Tag: fda

Section 711 of FDASIA and Regulatory Obligations

Too often, I see folks in pharma focus on 21 CFR Chapter 1, or at best all three chapters, maybe know the guidances and pay attention to little else. Unfortunately, that approach will often get one in trouble.

Section 711 of the Food and Drug Administration Safety and Innovation Act (FDASIA) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to enhance the safety and quality of the drug supply chain. Specifically Section 711 amends Section 501(a)(2)(B) of the FD&C Act by adding the following sentence:

“For purposes of paragraph (a)(2)(B), the term ‘current good manufacturing practice’ includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.”

This amendment clarifies that current good manufacturing practice (CGMP) requirements for drugs include:

  1. Implementing oversight and controls over the entire manufacturing process to ensure quality.
  2. Managing the risks related to raw materials, other materials used in manufacturing, and finished drug products to establish their safety.

In essence, Section 711 expands the FDA’s CGMP authority to explicitly cover supply chain management and drug manufacturers’ oversight of their suppliers and contract manufacturing operations. It also allows the FDA to enforce supply chain control requirements during inspections.

The legislative history shows that Congress intended to significantly expand the FDA’s authority over the increasingly global drug supply chain through this provision. It allows the FDA to scrutinize how manufacturers select, qualify, and oversee suppliers of raw materials and contract manufacturers to ensure drug quality and safety.

Please note that the FDA gets this expanded authority without revising 21CFR. That’s how it works; Congress can do that. Will we eventually see some 21 CFR updates? I have no idea.

But what this does mean is that the FDA has the authority to:

  1. Inspect risk management for GMPs, and assume you have it. What does good risk management look like? The agency has adopted ICH Q9(r1) as guidance, so start there.
  2. Inspect your supplier management, which includes qualifying and overseeing suppliers and contract manufacturers.

I’ve started to receive regulatory intelligence that this is coming up in inspections. Expect to be asked for the risk management evidence and for supplier qualification and oversight evidence.

FDA Reorganization

FDA’s Reorganization Approved for Establishing Unified Human Foods Program, New Model for Field Operations and Other Modernization Efforts

The FDA’s reorganization has been unveiled and will be implemented on October 1st. As a total wonk, this is exciting.

There are two major changes:

  • Forming a Human Food Program (HFP) to consolidate a preventive approach will not have much impact on me professionally, but I’m hoping that as a consumer, we see significant dividends from this refocus.
  • ORA is being renamed the Office of Inspections and Investigations (OII) and will focus on inspections, investigations, and imports as its core mission. If nothing else, this will make explaining the structure of the FDA a heck of a lot easier.

Everything else seems to be mostly a lot of shuffling of the deck chairs that will have little impact.

Leveraging Inspection Manuals for GMP Inspection Readiness

The various agency inspection manuals are critical tools for inspection readiness. I want to lay out where to find some of these manuals and then go deep into pre-approval inspections, focusing on data integrity.

European Medicines Agency

The European Medicines Agency (EMA) has established detailed procedures and work instructions for coordinating and conducting Good Clinical Practice (GCP), Good Manufacturing Practice (GMP), and pharmacovigilance inspections. Here are the key points regarding EMA’s inspection procedures:

GCP Inspection Procedures

  • EMA identifies applications for GCP inspections based on risk assessment criteria and exchanges information on shared applications with the FDA.
  • Inspections can be joint (conducted concurrently by EMA and FDA inspectors) or sequential (conducted separately by each agency).
  • EMA notifies the applicant/marketing authorization holder (MAH) and inspects sites about upcoming inspections through the IRIS industry portal instead of formal letters.
  • Applicants/MAHs must provide a signed statement accepting the inspection and granting direct access to documents and medical records.
  • Requested documents should be provided directly to inspectors in electronic format after consulting the reporting inspector.
  • After the inspection, EMA receives the draft inspection report, finalizes it with the inspectee’s responses, and publishes it in IRIS.

GMP Inspection Procedures

  • EMA coordinates GMP inspections based on risk assessment for marketing authorization applications, variations, and routine re-inspections.
  • Work instructions cover areas such as inspection announcement, fee calculation, product sampling/testing, and report circulation.

Pharmacovigilance Inspection Procedures

  • EMA has specific procedures for coordinating pharmacovigilance inspections and managing non-compliance notifications from MAHs.
  • Work instructions detail the inspection program creation, data entry in databases, and interactions with third-country inspectorates.

The EMA aims to harmonize inspection processes with the FDA and other regulatory bodies to streamline collaboration and information sharing while ensuring clinical trial subject protection and product quality.

FDA

The FDA Investigations Operations Manual (IOM) is the primary inspection manual used by FDA personnel when performing inspections and investigations.

The key points about the IOM are:

  • It provides comprehensive instructions, procedures, and policies for FDA investigators and inspectors to follow when conducting inspections, surveys, and investigations.
  • It covers inspectional activities for foods, drugs, medical devices, biologics, cosmetics, and other FDA-regulated products.
  • The manual details procedures for inspections of manufacturing facilities, sampling, import operations, recalls, consumer complaints, and other compliance activities.
  • It aims to ensure inspections are conducted consistently across FDA field offices and provide clear guidance to the industry on the FDA’s inspection approach.
  • The IOM is updated periodically to incorporate new laws, regulations, policies, and technological changes impacting FDA’s operations.
  • While not legally binding, the IOM represents the FDA’s current thinking and policies on inspections and investigations.

