Host Cell Proteins - FDA seeks Comments on Immunogenicity Assessment

Additional substantive information

I. Background

The FDA uses the term ‘peptide’ in this notice to refer to alpha-amino acid polymers consisting of 40 or fewer amino acids. Peptides can be isolated from natural sources or produced synthetically or by recombinant expression in a host cell. Peptides isolated from recombinant sources (i.e., genetically modified) prokaryotic or eukaryotic host cells by cell culture/fermentation processes are referred to as recombinant peptides (rPeptides). The FDA describes at this point:

HCPs are process-derived impurities from the host cell that copurify with the recombinant peptide of interest and may be present in the final drug product. HCPs are characterised and routinely well controlled during the manufacture of the peptide product. The types and amounts of HCPs in a product depend on many parameters, including differences in the substrate of the expression cells, culture conditions, purification procedure and between different facilities. Therefore, for a proposed rPeptide follow-on product, differences in HCP profiles between the follow-on product and the listed drug product are to be expected, and these differences may impact the safety and/or efficacy of the follow-on product by increasing the immunogenicity risk of that product. Advances in technology may support the use of IVISIA methods to assess comparative immunogenicity risk. Comments submitted by 23 September will be considered. This cannot be guaranteed for comments submitted later.

II. Request for comments

Interested parties are invited to submit detailed information (including supporting data) and comments on appropriate methods for the detection, identification and quantification of HCPs and the minimum residual levels of HCPs that can be achieved in commercial batches of rPeptide products. To assess the potential impact of HCP differences, the FDA is particularly interested in answers to the following questions:

1. What is the lowest and routinely achievable total HCP content in your well-controlled rPeptide manufacturing processes, and how is it calculated/determined?

2. What are the challenges in reducing HCP levels?

3. What analytical methods are currently used to detect, identify and quantify HCPs in a rPeptide product? Do you perform comparative assessments of HCPs during production development, e.g. ELISA (enzyme-linked immunosorbent assay) versus LC/MS/MS (liquid chromatography tandem mass spectrometry)? How sensitive are these methods for the detection of HCPs and what are their quantification limits? Do you use a combination of orthogonal analytical methods (e.g. ELISA + LC/MS/MS) for HCP control during process development and manufacturing?

4. What is the generally achievable percentage coverage of the HCP spectrum for your HCP quantification test? What considerations (e.g., percentage coverage of HCPs, other coverage characteristics, etc.) are important when selecting methods for evaluating HCPs?

5. Are there qualitative or quantitative characteristics of HCPs that are associated with a higher likelihood of adverse clinical outcomes?

6. What tools (in silico, in vitro or in vivo studies) do you currently use or plan to use to compare the potential immunogenicity risk of two products with different HCP profiles? What is your approach to risk assessment of HCPs based on such data?

FDA Issues Warning Letter for Repeated CGMP Violations and Quality Control Failures

The U.S. Food and Drug Administration (FDA) issued a Warning Letter dated 03 September 2024 to a Canadian over-the-counter (OTC) product manufacturer. The letter follows an inspection conducted in April 2024, discovering multiple violations of Current Good Manufacturing Practices (CGMP).

Key Findings

Key findings of the FDA include: 

Failure to Perform Identity Testing on Components: The company did not adequately perform identity testing for all incoming components used in drug manufacturing. The firm's failure to conduct these tests raises concerns about the potential for contamination or mislabeling of their products. The company also relied on certificates of analysis (COA) from suppliers without verifying the identity of the components themselves, which further compounded the issue.

Inadequate Validation of Manufacturing Processes: Another significant issue identified by the FDA was the company's failure to adequately validate its manufacturing processes. The inspection revealed that the firm did not establish and document the effectiveness of their manufacturing procedures through appropriate validation studies.

Lack of Proper Oversight by the Quality Control Unit: The inspection further highlighted deficiencies in the quality unit (QU), which failed to ensure the consistent quality of drug products. The FDA noted that the QU did not have sufficient oversight to review and approve materials used in production, the manufacturing processes themselves, and the final product testing.

Repeat Violations

The letter emphasized that many of the current violations were previously identified in earlier inspections of the facility. In fact, the FDA had already issued a warning about similar problems in the past, yet the company had failed to implement sufficient corrective actions. This repeated non-compliance indicates a systemic failure to maintain proper manufacturing standards over time, and the FDA expressed serious concerns about the company's commitment to adhering to CGMP regulations.

