What is Continued Process Verification

# Ongoing Process Verification: A European GMP Inspector's Essential Guide

In the evolving landscape of pharmaceutical manufacturing, **ongoing process verification** (also known as **continued process verification**) remains a cornerstone of compliance. Introduced as part of the **process validation life cycle**, this stage ensures processes stay robust amid real-world variables. Drawing from insights shared by Dr. Franz Schönfeld, a seasoned European GMP inspector, during an ECA Academy course, this post explores what inspectors expect—and how your team can meet those standards. If you're navigating GMP regulations, these perspectives could refine your validation strategy.

## Understanding the Process Validation Life Cycle: The PDAC Framework

At its core, **process validation** follows a structured life cycle, often visualized as the PDAC cycle (Plan-Do-Check-Act). Using an active ingredient synthesis as a practical example, Dr. Schönfeld breaks it down:

- **Plan**: Identify and mitigate potential contamination risks through thorough risk assessments.

- **Do**: Execute validation within proven acceptable ranges, whether via traditional, hybrid, or continuous approaches.

- **Check**: Analyze validation run results against the plan, scrutinizing deviations for root causes.

- **Act**: Approve the process or implement enhancements, such as intensified sampling.

This cyclical model isn't a one-off; it's designed for perpetual improvement, making **ongoing process verification** indispensable for long-term control.

## Detecting Anomalies in the Commercial Phase: Key Triggers

One of the biggest challenges? Spotting anomalies post-launch, when production scales up. Dr. Schönfeld stresses that **continued process verification** is your frontline defense. Watch for these common triggers:

- Shifts in personnel, including leadership changes that could alter oversight.

- Equipment maintenance, repairs, or upgrades that subtly impact performance.

- Manufacturing deviations, no matter how minor.

- Emerging trends in analytical testing results.

- Rising customer complaints signaling quality drifts.

- Evolving regulatory requirements that demand process tweaks.

By leveraging extensive commercial data, **ongoing process verification** not only flags issues early but also drives data-backed refinements—transforming potential pitfalls into opportunities for optimization.

## Moving Beyond Routine Revalidation: A Smarter Approach

Gone are the days of periodic revalidations, especially in non-sterile manufacturing. **Ongoing process verification** steps in as a dynamic alternative, guided by an approved plan that outlines:

- The processes under review.

- Verification scope and frequency, tailored to your process maturity and incremental changes.

- Integration with broader quality systems.

This shift emphasizes proactive monitoring over reactive checks, aligning with EU GMP Annex 15 guidelines.

## Harnessing Statistics and Product Quality Reviews (PQR)

Statistics aren't optional—they're expected. Dr. Schönfeld highlights their role in **product quality reviews (PQR)**, where trend analysis is already commonplace. However, PQR serves products, not processes, and arrives too late in the cycle to substitute for dedicated verification.

Pro tip: Embed statistical tools in your **validation master plan (VMP)** to:

- Mandate change control evaluations for process stability.

- Set thresholds for cumulative changes that prompt deeper reviews.

- Adopt rolling reviews to catch trends in real time.

The result? A **continued process verification report** that clearly states if your process is controlled—and flags any need for extra monitoring or sampling.

## EU vs. US: Harmonized Yet Distinct

Comparing notes with the US FDA's Process Validation Guidance, Dr. Schönfeld notes semantic differences but a unified life cycle philosophy. Both regions prioritize stage 3 (continued verification) for sustained control, ensuring global harmonization without compromising local nuances.

## Common GMP Pitfalls: Lessons from Inspections

From his inspection tenure, Dr. Schönfeld flags recurring deficiencies in **process validation**, including gaps in anomaly detection and inadequate statistical rigor. While specifics vary, the takeaway is clear: Robust documentation and forward-thinking plans are non-negotiable to avoid citations.

## Final Thoughts: Elevate Your GMP Compliance Today

**Ongoing process verification** isn't just a regulatory checkbox—it's a strategic imperative for pharmaceutical excellence. As Dr. Schönfeld's expertise reveals, embracing this stage with data-driven vigilance can safeguard quality, streamline operations, and impress inspectors.

Ready to audit your processes? Review your VMP against these insights and consider ECA resources for deeper dives. Share your experiences with **continued process verification** in the comments—how has it shaped your GMP strategy?

*For more on GMP trends, subscribe to our newsletter and stay ahead of compliance curves.*

Investigation Models

When conducting an investigation, the type of reasoning you use depends on the nature of the problem, the available evidence, and the goals of your inquiry. The two primary types of reasoning—**deductive** and **inductive**—are commonly used, alongside others like **abductive reasoning**. Here's a breakdown to help you choose the appropriate reasoning method for your investigation:

---

### 1. Deductive Reasoning

**Definition**: Deductive reasoning starts with general premises or rules and applies them to specific cases to reach a logically certain conclusion. It moves from the general to the specific.

**When to Use**:

- When you have established facts, rules, or principles that are known to be true.

- When you need a definitive, logically certain conclusion based on those premises.

- Common in investigations where you test a hypothesis against specific evidence.

**Example**:

- **Premise 1**: All employees with keycard access can enter the restricted area.

- **Premise 2**: John has keycard access.

- **Conclusion**: John can enter the restricted area.

- In an investigation, you might use deductive reasoning to confirm whether a suspect fits a specific profile based on established criteria (e.g., access logs, qualifications).

