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Conducting an Internal Audit

The internal audit function of life science companies is one cornerstone of an effective and efficient quality management system. There are several types of audits that comprise a robust internal control program including supplier audits, internal audits, and regulatory audits.

 

Compliance Audit

 

Compliance audit documents to be reviewed include the quality manual, list of standard operating procedures, open deviations, and corrective and preventive actions. Any additional supporting evidence an ISO audit team may choose to review will help the certified auditor team assess and decide the final facility compliance status.

 

Forensic Audit

 

Preparing for a forensic audit or regulatory audit typically consists of the regulatory inspector providing the facility being audit agenda. This listing would include any areas of the audit mentioned in a FDA 483 and audit trail documents. The audit report will focus on life science departments to be inspected. This can include incoming raw materials, quality control, chemistry and microbiology laboratories and manufacturing. 

 

IT Audit

 

Conducting an IT audit is also critical in times like these of high cybersecurity concerns. Internal audits are performed by the company as a self-assessment for the purpose of identifying areas/issues that might affect their IT compliance status. This specific audit committee may include employees from across the company to intentionally examine IT process and quality from a cross-functional perspective. 

 

Audit Committees

 

Preparing for an internal audit requires the same discipline as preparing for supplier and regulatory audits. This includes audit committees and the number of employees involved in the process. During the COVID-19 pandemic, many companies reduced the number of employees allowed at an audit site. Many of the other audit committee who helped conduct the audit were allowed to work remotely. It is important to consider where employees are globally and the role they each play during an internal audit. 

 

Internal audits are part of management team responsibilities. Conducting an internal audit is different from the other audit types, whether it is pre-, during, or post-pandemic. If designed and implemented appropriately, there is great value in the internal audit. It allows the company to find vulnerabilities in their systems and remediate before they are discovered by an external auditor.

 

Audit Procedures

 

Internal audits can provide valuable information that can be used to prevent issues before they become compliance concerns. Audit procedures often help develop a remediation plan to take action to mitigate compliance problems. Having corrective actions in place before others identify the issue may lessen the impact of the observation. Most importantly, show there is a process in place for continuous improvement. In addition, the internal audit can be used for training staff and communicating valuable information to the organization.

 

Audit Schedule

 

The ideal tone for an internal audit should be a collaborative team-oriented activity that is instructive, informative, open, honest, and inclusive. There are several factors that help contribute to establishing this tone. The most successful is hiring a certified information system auditor to help guide the process. 

 

Another way to set the proper tone is to publish the audit schedule or agenda in advance. This makes sure the functional areas personnel are informed of the time schedule. During a pandemic, the agenda takes on another level of importance because it ensures the proper documents are ready to go. Teams should upload all data either before or during the audit. Prior planning precludes poor performance in this area.

 

Audit Office

 

Each of these specific audits requires preparation to make sure the forensic audit is productive and accomplishes its intended purpose. In the manufacturing world, the goal of the audit office is to ensure facilities are manufacturing fit-for-use products in full adherence. This includes meeting current good manufacturing practice (CGMP) requirements.

 

Audit Trail

 

Supplier audits are performed to confirm the audit trail of raw materials, packaging, labeling components, etc.. An effective audit trail should provide documentation of a continuous, uninterrupted supply of materials that are compliant with CGMPs. Regulatory authorities perform inspections to determine if the manufacturing company is providing materials that comply to CGMPs.

 

Audit Risk

 

An operations audit conducted requires documents be shared electronically to the auditor using secure electronic systems. This electronic exchange helps reduce audit risk by increasing the efficiency between independent auditor and a facility being audited. The quality audit documentation can be reviewed by the auditor, and questions can be communicated to the audit manager via email, conference calls or virtual technology. While this may not be ideal, because it eliminates the audit planning in-person interaction, it is still an effective way to conduct a system audit.

 

Facility Audit Tour

 

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Touring the facility is challenging when a virtual audit or external audit is conducted. These challenges can be overcome with some flexibility and ingenuity. Live video feed could be streamed to the auditor while the company’s audit manager and/or subject matter experts are available. This can help answer questions that might arise during the live videoconference.