Conclusion

In light of these significant violations, the FDA strongly recommended to hire an external consultant to assist in bringing their operations back into compliance. The FDA expects a detailed action plan to address the specific issues identified in the inspection report. If the company does not take adequate corrective measures, it may face further regulatory actions, including the seizure of products or legal injunctions. The company was already placed on Import Alert 66-40 ("Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs").

FDA Observation Not using Statistical Process Control (SPC) in Validation

With the introduction of the updated FDA guidance on process validation, a process validation life cycle was introduced in 2011. One of the stages in the cycle is the so-called Continued Process Verification stage 3, which shows whether the process remains permanently in a validated state. Many companies use statistical process control (SPC) to show the 'state of control' in this stage 3.  

In a recent Warning Letter, the FDA criticised a drug manufacturer's statistical process control. What was criticised?

No control charts created

The methods used in the 'Continued Process Verification' to show the 'state of control' are not specified. One possibility mentioned in the Process Validation Guidance is statistical process control. This is what the company inspected by the FDA had planned.

Was it intended that way? Yes, that is how it was intended. Citing section 21 CFR 210/211, the FDA criticises the lack of activities that show that the process is permanently 'under control'. They are referring to the manufacturing and engineering departments, which have not created control charts to monitor and control the manufacturing process. This is exactly what the company had specified in its internal procedures. This was rectified during the inspection, with the result that four previously undetected trends were discovered. The usefulness of an SPC was thus demonstrated directly during the inspection.

The inspected company also recognised this and responded to the inspection report by stating that it was committed to complying with its internal procedures on SPC in future. This was not enough for the FDA. It also expects an investigation into how it was possible that the control charts were not created in the first place.

Scientific approaches in the context of process validation

One of the innovations in the update of the FDA Process Validation Guidance was the introduction of a more scientific approach to process validation. This is also clearly reflected in this Warning Letter. The FDA criticises an unscientific approach to a validation run. The mixing uniformity was criticised as insufficient in terms of sample locations and sampling (number, sample size, sample preparation).

Conclusion: Statistical process control is not a mandatory requirement in the context of process validation. However, if it is required by internal company specifications, then it must also be implemented. And in this case, the advantage of an SPC was demonstrated very impressively, which was then followed up. Four previously undiscovered trends were identified. Furthermore, a scientific approach to process validation is required.

Impact of the US BioShield Act on the Pharmaceutical Business

The BioShield Act of 2004 significantly influenced the pharmaceutical industry, particularly in the development and production of medical countermeasures (MCMs) against biological threats. Here's a breakdown of its primary impacts:

Increased Funding and Investment

 * Government Funding: The Act provided substantial funding to the U.S. government for the development and acquisition of MCMs.

 * Industry Investment: This increased government funding incentivized pharmaceutical companies to invest more in R&D for MCMs, which might have been considered riskier before the Act.

Accelerated Development and Approval

 * Expedited Processes: The Act introduced expedited development and approval processes for MCMs, reducing the time it took to bring products to market.

 * Faster Response: This was especially crucial during public health emergencies, as it allowed for a quicker response to biological threats.

Public-Private Partnerships

 * Collaboration: The Act encouraged collaboration between the government and pharmaceutical companies.

 * Shared Expertise: These partnerships leveraged the government's resources and expertise in public health with the private sector's capabilities in drug development and manufacturing.

Intellectual Property Protections

 * Incentives: The Act provided intellectual property protections for companies developing MCMs.

 * Investment: This created a more favorable environment for companies to invest in R&D, knowing their innovations would be protected.

Market Incentives

 * Demand Creation: The Act helped create a market for MCMs, which could potentially lead to increased sales and profits for pharmaceutical companies.

 * Uncertainty: However, the market for MCMs can be unpredictable, as demand is often driven by specific biological threats.

Overall Impact

 * Positive Influence: The BioShield Act had a generally positive impact on the pharmaceutical business, particularly for those involved in the development of MCMs.

 * Challenges: Despite the benefits, the industry still faces challenges such as the uncertainty of the market for MCMs and the need for ongoing investment in R&D.

In summary, the BioShield Act provided a significant boost to the development of medical countermeasures and strengthened the pharmaceutical industry's role in responding to biological threats. While the market for these products can be volatile, the Act's provisions have created a more favorable environment for investment and innovation in this critical area.