**Strengths**:

- Provides clear, certain conclusions if the premises are true.

- Useful for ruling out possibilities or confirming hypotheses with concrete evidence.

**Weaknesses**:

- Requires accurate and complete premises; if premises are false, the conclusion will be invalid.

- Limited to what is already known—doesn’t generate new hypotheses.

**Use in Investigation**:

- Testing specific hypotheses (e.g., "If the crime required technical expertise, only suspects with that expertise could be involved").

- Analyzing forensic evidence against known standards (e.g., matching DNA profiles).

---

### 2. Inductive Reasoning

**Definition**: Inductive reasoning involves observing specific instances or patterns and drawing general conclusions based on those observations. It moves from the specific to the general.

**When to Use**:

- When you have incomplete information and need to form hypotheses or generalizations.

- When analyzing patterns or trends in evidence to predict future outcomes or identify causes.

- Common in early stages of investigations where you’re gathering evidence and forming theories.

**Example**:

- **Observation**: Three burglaries occurred at night in the same neighborhood, targeting unlocked homes.

- **Conclusion**: Burglaries in this neighborhood are likely to occur at night and target unlocked homes.

- In an investigation, you might use inductive reasoning to identify a pattern in a series of incidents (e.g., a serial offender’s methods).

**Strengths**:

- Allows you to generate hypotheses or theories based on limited data.

- Useful for identifying trends or predicting future events.

**Weaknesses**:

- Conclusions are probabilistic, not certain—new evidence may contradict them.

- Risk of overgeneralization based on insufficient or biased data.

**Use in Investigation**:

- Identifying patterns in criminal behavior (e.g., a thief always strikes on weekends).

- Developing profiles of suspects based on observed behaviors or evidence.

---

### 3. Abductive Reasoning

**Definition**: Abductive reasoning involves forming the most likely explanation based on incomplete or uncertain information. It’s often described as "inference to the best explanation."

**When to Use**:

- When you have incomplete evidence and need to form a plausible hypothesis.

- When deductive certainty isn’t possible, and inductive generalizations are too broad.

- Common in complex investigations where you’re piecing together partial clues.

**Example**:

- **Observation**: A window is broken, and valuables are missing from a home.

- **Conclusion**: The most likely explanation is that a burglar broke the window to gain entry and steal the valuables.

- In an investigation, abductive reasoning helps you propose the most plausible scenario based on available clues, even if not all facts are known.

**Strengths**:

- Useful for generating working hypotheses in the absence of complete data.

- Balances creativity and logic to explain complex or ambiguous situations.

**Weaknesses**:

- Conclusions are tentative and may need revision as new evidence emerges.

- Relies on subjective judgment about what’s "most likely."

**Use in Investigation**:

- Developing theories about a crime when evidence is incomplete (e.g., hypothesizing a motive based on partial clues).

- Reconstructing events based on fragmented evidence (e.g., crime scene analysis).

---

### Comparing the Approaches

| **Reasoning Type** | **Starting Point** | **Conclusion** | **Certainty** | **Best for** |

|--------------------|--------------------|----------------|---------------|--------------|

| **Deductive** | General rules | Specific fact | Certain | Testing hypotheses, confirming facts |

| **Inductive** | Specific observations | General rule | Probabilistic | Identifying patterns, forming theories |

| **Abductive** | Incomplete evidence | Most likely explanation | Tentative | Explaining ambiguous or incomplete data |

---

### Other Reasoning Approaches

In addition to deductive, inductive, and abductive reasoning, you might consider:

- **Causal Reasoning**: Identifying cause-and-effect relationships (e.g., determining what caused a system failure in an investigation).

- **Analogical Reasoning**: Drawing comparisons to similar cases or situations (e.g., comparing a current crime to past cases with similar patterns).

- **Bayesian Reasoning**: Updating probabilities based on new evidence (e.g., adjusting the likelihood of a suspect’s involvement as new clues emerge).

---

### How to Choose the Right Reasoning for Your Investigation

1. **Assess Available Evidence**:

   - If you have clear, reliable facts or rules, use **deductive reasoning** to reach certain conclusions.

   - If you’re observing patterns or trends, use **inductive reasoning** to form hypotheses.

   - If evidence is incomplete or ambiguous, use **abductive reasoning** to propose the most likely explanation.

2. **Consider the Investigation Stage**:

   - **Early Stage**: Use inductive or abductive reasoning to generate hypotheses based on initial evidence or patterns.

   - **Mid-Stage**: Use abductive reasoning to refine hypotheses and deductive reasoning to test them against new evidence.

   - **Late Stage**: Use deductive reasoning to confirm conclusions or finalize the investigation.

3. **Combine Approaches**:

   - Most investigations benefit from combining reasoning types. For example:

     - Use **inductive reasoning** to identify a pattern in crime scenes.

     - Use **abductive reasoning** to hypothesize a suspect’s motive.

     - Use **deductive reasoning** to confirm the hypothesis with forensic evidence.

4. **Account for Uncertainty**:

   - If evidence is limited, lean on abductive reasoning to form working theories, but remain open to revising them.

   - Use Bayesian reasoning to update probabilities as new evidence emerges.

---

### Practical Tips for Applying Reasoning

- **Document Evidence Clearly**: Organize your evidence to distinguish between facts (for deductive reasoning), observations (for inductive reasoning), and incomplete clues (for abductive reasoning).