 

Audit Video Recording

 

Additionally, the operational audit could be recorded, and that recording could be provided to the auditor. The understanding would include the audit manager being available to answer any questions upon the review of the video. The recorded version of the tour has both positives and negatives. For example, a certified auditor needs to see things in as real time as much as possible. However, it does allow for the auditor to pause and go back to review audit control processes in more detail if warranted.

 

Audit Issues

 

The auditors should work with the functional area and talk with as many employees as possible to identify the issues of concern. Individuals who are responsible for performing the day-to-day activities often have the best insight. Questions would include what is currently working and what needs to be improved.

 

Excluding them from participating in the audit process might result in overlooking a serious issue. As a result, this could come up or inadvertently lead the auditor to think the site is hiding something. To be able to get the most valuable information about the potential compliance issues facing the organization, internal audits should not be judgmental or antagonistic. 

 

Audit Questions

 

Auditors should be direct and avoid asking questions designed to intentionally stump people. Another important behavior is the ability of the auditor to listen to the answers and refrain from judging. The exact same behavior defined for the auditor should also be the behavior displayed by the auditees.

 

Auditees should be direct and avoid deflecting or obfuscating answers. They should take the time to explain why they do things the way they do them. Performance audit answers should be proactive, point out things of concern and seek advice on how to remediate them. Both parties need to remember they are not enemies, rather they are the partners in improving the organization.

 

Conclusion

 

Conducting these types of each technical audit presents a multitude of challenges. Today’s audit risk model has allowed the life science industry to creatively utilize technology-based applications to communicate and perform an effective system audit. The documentation and supporting evidence review can be conducted remotely, and confidentiality can be maintained. After reviewing the documentation and supporting evidence, the auditor can request interviews with various personnel.

 

Integrated audit interviews can then be scheduled via Zoom or online video conferencing. With appropriate planning and the proper use of technology, remote auditing can have the same audit quality as in-person auditing. 

 

 

BioPharm International

Vol. 34, No. 2

Pages: 44-45

 

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Quality Inspection: Making the Most of Your Processes

Quality inspection results should be included as part of the batch release documentation, says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates.

 

Q: My company is a contract manufacturer. Our final product inspection process consistently delays timely release of the manufactured products to our clients. Is there a best process/practice for performing a quality inspection?

 

A: This is not a new problem for the industry. To me, some of the issue is the fact that we call the specific activity of the overall physical product evaluation the “final product inspection.” In my opinion, the physical product evaluation should start at the beginning: the receipt of the individual components (stoppers, vials, labels, etc.) that are used in manufacturing.

 

Quality Inspection

 

Each component should pass an incoming quality inspection with defined acceptable quality limits (AQL) and clear directions for rejection of the component should it exceed the AQL. The specific elements to be looked at on incoming inspection will vary depending on the component.

 

Let’s assume your company manufactures sterile injectable products and the major component you will use in manufacturing is a glass vial. The first step in the process is to perform an incoming inspection of the glass vials. The number of vials to inspect from the shipment will depend on the number of vials contained in the shipment. The sample size to be inspected should be recorded in the appropriate standard operating procedure (SOP). The specific defects to be inspected should also be included in the SOP.

 

Quality Control Inspection

 

When evaluating quality control defects, most companies employ definitions of critical, major, and minor to the reject/accept criteria. In the case of vials, critical might be defined as likely to cause harm to the patient; major might be defined as leading to impairment to the patient; and minor would be defined as cosmetic defect causing no threat to the patient. Defining the acceptance criteria upfront may save you a lot of time at the end of the process.

 

Once the vial is accepted, it will be used in the manufacturing process. Defects that exist in the vial after initial acceptance may be detected during this step of the process. Many manufacturing lines have automatic sensors that detect vial imperfections and eliminate the vial from the batch before it is sent for labeling. The line operators need to be trained to recognize when there is an increase in rejected vials because this could mean that the incoming inspection did not pick up the vial defect. Again, if the defect can be detected and categorized at this process stage, it will save time at the product release stage.