Biosimilars: A Game-Changer in Healthcare

Introduction

Biosimilars, often referred to as biological generics, are a relatively new addition to the pharmaceutical landscape. They offer a promising solution to the high costs associated with many biological medications. In this blog post, we'll delve into what biosimilars are, how they differ from generic drugs, and the impact they're having on healthcare.

What are Biosimilars?

Biosimilars are highly similar to original biological drugs (also known as biologics) but are produced by different manufacturers. Unlike generic drugs, which are chemically identical to their brand-name counterparts, biosimilars are produced using biological processes and may have minor differences in their structure or manufacturing process.

The Difference Between Biosimilars and Generic Drugs

The key difference between biosimilars and generic drugs lies in the complexity of the molecules they mimic. While generic drugs can be chemically synthesized, biologics are often proteins or other complex molecules produced by living organisms. This complexity makes it more challenging to create an exact replica, leading to the term "biosimilar" rather than "generic."

The Benefits of Biosimilars

 * Lower Costs: Biosimilars can significantly reduce the cost of prescription medications, making them more accessible to patients.

 * Increased Competition: The introduction of biosimilars can increase competition in the pharmaceutical market, potentially leading to lower prices for both original biologics and their biosimilar counterparts.

 * Improved Patient Access: By reducing costs, biosimilars can help ensure that more patients have access to the life-saving treatments they need.

 * Innovation: The development of biosimilars can drive innovation in the pharmaceutical industry, leading to new and improved treatments.

Challenges and Concerns

Despite their many benefits, biosimilars also face challenges. Some concerns include:

 * Regulatory Hurdles: The approval process for biosimilars can be complex and time-consuming.

 * Patient and Physician Acceptance: There may be concerns about the safety and efficacy of biosimilars, particularly among patients and healthcare providers who are unfamiliar with them.

 * Intellectual Property Issues: Patent disputes and other legal challenges can hinder the development and commercialization of biosimilars.

The Future of Biosimilars

As the biosimilar market continues to grow, we can expect to see even greater benefits for patients and healthcare systems. Continued advancements in technology and regulatory frameworks will help to address challenges and ensure the safe and effective use of biosimilars.

Conclusion

Biosimilars represent a significant advancement in healthcare, offering the potential to improve patient access and reduce costs. By understanding the differences between biosimilars and generic drugs, and by addressing the challenges associated with their development and use, we can help to realize the full potential of this innovative approach to medication.

Would you like to explore a specific aspect of biosimilars in more detail, such as their regulatory landscape or their impact on specific diseases?

Switzerland to implement Measures to combat Shortages of Medicines

The Swiss Federal Council has discussed measures to improve the supply of medicines in Switzerland and is endeavouring to implement a number of measures. In view of increasing global shortages, storage obligations for essential medicines are to be extended, price reductions partially suspended and imports simplified. The aim is to secure the production of essential medicines and better prepare Switzerland for pandemics. A panel of experts is to draw up additional measures.

The measures envisaged by the Federal Council to combat drug shortages include the following points:

• The stockpiling obligation for essential medicines is to be extended to ensure supplies also in times of crisis.
• Planned price reductions for certain medicines will be temporarily suspended so as not to jeopardise availability on the market.
• The federal government should be able to conclude capacity contracts with manufacturers to ensure the production of certain quantities of certain medicines. The extent to which the Armed Forces Pharmacy can take over production is also to be examined.
• The regulations for importing medicines are to be relaxed in order to be able to react more quickly to shortages.
• The Federal Office of Public Health is to assume central responsibility for the procurement of medical supplies in crisis and pandemic situations.

Quality Risks Associated with Uncalibrated Pressure Gauges

If a pressure gauge is not calibrated within its scheduled date, it can lead to several quality risks:

 * Inaccurate Measurements: An uncalibrated gauge may provide readings that are significantly different from the true pressure. This can result in errors in processes, calculations, and decision-making.

 * Non-Compliance: Many industries have regulations or standards that require regular calibration of pressure gauges. Non-compliance can lead to fines, penalties, and damage to the organization's reputation.

 * Product Defects: Inaccurate pressure measurements can lead to product defects, especially in processes that rely on precise pressure control. This can result in wasted materials, rework, and customer dissatisfaction.

