FDA Warning Letter to a Manufacturer of an Athlete Muscle Maintenance Creme

On 9 July, the FDA issued a Warning Letter to a Korean manufacturer registered as a manufacturer of over-the-counter drugs. With the Warning Letter, the FDA is responding to the documents it received from this manufacturer in response to two requests in 2022 and 2024. Since the methods, facilities or controls described in the company's response for the manufacture, processing, packaging or storage of drugs do not comply with CGMP, they are automatically considered adulterated and non-compliant.

Content

The Warning Letter lists a number of violations:

1. Lack of an adequate and written testing programme to assess stability properties. Only 3 months of data were available, with a shelf life of 2 years. There was therefore a lack of sufficient chemical and microbiological tests and data. This meant that there was no proof of compliance with the defined specifications and quality over the shelf life period.

2. The raw materials used had not been sufficiently tested with regard to identity and conformity, e.g. purity, starch and quality. This also included the error frequently identified in recent months that the batches of glycerine used were not tested for the limit values of diethylene glycol (DEG) and ethylene glycol. The FDA points this out again in its Warning Letter:

"The use of glycerin contaminated with DEG and EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.."

Conclusion

Since the company could not demonstrate that adequate testing of the manufactured products and starting materials was performed, e.g., the certificates of analysis you submitted for dermaFIT Athlete Muscle Maintenance Cream did not include adequate assay testing for active ingredient content or microbiological testing.

Accordingly, the FDA recommends that a GMP consultant be consulted and advises that the FDA may withhold approval of new applications or supplements until all violations are fully corrected and compliance with CGMP is confirmed.

FDA describes detailed CAPA Procedure in Warning Letter

An FDA Warning Letter is a formal communication from the US Food and Drug Administration (FDA) notifying a company or individual of regulatory violations. These typically describe observations made during an inspection and list violations found (referencing the specific sections of the FD&C Act, the Code of Federal Regulations (CFR), and other applicable laws as appropriate). In addition, specific measures are listed that the recipient must take to remedy the violations. It does not go into great detail, especially not with regard to instructions on the desired procedure.

In a Warning Letter issued to Sun Pharmaceutical Industries Limited (India) at the beginning of July, this is now different. It describes in great detail what the FDA considers to be appropriate CAPA measures in a specific case.

What happened?

The company was criticised for not adequately cleaning and maintaining the equipment used to manufacture drug products. According to the company's response, a defective valve was the cause of the observed liquid build-up. This was discovered in the course of investigating the cause following the inspector's observation. Affected batches were recalled, but this was not enough for the FDA, which now lists very specifically what to expect:

A comprehensive, independent retrospective evaluation of the effectiveness of cleaning measures, including consideration of production equipment that may have been improperly cleaned.

A corrective and preventive action plan (CAPA) based on the retrospective assessment of the cleaning programme, including appropriate corrective actions for cleaning procedures and practices and a timeline for completion.

A detailed summary of weaknesses in the process for the life cycle management of equipment cleaning.

Identification of improvement actions to the cleaning programme, cleaning effectiveness and improved ongoing verification of proper performance.

Among other things, the CAPA plan should ensure that potential problems with equipment are recognised immediately so that, for example, repairs are carried out effectively. The plan should also ensure that appropriate action is taken across the organisation's network.

The CAPA plan must comprehensively address any gaps identified by an external consultant when assessing the maintenance programme.

The review of the effectiveness of the CAPA measures must include at least the following:

Evaluation of improvements to cleaning and maintenance procedures, including determining the specific frequency and locations to be cleaned at all relevant facilities

Adequacy of maintenance and repair history analysis

Assessment of all major production facilities for other sources of cross-contamination

Adequacy of improvements to the method of analysis to identify residual carryover

Adequacy of investigations of other unknown (unidentified) peaks

Assessment of whether the scope of the investigation and the associated CAPA were sufficient

However, the FDA was also not satisfied with the measures taken in the investigation of OOS results: "Your investigations of out-of-specification (OOS) results were inadequate because they lacked scientific rationale for root cause determinations."

FDA Warning Letter - Missing incoming Control Tests

In June 2024, the U.S. FDA issued a Warning Letter to the Portuguese company "Fancystage Unipessoal, LDA" after having inspected its site in January 2024.