 

Quality Assurance Inspection

 

The last quality assurance stage before labeling would be visual inspection of the stoppered vial. Some companies perform this step manually with trained visual inspectors while others utilize visual inspection equipment to perform the final inspection of the vial before labeling. Companies using vial inspectors typically focus those inspectors on looking for particulates in the vial, but they should also be trained to recognize vial defects. Regardless of which inspection format is used, there should be SOPs and AQLs governing the inspection process.

 

Final product inspection results should be included as part of your , so it is important to have repeatable, defined process/processes in place at all stages of the manufacturing process that is/are suitable for the product being inspected. The more time you spend upfront in the component inspection process, the more efficient your quality checks in manufacturing and batch release process will be.

 

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Pharmaceutical Technology
Vol. 47, No. 12
Page: 34

 

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Biologics Investigation

biologicsContract manufacturing organizations that manufacture traditional and biotech pharmaceutical products are responsible for performing investigations and reporting the results to their clients. But how do biologics consultants recognize the differences between performing an investigation of a biologic product versus pharmaceutical products?

 

Biologics Manufacturing

 

The short answer is there is no process difference when performing deviation investigations for traditional pharmaceutical products vs. biologic products. The differences lie in the complexity of the manufacturing processes. Further, these are the variables that should be considered regarding what could impacted the deviation.

 

Biotechnology Process

 

Chemical processes, although sometimes quite complex, often have fewer variables even though many of the categories are the same. For instance, when investigating an unknown impurity in a biological process from an oligopeptide fermentation process, the considerations are many. This often includes understanding the fermentation conditions, such as time, temperature, oxygen uptake and byproduct production.

 

Contamination

 

Moreover, potential contamination of reactants can include master cell banks and fermentation reagents, equipment integrity, and overall performance. Further considerations for the downstream purification process variables and the effect of a final configuration (e.g., folding) also need to be considered.

 

The purpose of a deviation investigation is to determine why the deviation happened and what its impact was on the product quality. To determine the impact of the deviation on biotechnology engineering in general, it is critically important to find the deviation root cause.

 

Root Cause Analysis

 

Conducting a root cause analysis is especially important when considering the COVID-19 pandemic and global impact on biological matrix supply chain. Small cap or start up biologics companies have virtually no room for production errors in this type of environment. For example, patients may be waiting for biologic medications and any production interruption can impact more than just the manufacturer. 

 

The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of whether the product is biotech or traditional, should require the investigator to review various production systems. Equally important, the system review during the investigation should help determine whether they were the cause of the deviation under investigation.

 

Engineering Validation

 

Every biologics consultant understands it is important to remember when performing an investigation to keep in mind a few general rules. Naturally, one size does not fit all. Simple errors require simple corrections while serious deviations require broader investigations. Validating the investigation is related not only to the seriousness of the deviation but also to the complexity of the factors that could influence the outcome.

 

Fishbone Diagram

 

The best tool to have during any investigation is inquisitiveness. Continuing to ask questions and avoid assumptions will lead to a better outcome. Using other tools, such and fishbone diagrams and determination of most probable number (MPN), are always encouraged. Undeniably, they do not take the place of a biologics consultant asking questions.

 

Biologic Performance

 

In performing an investigation, it is important for the biologic investigator to widen their performance perspective and look for ways to relate similar issues. The best way to ensure events are not related is to try and relate them, not the other way around. Keep in mind that human error is rarely a true root cause. There is usually something in the process that causes that human error.

 
And finally, always verify the facts of the investigation. It is also important to include a historical review. This review should determine if the deviation occurred with this or other products, with the specific manufacturing line or other manufacturing lines, and/or with the operators.

 

Biopharma Tools

 

The historical review can help to prioritize the resources and detailed system review. In addition, many biopharma companies make use of tools (fishbone diagram, MPN) to help prioritize resources. These tools, if used correctly, can be helpful in determining root cause. However, keep in mind they are just tools and do not take the place of thinking.