 * Safety Hazards: Inaccurate pressure readings can pose safety hazards, particularly in applications involving hazardous materials or equipment. For example, a faulty gauge might indicate a lower pressure than is actually present, leading to an unsafe operating condition.

 * Increased Costs: The consequences of inaccurate measurements, non-compliance, product defects, and safety hazards can lead to increased costs due to rework, repairs, waste, and potential legal liabilities.

Risk Evaluation

The risk associated with an uncalibrated pressure gauge depends on several factors, including:

 * Criticality of the Process: If the pressure gauge is used in a critical process, such as a chemical reaction or a safety system, the risk of inaccurate measurements is higher.

 * Consequences of Inaccurate Measurements: The potential consequences of inaccurate measurements, such as product defects or safety hazards, also influence the risk level.

 * Frequency of Gauge Use: Gauges used frequently are more likely to require calibration more often, and the risk of failure increases if calibration is delayed.

 * Regulatory Requirements: The specific regulations and standards applicable to the industry or process determine the severity of non-compliance risks.

Mitigation Plans

To mitigate the risks associated with uncalibrated pressure gauges, organizations can implement the following measures:

 * Regular Calibration Schedule: Establish a clear and consistent calibration schedule for all pressure gauges, based on the gauge's specifications, the criticality of the process, and regulatory requirements.

 * Calibration Records: Maintain accurate and up-to-date calibration records for each gauge, including the calibration date, results, and any corrective actions taken.

 * Verification Procedures: Implement procedures for verifying the accuracy of pressure gauges between calibration intervals, such as comparing readings with reference gauges or performing simple checks.

 * Emergency Procedures: Develop emergency procedures to address situations where a pressure gauge is suspected of being inaccurate or faulty, including procedures for isolating equipment and notifying relevant personnel.

 * Training: Provide training to personnel on the importance of accurate pressure measurements, the procedures for verifying gauge accuracy, and the consequences of using uncalibrated gauges.

 * Gauge Selection: Select pressure gauges that are appropriate for the specific application and have a suitable accuracy rating.

 * Environmental Factors: Consider the environmental factors that can affect gauge accuracy, such as temperature, vibration, and corrosion, and take appropriate precautions to minimize their impact.

By implementing these mitigation plans, organizations can significantly reduce the risks associated with uncalibrated pressure gauges and ensure the accuracy and reliability of their processes.

Assessing Specificity in Potentiometric Assays

Specificity in a potentiometric assay refers to the ability of the method to measure the analyte of interest without interference from other substances. This is crucial to ensure accurate and reliable results.

Methods to Assess Specificity

Here are some common methods to evaluate the specificity of a potentiometric assay:

 * Blank Analysis:

   * Purpose: To determine the baseline signal or response in the absence of the analyte.

   * Procedure: Prepare a blank sample containing all the reagents and solvents used in the assay except for the analyte. Measure the potential or response.

   * Evaluation: If the blank signal is significantly low compared to the signal obtained with the analyte, it indicates good specificity.

 * Matrix Effect Study:

   * Purpose: To investigate how different matrices (e.g., excipients, impurities) can affect the assay's response.

   * Procedure: Prepare samples with varying concentrations of the analyte in different matrices. Measure the potential or response.

   * Evaluation: Compare the results obtained with the analyte in different matrices. If there are no significant differences, the assay is less susceptible to matrix effects.

 * Interference Studies:

   * Purpose: To identify potential interfering substances that may affect the assay's accuracy.

   * Procedure: Add known amounts of potential interfering substances to samples containing the analyte. Measure the potential or response.

   * Evaluation: Compare the results obtained with and without the interfering substances. If the interfering substances significantly affect the assay's response, it indicates a lack of specificity.

 * Spike Recovery Studies:

   * Purpose: To assess the accuracy of the assay in the presence of potential interfering substances.

   * Procedure: Add known amounts of the analyte to samples containing potential interfering substances. Measure the potential or response.

   * Evaluation: Calculate the recovery percentage of the spiked analyte. A recovery percentage close to 100% indicates good accuracy and specificity.

Additional Considerations

 * Selectivity of the Electrode: The selectivity of the electrode used in the potentiometric assay is crucial for specificity. A highly selective electrode will minimize interference from other ions or substances.

 * Sample Preparation: Proper sample preparation can help to reduce interference from matrix components. This may involve steps like filtration, dilution, or extraction.