- **Test Hypotheses**: Use deductive reasoning to test hypotheses generated through inductive or abductive reasoning.

- **Avoid Bias**: Be cautious of confirmation bias (favoring evidence that supports your hypothesis) or overgeneralization in inductive reasoning.

- **Iterate**: Revisit your reasoning as new evidence emerges, refining or discarding hypotheses as needed.

---

### Example Scenario

**Investigation**: A series of thefts in an office building.

- **Inductive Reasoning**: You notice all thefts occur on Fridays when the cleaning crew is present. You hypothesize the thief is someone on the cleaning crew.

- **Abductive Reasoning**: A broken lock is found, and only small items are stolen. You infer the thief is likely an opportunist who entered through the broken lock.

- **Deductive Reasoning**: The company’s access logs show only three employees were present during the thefts. You conclude one of them must be involved, assuming the logs are accurate.

---

By understanding the strengths and limitations of each reasoning type, you can strategically apply them to different phases of your investigation, ensuring a thorough and logical approach to uncovering the truth. If you have a specific investigation in mind, I can help tailor these methods to your case!

Annex 22: Artificial Intelligence in GMP – What Pharma Needs to Know

Annex 22: Artificial Intelligence in GMP – What Pharma Needs to Know

Artificial Intelligence (AI) is rapidly transforming pharmaceutical manufacturing, but regulatory compliance remains critical. To guide the safe and effective use of AI, the European Commission has introduced Annex 22: Artificial Intelligence under EU GMP (Good Manufacturing Practice). This annex complements Annex 11 (Computerised Systems) and outlines expectations for the use of machine learning (ML) models in regulated pharma environments.

Scope of Annex 22

Applies to AI/ML models that are trained on data, not hard-coded.

Covers only static, deterministic models (those that do not adapt once deployed).

Excludes dynamic learning systems, probabilistic models, Generative AI, and Large Language Models (LLMs) for critical GMP applications.

Such advanced AI tools may only be used in non-critical GMP processes with strong human-in-the-loop (HITL) oversight.

Core Principles for AI in GMP

Cross-functional collaboration: QA, process SMEs, IT, and data scientists must work together.

Quality risk management: Risk to patient safety, product quality, and data integrity drives all activities.

Strong documentation: Model development, validation, and testing records are mandatory.

Qualified personnel: Staff must be trained to understand AI risks and responsibilities.

Intended Use & Acceptance Criteria

The intended use of an AI model must be clearly defined and documented.

Input data, variations, and possible limitations should be characterized.

AI must perform as well as or better than the process it replaces.

Acceptance metrics may include accuracy, sensitivity, specificity, precision, and F1 score.

Test Data & Validation

Test data must be representative, independent, and verified.

Pre-processing, exclusions, or synthetic data use must be justified.

Independence is key: training, validation, and testing datasets must remain separate.

All testing requires a formal plan, documentation, and deviation handling.

Explainability & Confidence in AI Decisions

AI systems must provide explainable results using techniques like SHAP, LIME, or heat maps.

Confidence scores should be logged; low-confidence predictions flagged as “undecided” instead of forcing unreliable decisions.

Ongoing Operations & Monitoring

AI models must be under change control and configuration control.

Continuous performance monitoring is required to detect data drift or system changes.

Human review remains essential for AI-assisted decision-making in GMP.

Why Annex 22 Matters

Annex 22 marks a regulatory milestone in pharma AI adoption. It emphasizes:

Safety first: patient safety and product quality cannot be compromised.

Transparency: AI decisions must be explainable.

Accountability: human oversight and strong governance remain non-negotiable.

For pharmaceutical companies, this guidance provides a clear compliance roadmap for AI implementation. While Generative AI and LLMs are not permitted in critical processes, their use in supportive, non-critical applications is acknowledged — as long as there is qualified human oversight.

👉 In short, Annex 22 bridges innovation and regulation, ensuring that pharma can leverage AI responsibly, without risking GMP compliance.

EU Aneex 22 AI/ML Artificial intelligence and Machine learning

Understanding "Human-in-the-Loop" in Pharmaceutical Manufacturing

In the evolving landscape of pharmaceutical production, the integration of artificial intelligence (AI) and machine learning (ML) is transforming how active substances and medicinal products are manufactured. The forthcoming EU GMP Annex 22 outlines stringent guidelines for implementing these technologies, emphasizing validation, training, and oversight. Central to these guidelines is the principle of "Human-in-the-Loop" (HITL), which ensures that human expertise remains integral to AI-driven processes, safeguarding quality and safety.

Defining "Human-in-the-Loop"

At its core, "Human-in-the-Loop" describes a collaborative framework where AI or ML systems provide insights or recommendations, but final decisions rest with qualified human operators. This approach prevents fully autonomous AI operations in regulated environments, particularly where patient safety, product quality, or data integrity could be at stake. Instead, it positions humans as the ultimate validators, reviewing and approving AI outputs to align with established standards.

Notably, the guidelines exclude generative AI and large language models from critical Good Manufacturing Practice (GMP) areas, deeming them unsuitable due to inherent uncertainties. However, in non-critical applications—those with minimal direct impact on core GMP principles—these tools may be employed under strict human supervision.