 

The detailed investigation should include a review of various systems. The systems most often reviewed are equipment and machinery, the manufacturing process, the raw materials used in manufacturing, the specifications, the environment, and finally, the operators.

 

Finally, this is not to imply that these systems are the only areas you should look at during the investigation. These are simply the most probable areas where you will uncover the root cause of the deviation.

 

CAPA & Corrective Action

 

Each investigation must address the following elements: root cause, impact to the material or product, the immediate correction taken, the corrective action to prevent re-occurrence for specific product/operation, and the preventive action taken to prevent re-occurrence for all products/operations.

 

Once these elements have been investigated, results from the investigation must be documented. The written narrative should clearly explain what happened, when it happened, and who was involved or observed what happened. The narrative documents the solution and rationale for the root cause that was determined through the investigation process.
 

Quality Assurance

 
The key to any successful investigation is not assuming you have the solution prior to completing the investigation. Increase your quality assurance and compliance by asking questions until you can think of no more questions to ask. Be sure to document the answers to your questions.
 
 
If you follow your investigation procedure and thoroughly document your results, you should have an acceptable investigation regardless of whether you are manufacturing a traditional product or a biotech product. 

 

 

BioPharm International
Vol. 28, No. 11
Page: 46–47

 

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Compendial Methods & Pharmacopoeias

Experts Susan J. Schniepp, distinguished fellow for Regulatory Compliance Associates® (RCA), and Steven J. Lynn, executive vice-president of Pharmaceuticals for RCA, discuss the verification of compendial methods.

 

Q. Are compendial methods considered validated?

 

A. According to the pharmacopoeias, compendial methods are validated—that’s about as simple as it gets. The United States of Pharmacopeia National Formulary (USP–NF) states,

 

“…users of analytical methods described in USP–NF are not required to validate the accuracy and reliability of these methods but merely verify their suitability under actual conditions of use”

 

European Pharmacopoeia

 

The European Pharmacopoeia (Ph.Eur.) and the (JP) also consider their methods validated. Ph.Eur. states:

 

“The analytical procedures given in an individual monograph have been validated in accordance with accepted scientific practice and recommendations on analytical validation. Unless otherwise stated in individual monograph or in the corresponding general chapter, validation of these procedures by the user is not required”

 

Japanese Pharmacopoeia

 

The Japanese Pharmacopoeia says:

 

“when an analytical procedure is to be newly carried in the Japanese Pharmacopoeia, when a test carried in the Japanese Pharmacopoeia is to be revised, and when the test carried in the Japanese Pharmacopoeia is to be replaced with a new test according to regulations in General Notices, analytical procedures employed for these tests should be validated according to this document”.

 

Validation

 

Supporting validation information for pharmacopeia methods is retained by the compendial authorities and not by the users of the methods. However, this does not change the fact that the official methods in these publications are supported by validation information.

 

Verification

 

regulatory compliance

The methods need to be verified as suitable for use in the user’s laboratory. The USP–NF and the Ph.Eur. both describe the requirements for verification in their respective compendia.

 

Compendial Procedures

 

The USP–NF and Ph.Eur. explicitly require that compendial procedures demonstrate suitability under actual conditions of use. This information can be found in General Chapter, Verification of Compendial Procedures <1226> in the USP–NF, and General Notices in the Ph.Eur. (1,2).

 

On the other hand, the European Directorate for the Quality of Medicines (EDQM) stipulates on their website:

 

“When implementing a Ph.Eur. analytical procedure, the user must assess whether and to what extent its suitability under the actual conditions of use needs to be demonstrated according to relevant monographs, general chapters, and quality systems.”

 

In other words, it is the user’s responsibility to transfer the procedure correctly” 

 

Monograph 

 

Once a monograph has been established and it is accepted that the published method is validated, users of the monograph need to verify that the method is suitable for determining the product quality. Moreover, the purpose of verification is to establish that the official method is reproducible when used by others.