 * Method Optimization: The assay conditions, such as pH, temperature, and ionic strength, can be optimized to improve specificity.

By carefully considering these factors and employing appropriate specificity assessment methods, you can ensure the reliability and accuracy of your potentiometric assays.

Would you like to discuss a specific potentiometric assay or explore any of these methods in more detail?

Warning Letter to US Company due to Lack of Product and Process Control

On 05 August, the FDA issued a warning letter to the US company LS Promotions Inc. in Hicksville. The warning letter is the result of a review of the company's responses to a 483 letter from the FDA. It summarises the violations of Current Good Manufacturing Practice (CGMP) for finished drug products under Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 21) found during the inspection as follows.

Laboratory Testing

Adequate laboratory testing was not performed on each batch of manufactured drug product prior to release to ensure compliance with specifications, including the identity and strength of the active ingredients. Similarly, microbiological testing was not carried out, although this is required for certain products, such as SPF 15 lip balm, SPF 30 sunscreen and hand sanitiser. The lack of testing means that it is not certain whether the products meet the specifications. The FDA therefore expects the company to provide a list of chemical and microbial tests, an action plan for conducting reserve sample analyses and a summary of the test results, including the measures to be taken in the event of substandard quality.

Stability

A suitable testing programme to assess the stability of the medicinal products to determine storage conditions and expiry dates was also missing. There was a lack of robust data to demonstrate that the chemical and microbiological properties remain acceptable throughout the shelf life. In the response to the 483 form after the inspection, there were also no details of any planned stability studies, particularly for products such as SPF 30 sunscreen and hand sanitisers. Without these studies, there is no scientific basis to ensure quality until the expiration date. Therefore, the FDA requires a comprehensive stability testing plan, including the definition of test methods and a continuous shelf life monitoring programme.

This was also seen in the particular aspect that LS Promotions further processed your supplier's SPF 15- lip balm bulk product by adding additional ingredients prior to bottling, but did not have data to demonstrate the stability of this altered formulation product in the finished containers throughout the shelf life.

Product and Process Control

Adequate written procedures for production and process control were not established to ensure the quality of the medicinal products manufactured. There was insufficient validation of manufacturing processes, including cleaning of production equipment. Again, LS Promotions' response was inadequate as neither a detailed validation programme nor a timetable for implementation was provided. A process validation programme covering the entire product life cycle and improvements to the cleaning validation programme are required to ensure that all manufactured products meet quality requirements.

Also in relation to the necessary cleaning and its validation for the filling lines used for multiple products was not in place, Here the FDA requires validation with worst case scenarios such as:

Drugs with higher toxicity 

Drugs with higher concentration of active ingredients

Drugs with lower solubility in their cleaning solvents

Drugs with properties that make them difficult to clean

Swabbing sites for the most difficult to clean areas

Maximum holding times before cleaning

Poor change control management was also identified in this context.

Responsibility and authorisation of the quality units

In general, the FDA found that the Quality Unit (QU) did not fulfil its responsibility to ensure that the manufactured drug products comply with CGMP requirements. Adequate procedures to define the responsibilities of the QU, verify the identity of ingredients and ensure control over labelling were also lacking. No detailed plans for revising the QU procedures were submitted. Therefore, the FDA expected a comprehensive assessment and remediation plan to strengthen the QU, including review of procedures and oversight of production processes.

Further details can be found in the corresponding Warning Letter at the FDAs website.

EMA/CMDh: Q&A Document Nitrosamines revised

In July 2024, the nitrosamine Q&A document "Nitrosamines EMEA-H-A5(3)-1490 - Questions and answers for marketing authorization holders / applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products" of the EMA/CMDh was revised again and published on the EMA website under "Questions and answers".

This list of questions and answers was first published in 2020. The new version 21 now contains updates and changes in the following questions and their answers:

• 8. How should confirmatory tests be conducted by MAHs and manufacturers?
• 9. What are the requirements of the analytical method(s)?
• 10. Which limits apply for nitrosamines in medicinal products?
• 14. What is the approach for new and ongoing marketing authorisation applications (MAA)? 
• 15. When should a test for nitrosamines be included in the MA dossier?
• 16. What are the responsibilities of MAHs for APIs with CEPs or ASMFs?

The current version of the Q&A document "Nitrosamines EMEA-H-A5(3)-1490 - Questions and answers for marketing authorisation holders / applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products"