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Root Cause Analysis and Deviations

Q. What is a deviation & do all deviations need a root cause analysis?

 

A. A deviation is when there is a failure to follow the instructions guiding the performance of an activity. The purpose behind understanding a standard deviation is critical to execute for optimal results. Simply put, deviations result from people not following their standard operating procedures (SOP) and is often the root cause analysis of many quality problems.

 

For example, deviation meaning can often be based on work instructions or batch record instructions. A root analysis often starts with documents that explain how a team performs certain functions or tasks. Deviation investigations related to non-compliance look to determine the root cause of the problem. While not all SOP deviation issues are equal in their impact on root cause, any quality deviation should be investigated. The basics of this investigation is historically considered the “five whys”  (or 5whys). 

 

Q. What is a planned deviation?

 

A. In our opinion, there is no such thing as a planned deviation. Planned deviations were often a SOP deviation supposed to justify changes from SOPs that would be utilized to carry out the operation over a certain period of time.

 

The current thinking by regulatory authorities is there is no such thing as a planned deviation. During a breakfast session at a recent PDA  Joint Regulatory Conference, a representative from the FDA stated, “it’s a very strange term, and it kind of makes your skin crawl a little bit”.

 

If you need to make a CAPA deviation change to a procedure, we suggest using the change control system to document. This may seem like a picky point in average deviation process flow. However, until the change is evaluated in process validation requirements, a short term deviation is still non compliance. The deviation process in manufacturing must product reliable and durable solutions. This standard deviation step by step process can only help to reduce quality issues in the long term, especially for large deviation issues. 

 

Q. What’s the best process for investigating deviations?

 

A. There is no single best process for investigating deviations. The ultimate goal of deviation investigations is to determine why something went wrong in the final pharmaceutical deviation report. Above all, understand what caused the deviation to go wrong and how to address the issue from reoccurring. To achieve successful resolution of deviations, keep the following in mind when searching for types of root causes:

 

  • A one-size investigation doesn’t fit all situations. Simple errors require simple documentation while more serious deviations require broader investigations.
  • The best tool to have is inquisitiveness during the 5why analysis. Ask yourself how far this process deviation could extend.
  • Widen your perspective. Look for ways to relate, not separate, similar issues across CAPA deviation investigations.
  • Human error in the 5whys is rarely a sufficient root cause.
  • Always verify information or your instincts and never assume you are correct without proper data to support your instincts.

 

Q. Why is human error not an acceptable finding for deviations?

 

A. The overuse of human error as a root cause to a deviation represents lost opportunities to reduce future issues. A root cause analysis must identity of the true root cause of the problem and not mask it. Sometimes in a rush to get to the root of the problem, the problem lies within the human error inside human error. 

 

There is a bigger root cause corrective action question that needs to be considered. The initial investigation should determine what the root causes are that led the employee to make the human error. Asking this question early in the root analysis leads to better identification for continuous improvement. It can also solidify agreement in the team regarding the cause analysis associated with improvement priorities. 

 

Root Cause Analysis Example

 

Let’s look at types of root causes that might help clarify examples of why human error can mask the real root cause of a deviation. Suppose, for example, you have a second shift manufacturing operator who continually forgets to sign the batch record for a specific product. This operator is the only one who seems to have this issue. Your initial investigation into the first occurrence of the issue determines a root cause of human error.

 

Because the operator works the second shift, it is inconvenient to interview him and find the root problem. This relies on the word of his supervisor as an important source that influences the root cause corrective action, which may not be the whole story. This small factor can impact the root causes of the bigger issue while the team may not recognize the significance. 

 

Root Cause Failure Analysis

 

You decide to retrain the operator on the proper use of filling out the form and skip the operator interview. This helps to increase the speed of the root cause failure analysis in order to complete the investigation in the allotted 30-day time frame. This scenario repeats itself 10 times over the course of four months. You finally decide to interview the operator directly after the root cause investigation is completed.

