the acquiring firm has limited technical staff and a narrow bandwidth to take on such extensive research let alone the implementation in every country, and this often results in revenue delays.

 

The technical executives must deliver the message about these delays to the management team, who made the deal expecting they were buying an established revenue stream from the legacy product.

 

One remedy for delayed revenues is to outsource the product reregistration process. Compliance consultants typically know the county-by-country requirements, which can help to eliminate the delays (see the sidebar “Potential Revenue Delays in Canada and Brazil”).

 

Ideally, the compliance consultants would be brought into the acquisition process during the due diligence stage. This introduction helps the acquiring firm anticipate revenue delays, quantify the reregistration costs, and identify any gaps in testing or technical data, which can be factored into the deal price and/or the post-transition agreements. For example, the post-deal transition agreement might require the seller to continue manufacturing the product until the buyer can reregister the product.

 

Cross-functional Complexities Behind Re-registrations

 

The reasons that drive product re-registrations are oftentimes fraught with cross-functional complexity. So while the technical team is reregistering the product and introducing new labeling into multiple manufacturing plants, they’re also responsible for complex tasks resulting from the acquisition.

 

This process could include transferring production, which will trigger reregistration in most countries, managing inventory across multiple country locations, and coordinating product with multiple distributors in various countries. It all takes place while the technical executives must remain focused on their primary job functions such as getting product out the door for sale to customers.

 

Manufacturing Transfer

 

Oftentimes the manufacturing location changes as part of the merger or acquisition. Acquiring firms may see value in aggregating plants or in transferring production. The resulting changes in manufacturing location must be included in the registration process.

 

The added registration complexities of changing location fall upon the shoulders of technical executives who have full plates with shutting down the old facilities while bringing new facilities onboard. In addition, they have the challenge of introducing new labeling into the manufacturing process, and a change in location can be a trigger for facility inspections in many countries.

 

Distribution Challenges

 

Introduction of new product and obsolescence of the old product requires coordination across manufacturing and distribution sites for each country. For countries with a long reregistration process, it means old product needs to be reserved. Other countries, such as Spain, will allow a mixture of old and new product to be imported but will fine the company for sending the old product after they start receiving the new product.

 

For some manufacturers with multiple distributors in each export country, the coordination is very complex and falls upon technical personnel already engaged in other aspects of the merger or acquisition.

 

Some countries allow for a transfer of registration between distributors with a short approval time, however other countries require new or reregistration when a distributor is changed as the distributor or in country representative is the owner of the registration.

 

Planning is Everything

 

A clearly laid-out plan that coordinates the registration with the labeling revision process and any potential manufacturing site changes is essential to ensure continued market access and channel inventory for the product. The plan provides visibility for introducing the newly labeled product into the various U.S. and export markets.

 

Conclusion

 

Changes to the company name require modifications to the labeling and reregistration of the product in every country of distribution. It requires a well-researched project plan that addresses the requirements of each country and coordinates cross-functional activities across the company. Given the complexity of determining and implementing the plan, experts recommend that companies determine the costs and potential revenue delays before embarking upon a name change.

 

In the case of mergers or acquisitions, it’s important that technical executives are part of the due diligence team so these costs and revenue delays can be factored into the deal price. When the technical executives are stretched thin between doing their day jobs and handling the reregistration, expert consultants can help quantify these costs and delays and are available to help implement the plan after the deal closes.

 

Complete article published on Medical Device and Diagnostic Industry.

 

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Quality Culture & Data Integrity

Among the current and emerging topics of interest to the pharmaceutical industry, the topics of quality metrics, quality culture, and data integrity are of particular concern to both the industry and regulatory authorities. The integrity of the data supporting product quality throughout the product life cycle has always been a priority for global regulatory authorities. Requirements specifying that data records need to be attributable, legible, contemporaneous, original, and accurate (ALCOA) have been included in regulations around the world for several decades. In addition to the ALCOA there is ALCOA+ which also requires data to be complete, consistent, enduring, and available.

 

regulatory complianceThe increase in data integrity observations has prompted the regulatory authorities to address the issue by releasing a series of guidelines that reemphasize the importance of data integrity. The U.S. Food and Drug Administration (FDA), Medicines and Healthcare Products Regulatory Association (MHRA), World Health Organization (WHO), and Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) have all released documents to reeducate the industry on data integrity concepts and expectations.

 

In addition to the regulatory guidelines, the Parenteral Drug Association (PDA) released a free document titled “Elements of a Code of Conduct for Data Integrity” to help address the problem.

 

Over the course of your career, you will run into data integrity situations that could have been mitigated if the company had a better-quality culture. Below are some real-life scenarios that demonstrate how data integrity and quality culture are linked and how either quality culture improves it or drives undesirable outcomes.

 

It is important to note that when we speak of quality culture, we are not describing the culture of the quality department. We are discussing the culture of the organization and what affect that imbedded, widespread culture had on the entire organization.

 

Situation 1: CMO Audited by a Client

 

A contract manufacturing organization (CMO) was being formally audited by a client and was asked for a training record. The particular training record was missing from the file. The Quality Assurance (QA) manager in charge of the audit chose to wait until the auditors left for the day and then asked the staff to do a comprehensive search for the missing training record.

 

The record was not located so the QA manager decided to reproduce the training record from memory and present it to the client in the morning. The auditor was suspicious of the record and indicated in his audit report that he felt there were data integrity issues at the site. The client listed the CMO as “at risk” based on the suspicion of falsification of data regarding the training record that was noted in the audit report.

 

When a new head of quality for the company was hired to help fix some of the risky behavior present at the company, they investigated the client concern and confirmed that the QA manager had falsified the record. The QA manager was fired and the new head of quality hired a third party to perform an in-depth audit to determine how imbedded the practice of falsification was in the organization.

