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?