 

When you talk to the operator, he informs you of the process to sign the batch record when it needs to be signed. He must exit the aseptic core, degown and sign the batch record. Now, you finally begin to determine the root cause meaning based on the common repetition of employee actions. 

 

Root Analysis and Process Flow

 

The root cause analysis deviation unveils the operator leaves the product unattended when signing the batch record. After signing the batch record, he must then regown and return to work.  The operator tells you he chose to stay with the product and sign the batch record later. Consequently, he sometimes forgets to sign after the manufacturing run. In this simple exchange with the operator, you find the root cause of the repeat deviation is not a result of human error but a result of poor process flow.

 

Q. How much time should I allow for a deviation to be investigated?

 

A. Interpreting standard deviation often depends on the length of time it takes to complete an investigation. This can change depending on the complexity of the circumstances involved. Simple deviations can be completed in a short time frame, but more involved deviations will take longer. We recommend you set a root cause investigation time frame that is reasonable for the size of your organization. For example, you might indicate that investigations will be completed between 30–60 days after the documented deviation. This gives you some flexibility to conduct a proper search during root cause problem solving.

 

Q. Are out-of-specification (OOS) results considered deviations?

 

A. No. OOS results need to be investigated separately due to the potential impact to the product. If the root cause of the OOS cannot be attributed to laboratory error, you should initiate a deviation/investigation.  Additionally, a separate root cause tree can help determine what happened during product manufacturing that led to the erroneous laboratory result.

 

Published:

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Pharmaceutical Technology

Volume 45, Issue 4

Pages: 66, 65

 

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CDMO’s & Contract Manufacturers

What is a CDMO?

A CDMO is a Contract Development and Manufacturing Organization. These are companies in the pharmaceutical, biotechnology, and medical device industries that provide outsourced services to other companies, typically pharmaceutical or biotech firms.

 

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, discusses the basics for maintaining an acceptable working relationship between a client and their CDMO.

 

Q. I work for a small company with a few products in the development phase. I am reviewing several CDMO (contract development and manufacturing organizations) partners to determine which one best fits our needs. Can you give me some general guidance on what I should look for when choosing an appropriate partner?

 

A. Contract manufacturing continues to be one of the fastest growing segments of the pharmaceutical industry. There are many small companies with products in development who do not own manufacturing facilities and must utilize CDMO partners to handle their development and manufacturing needs from clinical to commercial product. It is important for both parties to be invested and respectful in the relationship because it is a long-term commitment.

 

Contract Manufacturing Organization

 

The first step in this relationship is to establish a quality agreement (1–3). If we view the relationship between the two parties as an equation it would be:

A + B + C + D = E

 

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A represents needs of the CDMO, B represents the client needs, C represents the compliance requirements, D represents the regulatory commitments for both parties, and E represents the quality agreement/quality relationship between the two organizations.

 

CDMO Services

 

As we break the equation down a bit more, there there is more CDMO meaning behind each of the variables.

 

“Variable A” should take into account the needs of the CDMO. This includes auditing, testing, material sourcing, and any special client needs required to successfully manufacture the product. When defining the contract development organization responsibilities, the CDMO should consider determining the amount of involvement of the client(s) for all audit types.

 

CDMO Manufacturing

 

“Variable B” represents the client needs and should take into consideration unique account requirements. For example, there will be differences between a Biopharma CDMO, a Biologics CDMO and CDMO Pharma companies. This often includes data driven development, USFDA registration commitments and specific sourcing strategies. The client should also inform the CDMO of any additional quality agreements that are associated with pharmaceutical manufacturing.

 

At one point in my career, I worked for a small start-up company which had three quality agreements associated with one product in clinical trials. The three agreements were for three different contract organizations. One CDMO organization was manufacturing the material, another was performing the release testing, and the final one was performing the product labeling. These complicated relationships should be disclosed to all involved parties so communication between organizations can be optimized, particularly when issues arise.