 

Lab Equipment

 

The monograph sponsor proves the method works for its product with the manufacturer’s analysts using the firm’s laboratory equipment. They have already met the basic International Council for Harmonisation (ICH) requirements for reproducibility, repeatability, and intermediate precision. 

 

The task for the user of the USP monograph is to prove the published method is reproducible. Additionally, any analyst for their company’s product should be capable of testing using the lab equipment.

 

Test Methodology

 

There is no absolute guidance for verification requirements. Companies must decide for themselves how they will establish the method is verified and suitable for their product. Lastly, the test methodology verification will depend and fluctuate based on complexity of the test method.

 

Chromatographic

 

Chromatographic methods should, at a minimum, meet the system suitability requirements defined in the official method. Conversely, other method parameters, such as accuracy and precision, may be considered.

 

Microbiology

 

Method performance can be accomplished by using performance characteristics such as blanks in chemistry or un-inoculated media in microbiology. Finally, laboratory control samples and spiked samples for chemistry, or positive culture controls for microbiology to assess accuracy.

 

Training Records

 

Technique-dependent methodologies should not require verification. These methods include but are not limited to loss on drying, pH, residue on ignition, etc. Technicians should be trained, and their training records maintained, demonstrating their ability to perform the method regardless of the material being tested.

 

Lab Procedures

 

To simplify activities for their analysts, many companies translate monograph instructions into laboratory procedures. Although this practice has its benefits, it can also lead to compliance concerns.

 

Nevertheless, the author recommends that a baseline comparison be made between the standards and the internal testing documents to minimize this risk. Further, the comparison does not need to elaborate, but should focus on critical parameters for test methods.

 

System Requirements

 

Equally important, the reader may also want to consider reference standard usage, system suitability requirements, or other parameters that may help establish equivalency to the compendial methods.

 

Critical to Quality (CTQ)

 

Finally, the criteria listed above should not be considered all-inclusive. Establishing an internal method that complies with the official pharmacopeial method is critical to quality (CTQ). After all, many different users may have other requirements to consider for their specific laboratory usage.

 

 

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Pharmaceutical Technology
Volume 46, Number 4
Page: 58

 

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GMP Training

Q: I am in charge of GMP training for a contract-manufacturing site with approximately 350 employees. The budget for my department was recently cut, and now I am struggling to get my employees to training. I know that this will become a potential item when my clients inspect me. Do you have any suggestions on what I can do to remedy this situation?

 

A:  This is a great question. It seems cutting the gmp training and travel budgets are the first austerity measure companies take when they are facing some budgetary difficulties. In my opinion, training should probably be one of the last areas that should have its budget cut because training is one of the key elements management can use to assure their commitment to consistently producing a high-quality product. It is also a GMP requirement.

 

The US regulations, 21 Code of Federal Regulations (CFR) 211.25, define personnel qualifications and state:

 

“Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them”.

 

cGMP Training

 

Just because your budget is cut, however, doesn’t mean you can’t make sure employees receive meaningful training. There are many organizations and companies that offer cGMP training on many webinar topics. These can range from “How to Write Effective SOPs” to “How to Perform an Effective Technology Transfer” to “Risk Management Strategies for Quality Management in the Pharmaceutical Industry.”

 

Some of these webinars are free and some require a registration fee. They are usually 90 minutes in length, and many offer an opportunity to ask the speakers questions through a chatroom feature. If you are unable to listen to the webinar live, you may have the option to purchase a recording of it and listen to it at your convenience. The recorded option offered with these webinars can be valuable for training employees who work on the second and third shifts that can often be challenging.

 

GMP Training Certification

 

In some cases, the webinar may offer continuing education credits for GMP training certification for attending. The companies offering these webinars advertise them well in advance of the event and often send out multiple reminders. The advertising for the webinars highlight who will be speaking, their qualifications, what they will cover in the training, and what you will learn as a participant.