 

As a result of the findings, several individuals were relieved of their quality responsibilities. It has taken the company two years to move from an “at risk” to “needs improvement” status as a result of this issue.

 

The situation described above is not unusual because records do occasionally get lost or misfiled. When this happens during a FDA audit, it is certainly embarrassing but not unrecoverable. The quality culture present in the organization condoned falsification and misdirection. The situation could have been could prevented if the organizational culture rewarded honesty.

 

If the QA manager had been forthcoming with the situation to the auditor it probably would have resulted in an observation, but if all the other training records were in order it would have been a minor observation easily addressed and corrective action outlined in the audit response. The auditor should have been told the record was missing and a commitment to retraining the individual as a part of the investigation into the missing training record would have been a more honest and understandable response.

 

The bottom line, there should be no tolerance for falsification and lying to any auditor and a company culture that elicits this type of response is neither desirable or effective and has a detrimental impact on the entire business. When the QA manager chose to falsify and lie to the auditor, it sent a message to the entire organization that this type of behavior was acceptable. The new head of quality quickly corrected this misconception. The outcome of lying to a client was bad enough, and the outcome could have been much worse had this been done during an inspection by a regulatory authority.

 

Situation 2: Company Audited by a Regulatory Authority

 

In this next scenario, a company is being audited by a regulatory authority. They are reviewing the equipment validation/qualification program and they ask to see the most recent qualification for a depyrogenation oven that was the subject of a previous audit observation. The qualification for that oven has an investigation associated with it. The investigation was because the temperature recorder was out of tolerance and recording temperatures higher than the actual oven temperature.

 

In other words, the vials being depyrogenated were not exposed to the optimal condition leaving a question in the auditor’s mind as to whether the vials and the product in them were safe. The last passing qualification for the temperature recorder was two years ago and the investigation has no product impact assessment to justify the safety of the product. One of the inspectors asks the head of quality to justify why this issue should not be considered a public health issue. He indicates that he will expect a response before the close of the day. The culture present in the company may dictate what response you give the inspector.

 

If you have a poor quality culture, the response might be to tell the auditor that even though the chart recorder was recording an incorrect temperature you are confident that the oven was hot enough and the cycles were long enough to kill the pyrogen so the product is safe. The temperature recorder has been fixed and there should be no issues as described in a book explaining the principles of depyrogenation.

 

An acceptable quality culture would elicit a more thoughtful response supported by data and information collected on a daily basis. An effective response would indicate there is no risk to the product because of the endotoxin monitoring that is performed as follows:

 

  1. The Water for Injection (WFI) is monitored daily for endotoxin.
  2. The raw materials being used to manufacture the product, including the active pharmaceutical ingredient (API), is tested for endotoxin as part of incoming receipt.
  3. The glass is tested for endotoxin as part of incoming release.
  4. Each lot of product is tested for endotoxin as part of the final product acceptance criteria.
  5. There have been no complaints for the affected products during the last two years.

 

In this case, the CMO was being inspected by a regulatory authority. The inspector said they agreed with the assessment and the data supporting the statement should be included in the official 483 response. The inspector also indicated he would not make this a public health issue. The company included two years of data in their response. The only comment from the agency was to provide additional data to cover the products from the last successful calibration to the time the current calibration.

 

Situation 3: Company’s Quality Culture has the Wrong Focus

 

This situation demonstrates how an organizational culture can impact the investigation process. The company in question is very proud of their ability to complete 95% of deviations/investigations within 30 days. The company has hired a new head of quality and this person decides to familiarize themselves with the investigation/deviations that have occurred over the last six months.

 

During the review, they discover that one operator on the second shift has 25 separate batch record deviations for failing to sign critical documentation for a particular product. The deviations all indicate the operator has been retrained and the root cause of the deviation is listed as human error.

 

The new head of quality brings this information to the attention of the staff and whether the operator in question is suitable for the job they perform based on the high incident of repeat deviations for the same issue. The staff assures the head of quality that the operator is an excellent employee and also one of the most conscientious operators in the organization. The head of quality asks if the operator was appropriately interviewed and the staff indicates that they know the operator has a problem, but they feel that retraining is suitable.

 

Not satisfied with this answer the new head of quality decides to personally interview the operator in question. In the interview the operator tells the head of quality that in order to sign the batch record when indicated they need to leave the manufacturing area and leave the product unattended while they de-gown, sign the batch record, re-gown and reenter the manufacturing area. The operator says he does not think this is a good practice and has been requesting the batch record be revised, but the only outcome so far has been that he gets retrained and reprimanded.

 

In this scenario, the quality culture focuses on timeliness rather than getting to root cause. If the emphasis of the culture was on thorough and complete investigation, the root cause of human error for the same repeat deviation would have been noticed and corrective action initiated. The real data integrity issue here is not the repeat deviation but the action of the other operators. Clearly, the operator in question was concerned with product safety because he felt it wasn’t appropriate to leave the product unattended. The question to be answered is how the other operators were handling the signing of the batch record and what risk there was to the product.

 

Conclusion: Good Quality Culture Improves Data Integrity

 

It is important to understand that your quality culture is linked to data integrity. Once you acknowledge this relationship you can perform a necessary risk assessment, identify vulnerabilities, and remediate your risks before an inspection. Regulators have clearly delineated through the guidance documents that there is a link between the culture of an organization and the veracity of the data being generated. In the future, it is anticipated that audits will focus on determining the health of an organization based on their culture and the data it supports.

 

regulatory compliance

 

Published by MasterControl
Susan Schniepp, Distinguished Fellow
Regulatory Compliance Associates® Inc.

 

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