 

Compliance

 

“Variable C” represents compliance requirements of the CDMO. This is often influenced by multiple customers, regulatory agencies, and regulatory bodies. Company standard operation procedures (SOPs) (4–6), client SOPs, audit observations, and compendial requirements define this element of our equation. Clients should be aware that CDMOs are usually global in nature and may have obligations to meet compendial requirements of the United States Pharmacopeia–National Formulary (USP–NF), the European Pharmacopoeia (Ph.Eur.), and the Japanese Pharmacopoeia (JP) (7).

 

In my opinion, this would be the optimal section to include the communication expectations for regulatory audits conducted either at the CDMO or the client’s business locations. The need for the CDMO to communicate with the client when a regulatory audit is being performed at their facility is evident, but it is equally important that the client communicates with the CDMO when the positions are reversed. This two-way communication is crucial because each organization could be vulnerable based on the audit outcome regardless of where the audit was conducted.

 

Regulatory

 

The final variable in this equation is “Variable D”. Variable D considers the regulatory commitments of the client and/or the CDMO. Regulatory commitments are the evolving body of knowledge made up of new or impending regulations or guidelines that may require changes in operations in order to meet the expectations of the new requirements. A CDMO must communicate changes and commitments affecting their quality system to their client and vice versa because these changes may affect regulatory filings.

 

Quality

 

Finally, the solution to the equation is “Variable E”, which represents the robust quality agreement. The quality agreement should be a living, breathing document that is reviewed and revised as often as needed to clarify both party’s responsibilities and avoid conflict of responsibilities to ensure a successful partnership.

 

Contract Manufacturing

 

The relationship between the client and the CDMO is important and complex. Both parties need to be knowledgeable on the application and interpretations of the regulations. Each should work through any opposing opinions to reach an interpretation that works for both parties. A cooperative working relationship can be achieved if each party clearly identifies and communicates their needs through an effective quality agreement.

 

Article details

 

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Pharmaceutical Technology
Vol. 46, No. 6
Page: 50

 

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Standard Operating Procedure (SOPs)

The amount of quality assurance detail included in Standard Operating Procedures (SOP) may help a company stay QA compliant, says Susan J. Schniepp, Distinguished Fellow at Regulatory Compliance Associates, Inc.

 

Q. I am responsible for updating my company’s standard operating procedures (SOPs). My company has been cited several times in audits for not following them, and this situation has worsened since the onset of the pandemic. What advice do you have for me to make sure the SOPs are being followed for now and in the future?

 

A. You are not alone. Not following or having adequate procedures in writing continues to be one of the top SOP observations for the industry in 2021. Companies usually use their SOP to show that they have control over manufacturing processes, thereby demonstrating compliance with regulatory expectations. Both QA testing and QA engineering have even more stringent expectations in SaMD (software as a medical device) products. 

 

The problem you are having with your SOPs seems to be an ongoing issue not necessarily related to the pandemic. It would seem this situation is exacerbated by the pandemic but not caused by the pandemic. My advice to you would be to take a holistic look at how you create, implement, and modify your SOPs.

 

SOP Compliance

 

There are four simple concepts to keep in mind for having compliant SOPs: Say what you do, do what you say, prove it, improve it. The ‘say what you do’ phrase equates to the written SOP that defines the steps to achieve compliance to a regulatory requirement.

 

‘Do what you say’ equates to following the SOP. ‘Prove it’ means that you need to collect and be able to present data that indicate you have followed the instructions in your SOP and have investigated any incidents where you have deviated from those instructions.

 

SOP Process Improvements

 

Once you have mastered these concepts, you can begin to work on the ‘improve it’ concept by revising and updating your SOPs to reflect current practice and process improvements. These concepts are simple enough to follow, so the being cited by regulators for not following SOPs is disappointing.