The FDA Investigations Operations Manual serves as the comprehensive inspection reference and procedure manual for FDA field staff carrying out the agency’s oversight and enforcement activities across all regulated product areas.

Pre-Approval Inspections

For new facilities, CPGM 7346.832, the FDA’s Compliance Program Guidance Manual for Pre-Approval Inspections (PAIs) of drug manufacturing facilities, is critical to spend time with. It outlines the objectives and procedures for FDA inspectors to evaluate a facility’s readiness for commercial manufacturing before approving a new drug application.

The key objectives of CPGM 7346.832 are:

  1. Assess if the facility has a quality system capable of controlling commercial manufacturing operations.
  2. Verify that the manufacturing processes, formulation, and analytical methods conform to the application details.
  3. Audit raw data integrity to authenticate the data submitted in the application.
  4. Evaluate the facility’s commitment to quality in pharmaceutical development (new objective added in 2022 revision).

The guidance instructs inspectors on evaluating the firm’s quality systems, process validation, data integrity, laboratory controls, change management, investigations, batch release procedures, and compliance with current Good Manufacturing Practices (cGMPs). It aims to ensure the facility can reliably produce the drug product described in the application.

Data Integrity

CPGM 7346.832 has specific requirements for data integrity audits during drug manufacturing facility pre-approval inspections (PAIs). Utilizing this document is an excellent way to evaluate your data integrity program.

The key points are:

  1. Objective 3 of the guidance is “Data Integrity Audit”—auditing and verifying raw data associated with the product to authenticate the data submitted in the application.
  2. Inspectors must audit the accuracy and completeness of data reported by the facility for the product. This involves verifying the factual integrity (data matches what was submitted) and contextual integrity (supporting data is complete).
  3. Inspectors should examine raw data, such as chromatograms, analyst notebooks, electronic data, etc., and compare it to the summary data in the application’s Chemistry, Manufacturing, and Controls (CMC) section.
  4. The data integrity audit should focus on finished product stability, dissolution, content uniformity, API impurities, etc.
  5. Inspectors must identify any unreported relevant data, data falsification, improper invalidation of results, or unexplained data discrepancies.
  6. Indications of data integrity issues include altered raw data, references to failing studies, discrepancies between samples, and missing records.

The data integrity audit aims to ensure the CMC data submitted to FDA is complete, reliable, and can be fully authenticated from the raw data at the manufacturing site. Robust data integrity is critical for the FDA to decide on the application’s approval.

Commissioning, Qualification and Validation

Commissioning, qualification, and validation are three distinct but interrelated processes in the pharmaceutical and biotechnology industries that ensure facilities, equipment, systems, and processes meet regulatory requirements and produce products of the desired quality. Here are the key differences:

Commissioning

  • Commissioning is a systematic process of ensuring that equipment, systems, and facilities are designed, installed, and functioning according to operational and engineering requirements.
  • It involves design reviews, installation verification, functional testing, and handover to operations.
  • Commissioning primarily focuses on satisfying engineering requirements and does not have direct regulatory requirements.

Qualification

  • Qualification is a regulated and documented process that demonstrates that equipment, systems, and facilities are installed correctly and operate as intended for their specific use.
  • It applies only to equipment, systems, and utilities that directly or indirectly impact product quality and patient safety.
  • Qualification activities include Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).
  • Qualification is focused on by regulatory authorities like the FDA and EMA to ensure compliance.

Validation

  • Validation is a broader concept establishing documented evidence that a process consistently produces a product that meets its predetermined specifications and quality attributes.
  • It encompasses the entire process lifecycle, including process design, qualification of equipment/systems, and continued process verification.
  • Validation ensures that the equipment and systems are qualified and the entire process is controlled to produce the desired final product.

In summary, commissioning verifies engineering requirements, qualification demonstrates suitability for intended use, and validation provides a high degree of assurance that the process will consistently produce a quality product. These activities are interconnected, with commissioning often leveraged during qualification and qualification being a subset of the overall validation process.

FDA’s Framework for Process Validation

The FDA’s Process Validation Guidance is a core document outlining a lifecycle approach with outlines a lifecycle approach with three main stages:

Stage 1: Process Design

  • Establish a process design based on knowledge gained through development and scale-up activities.
  • Identify critical quality attributes (CQAs) and critical process parameters (CPPs) using risk assessment and multivariate studies like Design of Experiments (DoE).
  • Develop a control strategy to ensure CQAs are met.

Stage 2: Process Qualification

  • Evaluate the process design through facility, utility, and equipment qualification.
  • Conduct performance qualification (PQ) by running production batches to confirm the process design has reproducible commercial manufacturing.
  • Establish scientific evidence that the process meets all defined requirements and product specifications.

Stage 3: Continued Process Verification

  • Maintain the validated status and monitor performance to ensure a state of control.
  • Identify sources of variation and implement process improvements through an ongoing program.
  • Conduct product quality reviews periodically to evaluate process performance.

The guidance emphasizes using a science and risk-based approach throughout the lifecycle, leveraging process understanding and knowledge gained from development through commercial production. Effective process validation requires good planning, documented evidence, and a robust quality system.