Implementing Human Oversight in Practice

To operationalize HITL, organizations must clearly define the roles and responsibilities of human operators within the system's intended use. For instance, when an AI model analyzes data to suggest process adjustments, the operator is tasked with evaluating the recommendation, verifying its accuracy, and documenting the rationale for any actions taken. This oversight mirrors traditional manual processes but leverages AI to enhance efficiency.

Key implementation steps include:

Operator Training and Qualification: Personnel must possess relevant expertise and undergo targeted training on the specific AI tools, ensuring they can critically assess model outputs for appropriateness.

Monitoring and Review: Continuous evaluation of AI performance is essential, with operators reviewing outputs on a regular basis. In higher-risk scenarios, every output may require individual testing or approval to mitigate potential errors.

Record-Keeping: Comprehensive documentation of human interventions, model decisions, and validation steps is mandatory, providing an audit trail that demonstrates compliance and accountability.

These measures ensure that AI serves as a supportive tool rather than a replacement for human judgment, maintaining the reliability of pharmaceutical manufacturing workflows.

Benefits of the Human-in-the-Loop Approach

Adopting HITL offers several advantages in a GMP-compliant setting. It balances technological innovation with regulatory caution, allowing AI to streamline routine tasks while preserving human control over nuanced decisions. This reduces operational risks, enhances decision-making accuracy, and upholds the highest standards of product integrity. Ultimately, HITL fosters a culture of responsibility, where AI augments rather than supplants skilled professionals, leading to more robust and traceable manufacturing processes.

Navigating Challenges

While HITL provides essential safeguards, it introduces complexities that organizations must address. Human operators require ongoing training to stay proficient with evolving AI systems, and the need for meticulous monitoring can increase administrative demands. In non-critical areas, validating AI outputs—potentially for each instance—demands resources comparable to traditional methods. By proactively designing systems with clear protocols, pharmaceutical firms can overcome these hurdles, ensuring seamless integration without compromising compliance.

Conclusion

The "Human-in-the-Loop" concept, as highlighted in the draft EU GMP Annex 22, represents a forward-thinking strategy for incorporating AI into pharmaceutical manufacturing. By mandating human oversight, it reinforces the pillars of patient safety, product quality, and data integrity. As the industry advances, embracing HITL will be key to harnessing AI's potential responsibly, paving the way for innovative yet compliant production environments.

EU GMP Chapter 1 Revision: Key Updates and Stakeholder Consultation

The European Commission has announced a targeted revision to Chapter 1 of EudraLex Volume 4, the EU Good Manufacturing Practice (GMP) Guidelines, focusing on the Pharmaceutical Quality System (PQS). This update, developed collaboratively by the European Medicines Agency's (EMA) Good Manufacturing and Distribution Practice Inspectors Working Group (GMDP-IWG) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S), aims to align the guidelines with contemporary advancements in regulatory science and risk management principles.

The primary objective of the revision is to enhance the efficiency of regulatory frameworks by incorporating evidence-based approaches, including the recently updated ICH Q9(R1) guideline on Quality Risk Management  It places greater emphasis on knowledge management (KM) and fostering a proactive quality culture within pharmaceutical manufacturing operations. These changes build on the existing foundation of Chapter 1, which already mandates that a PQS must manage product and process knowledge across all lifecycle stages, ensuring compliance with modern GMP expectations.

A key aspect of the revision is its integration with ICH Q10, the guideline on Pharmaceutical Quality Systems. KM and QRM are positioned as essential enablers for an effective PQS.

Notably, a new paragraph (1.4(xviii)) introduces the application of KM in conjunction with QRM to create an early warning system for identifying and addressing emerging quality and manufacturing risks.

Additionally, paragraph 1.13 underscores the role of knowledge in driving informed decision-making, prompting re-evaluations, and promoting continuous improvement

The proposed amendments address three core areas: Quality Risk Management (QRM), Knowledge Management (KM), and Product Quality Review (PQR)

For QRM, the revision incorporates ICH Q9(R1) through seven new sections that promote risk-based decision-making, a proactive and evidence-based quality culture, scientific rationale in risk assessments, appropriate formality in QRM processes, awareness of subjectivity in evaluations, and the proactive identification of manufacturing risks to prevent shortages and strengthen supply chain resilience.

KM is elevated as a foundational element in GMP-regulated environments, working synergistically with QRM to improve oversight and risk mitigation

. Regarding PQR, the updates provide clearer requirements, such as incorporating trending data from prior reviews for products with limited batch production in a 12-month period, specifying minimum content for PQRs when no batches are manufactured, and permitting adjusted review timelines with proper justification.

### Key Takeaways

- **Consultation Deadline:** Comments on the revised draft must be submitted by December 3, 2025.

- **Core Focus Areas:** The revision targets enhancements in Quality Risk Management (QRM), Knowledge Management (KM), and Product Quality Review (PQR).

- **Integration with ICH Guidelines:** Aligns with ICH Q9(R1) for QRM and ICH Q10 for PQS, emphasizing KM and QRM as enablers for proactive risk oversight.

- **New Provisions:** Includes an early warning system via KM and QRM (paragraph 1.4(xviii)) and the use of knowledge for decision-making and improvement (paragraph 1.13).

- **PQR Clarifications:** Requires trending data from previous reviews for low-volume products, minimum content for zero-batch periods, and justified adjustments to review timelines.

- **Development Collaboration:** Joint effort by EMA GMDP-IWG and PIC/S to ensure science-based, risk-managed regulatory frameworks.