 

Previously in this column, we have discussed the elements of Standard Operating Procedures. The problem you are having seems to be related to the SOP content.

 

SOP Writing

 

To address this particular problem, you need to be aware of some of the pitfalls companies encounter when writing SOPs. Writing an SOP with the correct amount of information in it—neither too restrictive nor too ambiguous—is not an easy task. It takes time and effort to create an SOP with the right balance of information.

 

SOP Pitfalls

 

The three most common pitfalls when writing an SOP are providing too much information, providing too little information, and providing unneeded specific information. Quality assurance is always built upon a foundation of clear and concise data. Quality control engineering necessitates that a quality assurance inspection would fail without it. 

 

Providing too much information in Standard Operating Procedures results in a restrictive process with deviations. An example of too much information in an SOP would be listing the serial number for a piece of equipment. Should the piece of equipment need to be changed for any reason, the result is a deviation and an SOP that can’t be followed.

 

Equipment SOP 

 

When listing equipment requirements in an SOP, a Quality Analyst should be able to describe the piece of equipment but not necessarily to the serial number. It would be best to provide a list of the equipment needed with a general description of its function and capability. Additionally, the QA Manager should have a deeper level of knowledge about the QA process and be able to speak to the equipment validation.

 

FDA inspection SOPWhen an SOP provides too little information, it results in an out-of-control operating process that generates deviations. When there is lack of clarity, it allows for interpretation by the operator.

 

SOP Operators

 

There is the potential for each individual executing the process to interpret the instructions in their own unique way resulting in deviations that need to be investigated and the potential for the regulatory citation of insufficient SOPs.

 

An example of a quality assurance program with too little information for operators includes not specifying the order reagents need to be added to generate a reaction. If it is critical to add the reagents in a certain order, that information needs to be specified in the Standard Operating Procedures.

 

SOP Information

 

Quality control plans with SOPs that provide unneeded specific information are also problematic. An example of unneeded specific information might be how dates are recorded in a document. A company needs to be consistent in the way the date is recorded. The order of the day, month, and year can be flexible regarding the information being separated by hyphens or slashes. There is no difference between DD/MM/YY and DD-MM-YY. Specifying hyphens versus slashes sets you up for deviations that waste time and resources.

 

Other potential pitfalls for QA teams to avoid are providing ambiguous information. Similarly, restricting access to SOPs or allowing access to obsolete SOPs can lead to data integrity issues. Finally, having unnecessary SOPs or not providing clear instructions for recording data inhibits the culture of quality.

 

Effective SOP

 

Writing effective Standard Operating Procedures and keeping it current is not an easy task. It requires time, effort, and cooperation with the users to achieve the correct balance. Both quality control and quality assurance take time to develop and improve toward the end state. 

 

Employees must use a process that is easily followed, specifies the correct data, records the current operations, and can be improved. Taking a critical look at the level and detail provided in your SOPs involves right sizing the information. For example, accurately reflecting your operations will help in eliminating an audit observation. Above all, not following SOPs or having insufficient SOPs must be addressed to help improve your compliance position.

 

Article Details

Pharmaceutical Technology
Volume 44, Number 10
Pages: 74, 73

 

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Extractables and Leachables

Q: I am a regulatory professional working for a small company with a product in the early stages of development. Can you tell me when I need to submit the extractables and leachables information for my product?

 

A: There is a lot of information on what extractables and leachables are but there is little information on when this information should be submitted to the regulatory authorities. The best place to start in answering your question is to define what extractables and leachables (E&L) are and why they are considered important.

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Extractables are defined as chemical compounds that can be pulled from the primary container/closure components into the drug product. Basically, they are generated by the product and the packaging interacting over time, usually in the presence of a solvent under extreme condition of time and temperature.

 

Leachables are slightly different and are defined as compounds that leach or migrate into the product from the interaction between the product and the container/closure system.