 

In addition, they will also make recommendations on who should attend so you can determine if this is appropriate training for your employees.  This information should be printed out and used to demonstrate the appropriateness of the training during an audit.

 

FDA Training

 

FDA also offers training through the FDA Learning Portal for Students, Academia and Industry at www.fda.gov/Training/learningportal. This training, FDA reports:

 

“… provides educational resources related to FDA’s regulatory, product quality, and safety responsibilities. In each section you’ll find educational materials such as lectures and courses as well as web pages related to the particular topic.”

 

Some of the topics available include courses titled FDA 101, FDA’s Regulatory Framework, Current Initiatives, Human Drug Approval and Post-marketing. The modules also provide a course objective so you and your employees will understand what they should know after completing the training.

 

For example, there is also a module called A Tour of FDA, which, FDA states, will provide an understanding of FDA’s public health mission and how the agency is organized to carry out its mission (2). FDA also broadcasts some of its public meetings depending on the topic.

 

The agency’s public meeting regarding its Request for Quality Metrics Guidance for Industry was a great way to learn about the new guidance and what industry colleagues were thinking. This is another way employees can keep up-to-date on the current issues facing the industry.

 

GMP Training for Employees

 

Finally, for some personnel groups, GMP training for employees consists of discussions of current topics. This can include industry warning letters, 483s, or new guidance documents may be a low-cost alternative to a formal training experience. These discussions can be led by qualified company personnel and can cover not only the specifics of the issues but the rationale behind them. As with all other training, these discussions should be documented in your training system.

 

The bottom line is even though your budget has been cut there are still opportunities to get your employees the required needed training that will satisfy your customers in audits. You should sign up to receive emails from companies and organizations that offer online training, review them to determine if they are applicable to your operations, determine who should attend from your company, and make sure you document their attendance for their training record.

 

In addition, you should also monitor the FDA website for potential upcoming webcasts, past webcasts, and other public offerings that will help you and your employees receive the necessary training even with a limited budget.

 

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RCA

 

Pharmaceutical Technology
Vol. 40, No. 12
Pages: 66, 65

 

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CAPA Preventative Action: Getting Drug Quality Right

A well-functioning Corrective and Preventive Action (CAPA) program can make the difference between a deviation being corrected and prevented the first time. The consequence is reoccurring deviations that require reopened investigations — wasting limited resources and potentially causing product quality issues.

 

CAPA

It’s important to remember that a well-functioning CAPA program starts with a well-functioning investigations program. After you recognize you have a problem, the first step is investigating the deviation and determining the root cause. The root cause(s) will direct how, what and where the company will take corrective and preventive action.

 

Preventive Action

CAPAAs regulators note in ICH Q10, “CAPA methodology should result in product and process improvement and enhanced product development.”

 

In his book, quality consultant Phillip Crosby states, “Quality is free. It’s not a gift, but it’s free. What costs money are the ‘unquality’ things — all the actions that involve not doing jobs right the first time.”

 

QMS CAPA

To that end, setting up a CAPA quality system (QMS) must be surrounded by adequate standard operating procedure (SOP). Each SOP should monitor and include metrics to ensure nonconformances do not occur in the future. Especially when considering CAPA in pharma; this is the least costly way to deal with regulatory issues or product defect problems.

 

While the two terms in the CAPA acronym may sound similar, there are crucial differences between ‘corrective action’ and ‘preventive action’. If an FDA investigation and corresponding CAPAs are initiated, then both the corrective and preventive actions would be addressed to determine the root cause.

 

CAPA Quality Assurance

Further, impact on material or product and the direct correction to the issue (i.e., immediate correction) should be well documented. Corrective actions are taken to prevent the reoccurrence for a specific product or operation, while preventive actions prevent any occurrence for all products or operations.

 

One of the most useful strategies during a CAPA audit is to ask questions and avoid assumptions. A fishbone diagram, fault tree analysis or the ‘5 Whys Method’ are robust tools that often help determine adequate root cause.

 

CAPA Records

When conducting the investigation, companies must review multiple systems including manufacturing processes, machinery, equipment, environment, specifications, raw materials and people.