Unlocking Competitive Edge: How Digital Maturity Empowers CDMOs to Secure More Sponsor Contracts

In the fast-paced world of contract development and manufacturing organizations (CDMOs), compliance isn't just a box to check—it's a powerful tool for standing out in a crowded market. As regulatory demands intensify and sponsors seek reliable partners for outsourcing, CDMOs that elevate their compliance strategies through digital maturity can turn potential challenges into business wins. This blog post draws insights from a recent webinar on CDMO contract manufacturing, featuring experts like Gil Roth from the Pharma and Biopharma Outsourcing Association and Caitlin Minton-Smith from MasterControl. We'll dive into the evolving landscape, key regulatory hurdles, digital strategies, and future trends to help your CDMO business thrive. Whether you're a CDMO executive, quality manager, or operations lead, these specifics will provide actionable steps to enhance your operations and attract more clients.

## The Shifting Terrain of CDMO Operations: Opportunities and Challenges

The CDMO sector has transformed dramatically since the 1990s, evolving from simple facility spin-offs to full-service powerhouses that handle everything from early-stage development to commercial-scale production. Today, CDMOs are at the heart of global drug and biopharma innovation, often pioneering advanced technologies because of their exposure to diverse client projects—something single-product companies rarely achieve.

However, this growth brings complexities. CDMOs must juggle multiple client requirements, varied product lines, and international regulations, all while maintaining impeccable traceability and control. For your business, this means investing in robust systems early on. A key tip: Conduct a gap analysis of your current processes against client portfolios to identify where digital tools can streamline multi-client management, reducing errors and speeding up onboarding.

## Navigating the Top 6 Regulatory Frameworks Impacting CDMOs

Regulations are reshaping how CDMOs operate, demanding more than basic adherence—they require proactive, data-driven approaches. Here's a breakdown of the six critical frameworks, with specific guidance on how your CDMO can adapt for better compliance and efficiency:

1. **21 CFR Parts 210 and 211 (cGMP Basics)**: These form the core of good manufacturing practices, with recent FDA drafts pushing for real-time monitoring and science-based controls. Focus on ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, Available) in your QMS.  

   *Helpful Tip for CDMOs*: Implement digital process validation and CAPA systems to enable real-time quality oversight. This not only meets FDA expectations but also impresses sponsors by demonstrating proactive risk management, potentially shortening audit times by 20-30%.

2. **EU GMP Annex 1 (Contamination Control)**: Updated in 2023, this 60-page expansion emphasizes barrier technologies, cleanroom protocols, and integrated contamination strategies. It's not just about having isolators—it's about holistic system integration.  

   *Helpful Tip for CDMOs*: Develop a comprehensive contamination control strategy document and integrate it with digital monitoring tools for real-time environmental data. This can help avoid costly non-compliance issues and position your facility as Annex 1-ready for European sponsors.

3. **EU MDR (Medical Device Regulations)**: This requires end-to-end traceability, robust documentation, and enhanced post-market surveillance, including UDI support.  

   *Helpful Tip for CDMOs*: Build supplier oversight into your digital platform to automate traceability from risk assessment to production. For device-focused CDMOs, this can accelerate sponsor approvals and reduce recall risks by ensuring quick access to audit trails.

4. **21 CFR Part 11 (Electronic Records and Signatures)**: Evolving to prioritize data integrity with tamper-proof audit trails and strong authentication. Data integrity citations are common in FDA warnings, especially for drug products.  

   *Helpful Tip for CDMOs*: Validate your digital systems rigorously and use AI for anomaly detection in data logs. This builds "digital trust" with sponsors, making your CDMO a preferred partner for high-stakes projects.

5. **ISO 13485 (Medical Device Quality Systems)**: An international standard stressing lifecycle risk management, documentation, and even sustainability factors.  

   *Helpful Tip for CDMOs*: Align your QMS with ISO requirements by incorporating objective evidence tracking in digital tools. In Europe, adding climate considerations can differentiate your services, appealing to eco-conscious sponsors.

6. **21 CFR 820/QMSR (Harmonized with ISO 13485)**: The FDA's shift to global alignment means broader audits and deeper data scrutiny across the product lifecycle.  

   *Helpful Tip for CDMOs*: Expand your audit scope digitally to include execution metrics, not just docs. This ensures scalability for complex portfolios and helps win contracts by showcasing mature quality execution.

By addressing these frameworks head-on, CDMOs can avoid penalties and use compliance as a selling point in proposals.

## Turning Digital Transformation into a Business Advantage for CDMOs

Digital maturity isn't optional—it's a game-changer for CDMOs aiming to win more sponsor contracts. Sponsors now scrutinize your digital capabilities as part of their selection process, looking for seamless integration, real-time visibility, and automated oversight.

- **Compliance as a Revenue Driver**: Mature quality systems let you provide sponsors with instant access to batch status, inventory, and e-batch records, fostering trust and repeat business.

- **Boosting Efficiency and Confidence**: Automate decision-making and deviation handling to cut errors and downtime, while offering sponsors dashboards for monitoring training, environmental controls, and processes.

- **Strategic Edge**: Digital tools signal reliability and scalability, ideal for handling advanced therapies like cell and gene products.

For your CDMO, start with a digital maturity assessment: Evaluate your current tech stack against these needs and prioritize cloud-based, AI-integrated solutions. This can lead to faster operations, lower costs, and a stronger market position.