The significant violations of CGMP regulations for drug products, which are mentioned in the Warning Letter, are listed as follows:

"Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2))."

"Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a))."

"Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b))."

"Your firm's quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22)."

According to U.S. FDA Warning Letter, the firm failed to do proper incoming control tests to identify the goods. Testing and sampling of incoming goods are mandatory to verify the identity of the received materials and CGMP qualified suppliers are required. "ICH Q7 Good manufacturing practice for active pharmaceutical ingredients" guideline clearly describes these requirements in chapter 7.3 "Sampling and Testing of Incoming Production Materials".

The observed findings resulted in a long list of remediation activities and CAPA measurements requested.

Coming to the final conclusion mentioned in the Warning Letter, the U.S. FDA has issued an import alert for this company. Engaging a consultant to ensure that the company will be CGMP compliant from now on is highly recommended in the Warning Letter.

Fancystage Unipessoal, LDA WL

In June 2024, the U.S. FDA issued a Warning Letter to the Portuguese company "Fancystage Unipessoal, LDA" after having inspected its site in January 2024.

The significant violations of CGMP regulations for drug products, which are mentioned in the Warning Letter, are listed as follows:

"Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2))."

"Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a))."

"Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b))."

"Your firm's quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22)."

According to U.S. FDA Warning Letter, the firm failed to do proper incoming control tests to identify the goods. Testing and sampling of incoming goods are mandatory to verify the identity of the received materials and CGMP qualified suppliers are required. "ICH Q7 Good manufacturing practice for active pharmaceutical ingredients" guideline clearly describes these requirements in chapter 7.3 "Sampling and Testing of Incoming Production Materials".

The observed findings resulted in a long list of remediation activities and CAPA measurements requested.

Coming to the final conclusion mentioned in the Warning Letter, the U.S. FDA has issued an import alert for this company. Engaging a consultant to ensure that the company will be CGMP compliant from now on is highly recommended in the Warning Letter.

What are skills required to review documents

The key skills required to effectively review documents are:

1. **Analytical skills** to identify errors, inconsistencies, and gaps in information, and evaluate the importance and validity of documents[1][3].

2. **Attention to detail** to check for spelling, grammar, punctuation, formatting, and style errors, as well as factual or logical errors[1][2]. 

3. **Communication skills** to write clear, concise, and professional reports summarizing document review results, and convey findings to team members and stakeholders[1][2].

4. **Technical skills** to use document management systems, databases, search engines, and e-discovery software like Relativity, Ringtail, and Concordance[4].

5. **Critical thinking skills** to identify biases, assess credibility, compare arguments, and synthesize information from multiple documents[1].

6. **Ethical skills** to maintain confidentiality, privacy and security, and avoid conflicts of interest when reviewing sensitive information[1].

7. **Editing and writing skills** to review and summarize complex legal documentation[2].

8. **Organizational skills** to manage large volumes of information and documents[4].

Proficiency in specific document types like mortgages, loans, and foreclosure documents is also beneficial for document reviewers[4].

Citations:

[1] How to Master Document Review Skills and Competencies - LinkedIn https://www.linkedin.com/advice/3/what-skills-competencies-required-effective-1f

[2] How to Become a Document Reviewer (Plus Duties and Skills) https://ca.indeed.com/career-advice/finding-a-job/document-reviewer

[3] Document Reviewer Skills and Essential Traits - LiveAbout https://www.liveabout.com/top-document-review-skills-2164651

[4] 15 Document Reviewer Skills For Your Resume - Zippia https://www.zippia.com/document-reviewer-jobs/skills/

[5] Document Review Specialist Must-Have Skills List & Keywords ... https://www.ziprecruiter.co.uk

Difference between review and verification

The difference between review and verification lies in their purposes and methodologies:

- **Review** involves evaluating the suitability, adequacy, or effectiveness of an object to achieve established objectives. It is a process of determining whether the design or product meets the required standards. Reviews can occur throughout the design phase and at key milestones in the development process. Examples include management reviews, design and development reviews, and peer reviews[4].

- **Verification** ensures that specified requirements have been fulfilled by providing objective evidence. This can involve inspections, testing, reviewing documents, and performing alternative calculations. Verification occurs after the completion of development stages, prior to validation, to confirm that the product meets all specified design and requirement specifications[4].

In summary, review evaluates the design's ability to meet objectives, while verification confirms that the product meets specified requirements through objective evidence.