 

Deviations are not limited to these systems. Other systems should also be evaluated as necessary, but many deviations do reside within one of the listed systems.

 

CAPA Effectiveness

Another way to look at CAPA effectiveness is the metaphorical horse with blinders. Imagine the blinders are used to keep the horse focused and moving forward. This same metaphor can be used to think about the investigation and CAPA process.

 

If you go in with blinders on, just looking at the issue without reviewing other interconnected systems, important details can be missed and more costly problems may result.

 

CAPA Systems

Once all the elements of the deviation have been investigated, the narrative and its linked CAPAs should explain when and what happened. Documentation should also be included in your CAPA system for who was involved.

 

The narrative should also document the solution that was implemented to correct and prevent the reoccurrence of the issue. This includes a rationale for the root cause identified during the investigation. All these items should be well-documented within your quality system.

 

CAPA for Quality

A robust CAPA program designed to improve quality should include a well-documented system that identifies the root causes of a deviation. This includes the nonconformance, system failures, or process problems.

 

In addition, the CAPAs must address each of the root causes and identify the corrective action for remediation. Only after careful consideration about the deviation can the appropriate correction prevent the deviation from happening again.

 

CAPA Manufacturing

Qualified staff (with proper training, education, and experience) should run the CAPA program. Incorporating meaningful metrics to track the performance of overall systems can help provide early warning signals for deviations/nonconformances.

 

An appropriate Subject Matter Expert (SME) should be included in the process. Management should review potentially adverse information, oversee the overall adequacy of the CAPA program, and remediate identified deficient areas, including those that may need capital investment.

 

CAPA Quality

Once the appropriate solution for improving quality has been implemented, evaluating the solution’s effectiveness should be ongoing. There should be a process for monitoring the recurrence of the deviation and the closing out of the CAPA once the solution has been confirmed effective. All these items must be documented within the quality system.

 

The same level of depth and rigor of a CAPA for one issue may not be required for every deviation. For example, a small documentation error will likely only require a simple correction. More serious deviations, like a confirmed Out of Specification (OOS), will demand a much more robust investigation and CAPA. 

 

Deviation Meaning

The complexity of the deviation and its concomitant CAPAs not only determine the approach taken for the investigation but also inform the timeline. For example, while some standard operating procedures may call for a 30-day timeline for investigations and CAPAs, that timeline may need to be extended. Identifying the priority of the deviation helps the entire team to recognize meaning. 

 

In this case, you’d need to document the rationale for the extension and get the quality department’s approval. A critical caveat here is everything in the investigation leading to a CAPA does not need a time extension. If your company is extending a lot of investigations, then it may indicate another entirely different problem.

 

Pharmaceutical Manufacturing

The key to establishing a successful CAPA is a complete and thorough investigation focused on finding the reason the deviation occurred. This is essential in pharmaceutical manufacturing as well as many other regulated industries. 

 

Failure to identify the correct root cause will result in possible failed effectiveness checks and the dreaded reopening of the CAPA. Everything plays a part in the investigation: people, machines, materials, processes, etc.

 

CAPA Audit

Management of these players is key to identifying the deviation’s root cause. The audit process behind the investigations is crucial in addressing the issue at hand. The aim shouldn’t be to find a single root cause that management believes to be the reason for the failure but to analyze all possible root causes across all systems.

 

If an identified root cause isn’t the true reason for the failure, then the root cause can be eliminated. Each root cause eliminated narrows down the investigation. Any potential root cause that cannot be eliminated must be remediated, even if that root cause is not THE root cause of the failure.

 

Root Cause Analysis

A mistake companies make is identifying a root cause that needs remediation and stopping there. Companies should always identify all possible root causes and address them accordingly. When executed correctly, CAPAs help organizations remediate deviations/issues before they cause more technical problems and escalated costs.

 

A practical example of an investigation and CAPA process is as follows: Company X had an investigation related to the detection of nonconforming vials, which were discovered prior to packaging. The inspectors on the line found the nonconforming vials, informed the quality team, and an initial investigation ensued.