## Digital Solutions Tailored for CDMO Success

Tools like MasterControl's Manufacturing Excellence platform exemplify how CDMOs can tackle these challenges:

- **Integrated Quality and Manufacturing**: Use modular setups for quick client onboarding, risk-based validation, and multi-regulatory compliance.

- **Paperless Operations**: Digital batch records and automated data capture eliminate manual errors in multi-client setups.

- **AI-Driven Insights**: Leverage ML for recipe optimization, predictive maintenance, and contract analysis to stay ahead.

If exploring options, consider white papers on contract manufacturing software for building AI-ready capabilities—these can guide your tech investments.

## Future-Proofing Your CDMO: Key Trends to Watch

Looking ahead 5-10 years, three trends will define CDMO success:

1. **Supply Chain Reshoring**: With onshoring pushes in the U.S. and beyond, build agile digital infrastructure for transparent, efficient supply chains.

2. **Workforce Optimization**: Address talent shortages with automation and AI-guided execution to maximize productivity.

3. **Advanced Modalities**: Prepare for CGTs and ADCs by adopting flexible digital platforms that handle complex protocols.

*Pro Tip*: Invest in training programs tied to digital tools to upskill your team, ensuring your CDMO is ready for these shifts.

## Final Thoughts: Make Compliance Your Superpower

For CDMOs, embracing digital transformation turns compliance from a burden into a strategic asset, enabling faster responses, superior quality, and profitable growth. The key? Act now to implement cloud-based, AI-enhanced systems that align with evolving regulations and sponsor expectations. To dive deeper, check out on-demand webinars or resources on digital edges in manufacturing.

If you're leading a CDMO, what's your biggest compliance challenge? Share in the comments—we'd love to discuss how these insights can apply to your business!

Final Revised Good Agricultural and Collection Practice (GACP) Guideline Published: What You Need to Know About Revision 1

**Posted on August 28, 2025**

Hello, GMP compliance enthusiasts! If you're involved in the world of herbal medicinal products, you've likely been keeping an eye on updates from the European Medicines Agency (EMA). The big news is that the Committee on Herbal Medicinal Products (HMPC) has finally adopted Revision 1 of the *Guideline on Good Agricultural and Collection Practice (GACP) for Starting Materials of Herbal Origin*. This update replaces the original guideline from 2006, bringing it in line with modern practices and technologies.

In this blog post, we'll break down the key changes in Revision 1 in simple terms. We'll focus on why this revision matters, what's new (especially for indoor cultivation), and how it impacts everyone from growers to manufacturers. Whether you're a cultivator, collector, or quality assurance professional, this guide will help you understand how to ensure the safety and quality of herbal starting materials. Let's dive in!

## Why Was the GACP Guideline Revised?

The original GACP guideline came into effect in August 2006 to ensure consistent quality for herbal substances used in medicines. Herbal medicines are complex—think plants like chamomile or ginseng—and their quality can be affected by everything from how they're grown to how they're harvested.

Over the past decade-plus, things have evolved:

- **Technological advances**: Indoor growing (like in controlled environments) has exploded in popularity. This allows better control over factors like light and humidity but brings new challenges.

- **Legal and practical updates**: Interpretations from documents like Annex 7 of the EU GMP Guidelines (from 2009) on manufacturing herbal products have been incorporated.

- **Patient safety focus**: With more awareness of contaminants (e.g., heavy metals, pesticides, or toxic weeds), the guideline now emphasizes reducing risks at every step.

Revision 1 keeps the core goal: establishing a quality assurance system for cultivation, collection, harvesting, and primary processing. It applies to all players in the supply chain—cultivators, harvesters, collectors, traders, processors, and manufacturers. For organic production, it overlaps with EU Regulation 2018/848, but GACP adds specific recommendations for medicinal plants.

The guideline stresses that wild collection vs. cultivation (outdoor, greenhouse, or indoor) each has pros and cons. For example, wild plants might vary more in composition, while cultivated ones offer better control but require careful management to avoid contamination.

## Key Sections of the Guideline: What's Stayed the Same and What's New?

The structure remains similar to the 2006 version, covering topics like quality management, personnel training, equipment, and more. But Revision 1 adds depth, especially on documentation, contamination prevention, and environmental considerations. Here's a breakdown, focusing on revisions:

### 1. **Executive Summary and Introduction**

   - **What's new?** The summary highlights updates for indoor technologies and references recent legal insights. It notes that plant production directly affects herbal substance quality, and choices like wild vs. cultivated should consider risks (e.g., confusion with toxic plants in the wild).

   - **Easy takeaway**: Think of this as the "why" section—ensuring herbs are safe and consistent for medicines.

### 2. **Scope**

   - Covers cultivation (outdoor, greenhouse, indoor), collection from the wild, harvesting, and primary processing.

   - **What's new?** Explicit links to GMP Part II (for APIs) and Annex 7. Stricter rules apply closer to the final product (e.g., higher standards for herbal teas than for extracts). It emphasizes patient safety by minimizing microbiological load and contaminants like pyrrolizidine alkaloids (PAs) or heavy metals.

   - **Easy takeaway**: Everyone in the chain must document activities and comply with regulations like CITES (for endangered species) and the Nagoya Protocol (for genetic resources).

### 3. **Quality Management**

   - Agreements between producers and buyers must reference GACP, with regular audits.