 

Extractable and Leachable FDA Guidance

 

The regulatory requirements that justify performing E&L studies are defined by 21 Code of Federal Regulations (CFR) 211.94(a), which states:

 

“Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements”.

 

Regulation 21 CFR 600.11(h) states:

 

“All final containers and closures shall be made of material that will not hasten the deterioration of the product or otherwise render it less suitable for the intended use. All final containers and closures shall be clean and free of surface solids, leachable contaminants, and other materials that will hasten the deterioration of the product or otherwise render it less suitable for the intended use”.

 

Extractables and Leachables Testing

 

While the regulations in the United States seem to deal with extractable/leachables from the container/closure system, when deciding what to submit in your registration you should also consider your manufacturing equipment as potential sources of each extractable and leachability test.

 

This can include, but is not limited to, filters, tubing, and/or equipment materials of construction as indicated in the European regulations.

 

In Europe, EudraLex Volume 4, Part 1, Chapter 3 addresses the extractable/leachable concept by stating:

 

“Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to such an extent that it will affect the quality of the product and thus present a hazard”.

 

Traditionally, E&L data were gathered and submitted in the late stages of the drug development process. Packaging suppliers were often able to provide an extractable/leachable package for their materials to the pharmaceutical manufacturer in a format that could be submitted directly to the agencies. Lately, regulatory authorities are requesting this type of information for early stage clinical trial material. This change seems to have come about during the past few years.

 

FDA Extractables and Leachables

 

The extractables and leachables profile in clinical trial material has become a growing concern for regulatory authorities. Submissions for advances in unique packaging materials, and new and novel formulations continue to increase. New drug delivery systems often include new combination products being introduced. This has led to an increase in the emergence of biologics and biosimilars, and the increasing use of single-use disposables systems for manufacturing.

 

Why we need to submit this information is clear, but when to submit the E&L data depends on the product type, the container and closure system being used, as well as the materials and equipment used in manufacturing. If you are developing a generic with the same active and packaging components as the brand drug, the E&L report can be submitted and be available later in the process.

 

E&L Studies

 

If this is a new novel product associated with clinical trials or an old active being reformulated into a new dosage form (e.g., from a tablet to an injection) then you should probably have the E&L report much earlier in the process.

 

If you are updating the manufacturing process of an old product to use single-use disposable systems, you should include the E&L information as early in the filing update as possible. If you are developing a new, novel product using unique packaging components and new manufacturing advancements, this information should be evaluated early in the development of the product and be available to regulators as soon as is feasible.

 

Bottom line, there is no clear rule or guidance on when you need to submit E&L data. It depends on the type of product, the packaging materials being used, and the process and materials used to manufacture the product. Performing a risk evaluation on your product by asking the above questions can help your company determine when to have the extractable/leachable information available so the approval process is not delayed, and your product can be available for patients as soon as possible.

 

Article Details

 

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Pharmaceutical Technology
Vol. 42, No. 8
Page: 66

 

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FDA Inspection Procedure

Q: Companies have made a lot of operational changes to accommodate working through the pandemic. What changes do you think will become permanent in FDA inspection procedure as a result of the pandemic?

 

A: There are a number of operational changes that companies have made to accommodate working through the pandemic. Many of the changes were implemented out of necessity. That is to say, some of the changes have the potential to become normal operating procedures. Patients still need life-saving medicines. Likewise, companies need to find ways to continue manufacturing safe, effective, and compliant products. Conducting virtual audits, virtual training, and enhancing communications with suppliers are among the changes implemented. The goal is to ensure an uninterrupted supply chain to maintain operations and stay compliant. Each of the changes have positive and negative aspects that need to be evaluated to determine if they are effective.

 

Virtual Audit Procedures

 

Moving to virtual audits was one of the first changes that was implemented by companies and regulatory authorities. The necessity for virtual audits was to allow companies and regulators to continue to evaluate the compliance stature of manufacturers while respecting stay-at-home and social distancing requirements that prevented in-person site audits.