Does reviewer should be subject matter expert

A reviewer should be a subject matter expert in the specific domain or topic being reviewed. The key differences between a reviewer and a subject matter expert are:

- **Subject Matter Expertise**: A subject matter expert (SME) has deep, specialized knowledge and experience in the particular field or topic. They are considered authorities in that domain.

- **Review Role**: A reviewer, who may also be an SME, is responsible for evaluating the content, accuracy, and effectiveness of a product, process, or document against defined requirements or standards. The reviewer provides feedback and recommendations.

The main reasons why a reviewer should be a subject matter expert:

1. **Relevant Expertise**: An SME can provide informed, credible feedback based on their extensive knowledge of the subject area. This ensures the review is thorough and meaningful.

2. **Identification of Issues**: An SME can more readily identify technical inaccuracies, gaps, or problems that a non-expert may miss.

3. **Valuable Insights**: SMEs can offer strategic insights, best practices, and recommendations that improve the final product or process.

4. **Credibility**: Having an SME conduct the review lends greater credibility to the review process and its outcomes.

5. **Efficiency**: An SME can complete the review more efficiently since they already possess the necessary domain knowledge.

In summary, utilizing subject matter experts as reviewers is critical to ensuring the quality, accuracy, and effectiveness of the work being reviewed. Their specialized expertise is invaluable in identifying issues and providing meaningful feedback.

Role of verification in report review

The role of verification in report review is to confirm that the information presented in the report is accurate, complete, and meets the specified requirements. Some key aspects of the role of verification in report review include:

1. Confirming Accuracy: Verification ensures that the data, calculations, and conclusions in the report are factually correct and free of errors. This involves checking source data, re-performing analyses, and validating the logic and reasoning.

2. Validating Completeness: Verification checks that the report covers all the necessary information and addresses all the required elements as per the defined scope and objectives. This helps identify any gaps or missing components.

3. Ensuring Compliance: Verification confirms that the report adheres to relevant standards, guidelines, and organizational policies. This includes checking formatting, structure, and adherence to reporting requirements.

4. Identifying Improvements: The verification process can uncover opportunities to enhance the quality, clarity, and effectiveness of the report. Reviewers can provide feedback and recommendations for improvement.

5. Establishing Credibility: A thorough verification process lends greater credibility to the report's findings and conclusions, as it demonstrates the rigor and attention to detail applied.

6. Mitigating Risks: Verification helps catch and address any issues or discrepancies before the report is finalized and distributed, reducing the risk of errors, omissions, or misinterpretations.

In summary, the role of verification in report review is to ensure the accuracy, completeness, and compliance of the information presented, thereby enhancing the overall quality, reliability, and usefulness of the report.

difference between verification and review

The key differences between verification and review are:

1. Purpose:

   - Verification ensures that the product or information meets the specified requirements and is correct.

   - Review evaluates the suitability, adequacy, or effectiveness of a product or process to achieve established objectives.

2. Methodology:

   - Verification involves inspections, testing, document reviews, and alternative calculations to provide objective evidence.

   - Review is a more subjective process of evaluating design, content, and performance against standards.

3. Timing:

   - Verification occurs after development, prior to validation, to confirm the product meets requirements.

   - Review can happen throughout the design and development process at key milestones.

4. Expertise:

   - Verification is typically conducted by subject matter experts who have deep knowledge of the domain.

   - Reviewers may or may not be subject matter experts, but they provide an objective evaluation.

5. Outcome:

   - Verification confirms that the product is "built right" according to specifications.

   - Review determines if the "right product" is being built to meet user needs and objectives.

In summary, verification is focused on confirming correctness, while review is focused on evaluating suitability and effectiveness. Both play crucial and complementary roles in ensuring high-quality products and processes.

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Drug shortage Supply Chain Risk Assessment by EMA

On 18th of June 2024, the EMA has issued templates for Shortage Prevention Plans (SPPs) and Shortage Mitigation Plans (SMPs). Marketing authorization holders (MAHs) in the European Union/European Economic Area are encouraged to create Shortage Prevention Plans to minimize the risk of medicinal shortages.

The availability of medicinal products is a central point in the strategy of the European Medicines Agency Network until 2025 and the European Commission's pharmaceutical strategy, which led to the revision of the pharmaceutical legislation in April 2023. The draft regulation obliges MAHs to establish Shortage Prevention Plans and Shortage Mitigation Plans.