   - **What's new?** More emphasis on verifying compliance through site audits by experts.

   - **Easy takeaway**: It's like a contract ensuring quality—written down and checked regularly.

### 4. **Personnel and Training**

   - Staff need hygiene training, protection from toxic plants, and knowledge of identification, pests, and best practices.

   - **What's new?** Detailed training for collectors (e.g., spotting contaminated areas) and harvesters (e.g., IPM—Integrated Pest Management). For indoor setups, training on controlled climates is key. No smoking or eating near plants to avoid contamination.

   - **Easy takeaway**: People are the first line of defense—train them well to spot issues like diseased plants or environmental risks.

### 5. **Building and Facilities**

   - Buildings must be clean, pest-free, and protect against animals or fire.

   - **What's new?** Recommendations for storage (e.g., on pallets, away from walls) and hygiene facilities. For indoor (see Annex 1), facilities need systems for air, light, and humidity control to minimize contamination.

   - **Easy takeaway**: Keep things spotless—like storing food, but for medicinal plants.

### 6. **Equipment**

   - Equipment must be clean, calibrated, and non-contaminating.

   - **What's new?** Calibration for fertilizer/pesticide tools and post-use cleaning to prevent cross-contamination.

   - **Easy takeaway**: Tools are extensions of your hands—keep them in top shape.

### 7. **Documentation**

   - Field records must cover everything from location to pesticides used.

   - **What's new?** Traceability for batches from different areas; mix only if homogeneous. For indoor (Annex 1), daily records of critical parameters (e.g., temperature) and validation procedures.

   - **Easy takeaway**: Document like your quality depends on it—because it does!

### 8. **Seeds and Propagation Material**

   - Seeds must be traceable, pest-free, and from identified plants.

   - **What's new?** Emphasis on avoiding toxic seeds (e.g., those with PAs) and evaluating suppliers for changes.

   - **Easy takeaway**: Start with good "ingredients" to grow quality plants.

### 9. **Cultivation**

   - Covers soil, fertilization, irrigation, and plant protection.

   - **What's new?** Avoid contaminated soils; justify fertilizer use; implement IPM to minimize pesticides. For indoor (Annex 1), identify critical attributes, standardize processes, and qualify equipment.

   - **Easy takeaway**: Grow smart—rotate crops, use clean water, and monitor for pests.

### 10. **Collection**

   - Supervise collectors; comply with conservation laws.

   - **What's new?** Stronger focus on endangered species (CITES, Nagoya) and avoiding over-exploitation.

   - **Easy takeaway**: Collect responsibly to protect nature.

### 11. **Harvesting**

   - Harvest at optimal quality; avoid damage or wet conditions.

   - **What's new?** Use food-compliant tools; protect from soil contact; document pest control.

   - **Easy takeaway**: Time it right and handle gently to keep quality high.

### 12. **Primary Processing**

   - Includes washing, drying, cutting; conform to GMP where needed.

   - **What's new?** Avoid sun drying unless necessary; minimize fumigants (e.g., ban ethylene oxide); inspect and sieve materials.

   - **Easy takeaway**: Process quickly and cleanly to prevent spoilage.

### 13. **Packaging**

   - Use clean, labeled materials suitable for food contact.

   - **What's new?** Reference to EU regulations for plastics.

   - **Easy takeaway**: Package to protect and trace.

### 14. **Storage and Distribution**

   - Store in dry, aerated conditions; check trucks for hygiene.

   - **What's new?** Keep samples for 3 years; avoid moisture in humid areas.

   - **Easy takeaway**: Store like valuables—safe and controlled.

### 15-16. **Definitions and References**

   - New terms like "indoor cultivation" and contaminants (PAs, PAHs).

   - Updated references to current regs and papers.

## Spotlight on Annex 1: Indoor Cultivation Provisions

This is the star of Revision 1! Indoor growing (e.g., in closed environments with artificial light) gets its own annex because it's booming. Key additions:

- **Facilities**: Control access, air filtration, and cleaning to prevent contamination.

- **Documentation**: Daily logs of parameters like temperature; validate processes.

- **Cultivation**: Written procedures for materials; calibrate equipment; standardize for reproducibility.

**Why focus here?** Indoor setups offer precision but risk inconsistencies if not managed well. This ensures reproducible quality.

## What Does This Mean for You?

If you're in the herbal supply chain, update your procedures now. Conduct audits, train staff, and document everything. Manufacturers: Ensure suppliers comply—it's your patient's safety on the line.

For the full guideline, check the EMA site: [Guideline on GACP](https://www.ema.europa.eu/en/good-agricultural-collection-practice-starting-materials-herbal-origin-scientific-guideline). See comments on the draft: [Overview of Comments](https://www.ema.europa.eu/en/documents/comments/overview-comments-received-draft-guideline-good-agricultural-collection-practice-gacp-starting-materials-herbal-origin-revision-1_en.pdf).

Questions? Drop a comment below. Stay compliant!

*Disclaimer: This post is for informational purposes. Always consult official sources for compliance.*

US FDA WL to Indian pharm company after fire accident

Access WL

The recent FDA warning letter to an Indian manufacturer of active pharmaceutical ingredients (APIs) highlights major Good Manufacturing Practice (GMP) violations, particularly regarding the handling of fire-affected API batches and significant deficiencies within the company’s stability program[1].