 

There are many advantages of performing virtual audits and the key to making a virtual audit successful is preparation and communication. Informational (organizational charts, standard operating procedures, quality manual, etc.) requests should be made prior to the audit, and the requested documents should be reviewed before the commencement of the audit.

 

Documentation Procedures

 

Companies can save time and reduce travel expenditures because people will be reviewing documents from home offices. The documentation required for in-person audits will be the same as virtual audits, but rather than making copies for the auditor, the documents can be turned into a PDF file and be sent through a secure system to the requester. Questions regarding the documentation can be addressed through a number of virtual platforms as long as the platform chosen is acceptable to both parties.

 

FDA Inspection Facility Tour Procedures

 

Performing a tour of the facility poses unique challenges, and possible solutions need to be vetted between the two parties to determine the most efficient and secure way to share this information. The bottom line is that virtual audits have the potential to be as effective as in-person audits and perhaps maybe more time efficient and cost-effective.

 

FDA Inspection Virtual Training Procedures

The same principles applied to conducting virtual audits can also be applied to training. On-line training programs have been used to train remote employees for years. There are a number of technological platforms that can be used to deliver virtual training programs to employees. These platforms allow training material to be pre-recorded and comprehension questions that must be answered correctly in order to continue with the training can be inserted. Remote training allows the employee to complete the training as their schedule allows.

 

Another approach is to deliver the training as a webinar using a multiple-person meeting application. You can prepare and distribute the information you will cover in the training, schedule a meeting time, deliver the training, and take questions from the employees during the webinar. If you have multiple manufacturing shifts, you can schedule a training session during each shift to make it easier for second- and third-shift employees to receive the training.

 

Additionally, virtual training can be enhanced by taking advantage of online training and conference options offered by external organizations. Many external organizations have converted their conferences and training topics to virtual offerings covering a wide variety of topics. Some of these venues are free, and some require a registration fee.

 

FDA Inspection Supply Chain Procedures

 

Enhanced communication with suppliers to ensure an uninterrupted supply chain has also become a priority during the pandemic. Many companies are reviewing and enhancing their quality agreements. This is a positive change for the industry as a whole.

 

The quality agreement should be a living document that is reviewed and revised as often as needed to clarify the responsibilities of the client and the supplier and define how the two parties will communicate with each other. The agreement should clearly identify the roles and responsibilities needed for a successful partnership.

 

FDA Inspection Supplier Quality Procedures

 

Defining the quality relationship between a supplier and a client is complex and requires extensive discussion and attention to detail. The relationship should be open, and communication between the two parties should be as frequent as required to assure that the product being manufactured meets the highest quality standards for the client and for the patients. Bottom line is that quality agreements are important documents for ensuring the supply chain procedures during the pandemic. This is a welcome change that should carry forward in the future.

 

There are many changes that have the potential to become permanent procedures or operating principles even after the pandemic. Three that should become permanent in the future are the use of virtual audits, the implementation and utilizations of virtual training, and more robust quality agreements that enhance communications between the client and the supplier.

 

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Quality Risk Management Guidelines

Q. I have heard that the International Council for Harmonization’s (ICH’s) Q9 Quality Risk Management is being revised. Do you know what the industry can expect to see with the new version of the risk management guidelines?

 

A. You have heard correctly. The guideline was first published in 2005 and, at the time of publication, it offered an overview of general quality risk management (QRM) principles including an example of a risk management lifecycle approach.

 

Risk Management Program

 

In addition, the guideline provided a list of risk tools and quality system areas critical to establishing and maintaining an effective risk management program. As stated on the ICH website, “This Guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality.

 

These aspects include development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging and labeling materials in drug (medicinal) products, biological and biotechnological products)”.