In times of crisis, in form of a public health emergency or a major event, SPPs are already obligatory under Regulation 2022/123, for drugs listed in the list of critical medicines for that particular crisis.

The extent of the documents should correspond to the risk level of the medicine. For this reason, the ICH Q9 guideline on quality risk management is to be applied.

Companies are recommended to involve their highest level of management in the development of SMPs/SPPs. The plans should be created in English and, if necessary, translated into the local language upon request of the national competent authorities. As part of the pharmaceutical quality system, SPPs should be regularly updated and evaluated.

Shortage Prevention Plans help to identify and manage potential risks in the supply chain and include information on the MAH, the supply and manufacturing chain, key data on stock, sales, consumption and manufacturing and an analysis of the history of supply issues. A SPP should be in place for each medicinal product marketed by the MAH. The minimum requirements for the SPP state that MAHs should analyze and evaluate weaknesses in the supply chain. The robustness of shortage prevention measures is to be evaluated. MAHS are obliged to assess the risks of supply interruptions for patients. A medicine shortage risk register should be developed to identify clinically significant products based on therapeutic use and availability of substitutes. Using available information such as root cause analysis of shortages, the MAH is required to determine whether corrective and preventive actions or revalidation are needed, both nationally and internationally. Furthermore, MAHs should ensure that minimum stock levels are maintained at national levels. Measures to prevent drug shortages should be reviewed regularly.

Shortage Mitigation Plans are designed to eliminate potential or actual drug shortages and minimize the impact on patients.

The minimum requirements for the SMPs include procedures for dealing with shortages, from identification to resolution. These procedures should include measures to reduce the shortage's impact, notification to regulatory authorities, and follow-up actions. MAHs should define roles, responsibilities, escalation processes and maintain records of root causes and mitigation measures after resolving shortages.

SPPs and SMPs should be submitted to the competent authorities upon request.

Regulations link

For templates Click here

End Product Testing versus Process Validation

End product testing versus validation? This is a question that is frequently discussed in the GMP environment. The argument is that if the specification of the end product fits, which is even included in the marketing authorisation, then the process must also fit. Otherwise the product would not conform to the specification.

It's not just the FDA that sees things differently. But the FDA also addresses this issue directly in a Warning Letter.

The FDA criticised the fact that no process validation could be demonstrated for a product that was manufactured, released and distributed. Specifically, it was criticised that it could not be shown that the manufacturing process was controlled with regard to a constant yield with consistent quality.

The company's response is interesting. It suggested analysing the release data in terms of safety and efficacy and then showing a summary of the release data in terms of content and microbiological count.

This answer was not well received. It was criticised that the company could not demonstrate sufficient certainty that batches had sufficient strength, quality and purity. The lack of a stability monitoring plan and a plan for dealing with complaints was also criticised.

Following the FDA quotes from its Process Validation Guidance what validation means - starting with development, through the actual process validation (called PPQ in the USA) and the "stage of control" in phase three of a process validation cycle. Prior to market supply, process qualification studies are important for the FDA and subsequent monitoring of the process. As is often the case in FDA Warning Letters on the subject of process validation, the FDA Process Validation Guidance is also cited with a link.

Specifically, the FDA requires

• a complete list of all products that are still on the US market within the expiry
• a plan that provides an overview of the above-mentioned products, the responsibilities of the reserved samples and their storage. The stability programme and complaints received and how to deal with them. 
• a plan for dealing with products that have quality defects, including how customer get notified and recalls are handled.

Conclusion: The argument that the final product testing shows that the manufacturing process works is not accepted in this Warning Letter. Validation is mandatory.