 

Quality Assurance

The quality assurance team correctly put the lot on hold while the investigation was being conducted. During the early phase of the investigation, the nonconforming vials were sent away to be analyzed by a third-party qualified laboratory. The results came back stating the discoloration was due to chemical contamination.

 

The chemical in question was not part of the formulation or the container closure system and was not on any product contact surfaces within the equipment. Company X eventually decided the contamination happened at the vial manufacturer and closed the investigation. One week after the initial observation of the discolored vials was opened and closed, the same issue arose with another product and the original investigation was reopened.

 

Forensic Investigation

The company subsequently audited the vial manufacturer, but the results were inconclusive, with no identified source of the chemical responsible for the nonconforming vials. The company continued manufacturing while the investigation was ongoing and began a 100% incoming material inspection.

 

A week later, a line operator noticed a vial exiting the depyrogenation tunnel that had a discolored blob in it. Manufacturing was stopped and the vial was sent to the contract lab for analysis. Once again, the chemical in question was the culprit.

 

Supplier Audit

The company sent a consultant to do a supplier audit of the vial manufacturer while they continued manufacturing the product. Similar to the initial for-cause audit, the external consultant could not find the source of the chemical leading to the nonconforming vials.

 

Finally, after opening the line for inspection, the company discovered that the contaminating chemical was associated with the HEPA filters. Manufacturing was finally halted on the line.

 

Corrective Action and Preventive Action

After completing a more thorough investigation, the root cause was determined to be faulty cooling valves in the depyrogenation tunnel. This was previously identified by the company as a potential root cause in the initial investigation, but was not pursued because it was classified as ‘possible but highly unlikely’ and ranked lowest on the priority list.

 

There was no alarm associated with the cooling valve which explains why the issue was not caught under routine maintenance checks. Once the problem was correctly identified, the proper and effective corrective action could be taken, including the potential costly endeavor of evaluating all products made on the line and looking at other lines with the same depyrogenation oven.

 

Cost of Poor Quality

Hypothetically, let’s say the cost of a critical deviation for Company X is a million dollars. We start by looking at the cost of poor quality (COPQ) of a defect.

 

The cost is eliminated only if the pharma company’s quality management system (QMS) is organized. This includes the QMS system being designed to detect, investigate, correct and prevent issues/deviations.

 

QMS System

If the company can prevent defects with their robust QMS, they will save money because they allocated sufficient qualified resources toward an efficient QMS — which in turn meant they didn’t have to address many defects/deviations and CAPAs. Hence the quality system pays for itself.

 

If the issue is detected within the company before anything is shipped out, the cost rises tenfold to ten million dollars. This is due to the company needing to address the now-detected issue and implement corrections (corrective action) to rectify the issue. Additionally, the team would put measures in place to ensure issues do not occur in the future (preventive action).

 

Forensic Analysis

Finally, if the company detects an issue in a drug product after it has been released by the quality department and delivered to the customer, the cost raises tenfold again. The forensic analysis must now include the cost of recalls, as well as corrective and preventive actions. The cost of quality is important to understand — for Company X, they caused themselves a $100 million mistake.

 

Company X initially thought the issue seemed small and negligible, which led to an unfortunate quick closure of the investigation. Ultimately the deviation affected twenty-eight lots of manufactured products. These lots, produced over a two-month period for several clients, were rejected due to the nonconforming vials.

 

Root Cause Strategy

Company X should have utilized a more thorough investigation and root cause strategy to follow every possible root cause. Instead, the company chose what seemed like the easiest root cause and jumped to the wrong conclusion. Then the company quickly closed this initial investigation without a complete and thorough investigation. In conclusion, this mistake created a bigger issue and a compliance and business risk.

 

It takes diligence, thoroughness and a healthy number of questions to ensure you investigate, correct, and prevent problems. But without this, the quality and efficacy of the drug product being manufactured could be jeopardized. 

 

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