 

Risk Management Guidelines

 

Over the past 15 years, the industry has tried to implement risk management guidelines and principles as a part of their quality management systems. The introduction to ICH Q9 states,

 

“Although there are some examples of the use of QRM in the Pharma industry today, they are limited and do not represent the full contributions that risk management has to offer”.

 

This statement still holds true today as citations for incomplete corrective action and preventive action (CAPA)/investigations typically ranks in the top five inspectional observations for the pharmaceutical and biopharmaceutical industries.

 

QRM

 

To date, QRM implementation has used simple investigational tools to solve simple problems. In addition, the industry seems to struggle with providing data or metrics to demonstrate that information from investigation results have been used to effect continuous improvement.

 

Speakers at the PDA conference also talked about some of the challenges the industry has faced in trying to implement QRM. These reasons include using QRM to justify actions instead of assessing risk and substituting risk-assessment tools for the QRM process. Other problems that seem to prevent effective implementation of QRM is using it to confirm a hypothesis or rationalize non-compliance situations.

 

ICH 9

 

Understanding the original purpose of ICH Q9 is crucial in understanding what the industry might see in terms of its revision. Current thinking, as discussed at the PDA conference, is that the EWG will focus on clarifying certain aspects of the document’s concepts in an addendum to the document. Basically, the document itself will probably not be revised but instead will be enhanced by creating a partnering document that will focus more on ‘how to do’ and less on ‘what to do’ with respect to QRM.

 

The ICH Steering Committee approved the Q9 revised concept paper in 2019, and the EWG is expected to begin working on the revision at the ICH spring meeting. A development integrated addendum according to ICH parlance means only specific sections of the guideline will be targeted for revision but a complete revision is off the table.

 

QRM System

 

It is unclear whether the ICH Q9 revision will become more of a QRM tutorial or whether it will clarify what needs to be achieved in order for a QRM system to be considered robust and effective. To accomplish the vision of making appropriate and acceptable risk-based decisions, QRM needs to be iterative and not a once-and-done exercise within the quality management system. An effective QRM system should implement a risk review program to facilitate continuous improvement efforts.

 

At a recent PDA conference, attendees were given an opportunity to tell EWG representatives what they felt needed to be added or clarified in ICH Q9. They were asked to answer the following question: If you could recommend changes to ICH Q9, Quality Risk Management, what would you recommend? The information will be provided to the EWG representatives for consideration when they begin work enhancing the document and will be posted on the PDA Letter website.

 

Some of the recommendations were as follows:

 

  • Ensure that QRM is recognized by FDA as a required quality system. Currently, the European Medicines Agency (EMA) is more likely to inspect for QRM. There should be consensus regarding more alignment between Europe and the United States on QRM.
  • Include a standardized CAPA.
  • Remove the perception that QRM is not enforced and not part of the quality system.
  • Include language that drives a holistic systems approach.
  • Provide examples or a case study featuring a QRM tool.
  • Expand clarity on the training and documentation needed for applying QRM.
  • Clarify difference between risk evaluation and risk control.
  • Define roles, particularly decision-maker roles.
  • Provide more guidance on risk acceptance.
  • Provide additional examples such as how to apply QRM to legacy products.
  • Include examples of communication flow.
  • Clarify levels of maturity for QRM in enterprise risk management.
  • Offer strategies for demonstrating QRM compliance to regulators.
  • Recommend how to prioritize compliance versus patient safety concerns.

 

Continuous Improvement

 

Bottom line, ICH Q9 is scheduled to be revised, but the risk management guidelines to be revised have yet to be identified. There is no timeline available for completion of the revision. Industry has provided feedback to representatives of the EWG on some of their thoughts on what needs to be clarified so that implementation of an effective QRM program can be achieved, and the industry can drive toward continuous improvement realizing what Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, described as:

 

“A maximally efficient, agile, flexible, pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight”.

 

Article Details

 

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Pharmaceutical Technology
Vol. 44, No. 2
Pages: 58, 57

 

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