Access Warning Letter here

Example for common cause variation in Stastical process control

Here are some real-world examples of common cause variation in Statistical Process Control (SPC):

- Minor fluctuations in raw material properties, such as the thickness or density of a material, leading to small variations in the final product dimensions[1][2][3]

- Slight changes in environmental conditions like temperature or humidity from day to day, causing small shifts in a chemical process's yield[1][3]

- Natural variation in operator technique or skill level, resulting in small differences in product quality characteristics between individual workers[1][3]

- Random variation in machine performance over time due to normal wear and tear, leading to gradual changes in a process output[1][2][3]

- Minor differences in measurement instruments or calibration, contributing to small variations in data collected during the process[1][3]

Common cause variation is the inherent, random variability that is always present in a stable process. It represents the normal "noise" of the system and cannot be traced back to a specific, assignable source. As long as this variation remains within the control limits on a control chart, it indicates the process is in a state of statistical control.[1][2][3]

Citations:

[1] Achieving Process Stability with Common Cause Variation - iSixSigma https://www.isixsigma.com/dictionary/common-cause-variation/

[2] How to Identify Causes of Variation in Statistical Process Control https://safetychain.com/blog/identifying-variation-statistical-process-control

[3] What is Common Cause Variation in Six Sigma? - SixSigma.us https://www.6sigma.us/cause-variation/what-is-common-cause-variation/

[4] Common and Special Causes in Statistical Process Control - LinkedIn https://www.linkedin.com/advice/0/what-some-common-tools-techniques-identifying

[5] Common Cause and Special Cause - MSI Six Sigma Training https://www.msicertified.com/common-cause-and-special-cause/

Special cause variation in Stastical Process Control

Let's consider a manufacturing scenario where Statistical Process Control (SPC) is used to monitor and improve the quality of a production process for a specific product, such as automobile brake pads. 

In this example, the critical quality characteristic of interest is the thickness of the brake pads, which must fall within a specified range to meet safety and performance requirements.

Here's how SPC can be applied to monitor and control the thickness of brake pads:

1. Data Collection: The manufacturing process involves producing brake pads of a certain thickness. Measurements of the thickness are taken periodically from samples of brake pads produced during the production run.

2. Control Chart Creation: A control chart is created to monitor the thickness of the brake pads over time. The control chart typically consists of a central line representing the process mean and upper and lower control limits based on process variability.

3. Data Analysis: As measurements are collected and plotted on the control chart, the process variability and trends are analyzed. Any points that fall outside the control limits or exhibit non-random patterns (such as trends, shifts, or cycles) are investigated as potential special causes of variation.

4. Process Adjustment: If special causes of variation are detected, corrective actions are taken to address the root cause of the issue. This could involve adjusting machine settings, changing materials or processes, or providing additional training to operators.

5. Continuous Monitoring and Improvement: The process is continuously monitored using SPC techniques to ensure that the thickness of the brake pads remains within the desired range. Regular data collection and analysis help to identify opportunities for process improvement and prevent quality issues from recurring.

By using Statistical Process Control in this example, the manufacturer can ensure that the thickness of brake pads meets quality standards consistently, leading to improved product performance, customer satisfaction, and cost savings through reduced rework and scrap.

give me real world example for special cause variation in Stastical process control

Here are some real-world examples of special cause variation in Statistical Process Control (SPC):

Few other examples 

- A machine breaks down unexpectedly, causing a spike in cycle time or defect rate[1][2][3]

- A shipment of raw materials is contaminated, leading to an increase in product failures[1][2][4] 

- A power outage shuts down production for several hours, disrupting the normal process[2][3]

- A new operator makes a mistake in a critical process step, resulting in off-spec product[1][3]

- An earthquake or severe weather event damages equipment and facilities[2][4]

Special causes are unexpected, non-routine events that are not part of the normal process variation. They are assignable to a specific cause and can be corrected by adjusting the process. When special causes occur, they will show up as points outside the control limits or non-random patterns on a control chart[1][4].

The key is to quickly identify the special cause, determine the root source, and implement corrective action to bring the process back into a state of statistical control[1][3]. Preventing special causes requires proactive measures like preventive maintenance, operator training, and supplier quality audits[3].

Citations:

[1] The Power of Special Cause Variation: Learning from Process Changes https://www.isixsigma.com/dictionary/special-cause-variation/

[2] Common Cause Variation Vs. Special Cause Variation - Simplilearn.com https://www.simplilearn.com/common-vs-special-cause-of-variance-article

[3] Common and Special Causes in Statistical Process Control - LinkedIn https://www.linkedin.com/advice/0/what-some-common-tools-techniques-identifying

[4] How to Identify Causes of Variation in Statistical Process Control https://safetychain.com/blog/identifying-variation-statistical-process-control

[5] Common cause and special cause (statistics) - Wikipedia https://en.wikipedia.org/wiki/Common_cause_and_special_cause_%28statistics%29