## Regulatory Findings: GMP Breaches

During the FDA’s inspection in September 2024, the agency discovered that multiple API batches stored in warehouse areas directly impacted by a fire in December 2022 were released and exported to the U.S. market[1]. These products had been exposed to severe environmental conditions such as heat and smoke, yet the company’s Quality Unit approved their release without initiating a recall, despite internal records confirming the adverse impact of the fire[1]. The FDA deemed the company’s retrospective assessment inadequate and emphasized that pharmaceuticals exposed to uncontrolled conditions should be considered **adulterated** and are not permissible for U.S. distribution[1]. Additionally, there was no commitment from the manufacturer to address other potentially impacted batches identified in post-incident documentation[1].

## Stability Program Gaps

The FDA also identified severe shortcomings in the manufacturer’s stability program[1]. Over the previous two years, repeated power outages—some lasting up to 40 hours—compromised storage chamber conditions. The absence of data loggers meant temperature and humidity changes during outages were not recorded[1]. While the manufacturer acknowledged these weaknesses and promised further temperature-assessment studies during power failures, there was no comprehensive study protocol, formal risk assessment, or effective measures to stabilize electrical supply — all critical requirements for ensuring GMP compliance[1].

## Regulatory Guidance

The FDA referenced existing guidance documents for handling pharmaceutical products or components exposed to substandard storage conditions, especially as a result of natural disasters or facility incidents[1]. Notably, the agency stressed that failing to adhere to these established protocols threatens drug safety and quality, posing risks to patient health[1].

## Industry Context and Upcoming Events

GMP professionals may benefit from upcoming industry events spotlighting compliant site transfers, granulation & tableting technology, and advanced visual inspection methods. Conferences in Barcelona and Vienna during September–October 2025 will provide in-depth guidance on these topics[1]. Recent related news includes updates to pharmaceutical water standards, cleanroom guidelines, and advances in compaction simulation — all reflecting evolving regulatory expectations for drug manufacturers[1].

This warning letter serves as a strong reminder of the regulatory scrutiny and operational rigor required to maintain global pharmaceutical supply chain integrity and public health[1].

Mr. Achal Agrawal

CEO

Macsen Drugs

F-261, 262, 263 Riico Industrial Area, Gudli

Tehsil Mavli, Udaipur 313024 Rajasthan

India

US FDA Glenmark Pharmaceuticals Limited 2025

The United States Food and Drug Administration (FDA) issued a warning letter to Glenmark Pharmaceuticals Limited on July 11, 2025, following an inspection of their drug manufacturing facility located at Phase – II, Sector III, Plot No 2, Pharma Zone, SEZ, Pithampur, Madhya Pradesh, India, conducted from February 3 to 14, 2025. The FDA’s inspection revealed significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals, as outlined in Title 21 of the Code of Federal Regulations (CFR), parts 210 and 211. These violations indicate that Glenmark’s methods, facilities, and controls for manufacturing, processing, packing, and holding drug products do not comply with CGMP standards, rendering their drug products adulterated under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B). This letter underscores the FDA’s commitment to ensuring that pharmaceutical products meet stringent quality and safety standards to protect public health. Below, we elaborate on the key findings, their implications, and the FDA’s expectations for corrective action, tailored for pharmaceutical professionals to understand the regulatory intent and necessary compliance measures.

### Key Violations Identified by the FDA

1. **Inadequate Cross-Contamination Prevention Strategies**  

   During the inspection, FDA investigators observed that Glenmark was manufacturing drug products containing a specific active pharmaceutical ingredient (API) (redacted as (b)(4) in the warning letter) using shared equipment and air handling units alongside other drug products. While complete facility separation is not mandatory for such manufacturing, the FDA emphasizes the need for robust strategies to prevent cross-contamination, such as dedicated production suites or validated cleaning procedures. The absence of adequate controls increases the risk of unintended API residues contaminating other products, potentially compromising patient safety.

   **FDA’s Intent**: The FDA is signaling that manufacturers must implement stringent controls to prevent cross-contamination, especially when handling potent or sensitizing compounds. This aligns with CGMP requirements under 21 CFR 211.67 (Equipment Cleaning and Maintenance) and 21 CFR 211.42 (Design and Construction Features), which mandate that equipment and facilities be designed and maintained to prevent contamination. The FDA acknowledges Glenmark’s decision to discontinue manufacturing these specific drug products but requires a detailed cross-contamination prevention plan if production resumes, emphasizing proactive risk management.

2. **Delayed Stability Sample Testing and Inadequate Response**  

   The inspection revealed a backlog of pending stability sample testing, which is critical for ensuring that drug products maintain their quality, safety, and efficacy throughout their shelf life. Glenmark’s response to the FDA’s Form 483 (issued post-inspection) outlined the root causes for these delays, including insufficient quality control (QC) laboratory capacity. The company claimed that all delayed stability testing for U.S. commercial products was completed by December 2024 and described plans to enhance QC resources, such as increasing laboratory capacity, purchasing additional equipment, and hiring personnel. Additionally, Glenmark implemented oversight mechanisms to monitor stability testing progress. However, the FDA deemed the response inadequate because it lacked critical details, such as the test results from the delayed stability analyses and a comprehensive investigation report identifying root causes and corrective actions.

   **FDA’s Intent**: The FDA is emphasizing the importance of timely and robust stability testing under 21 CFR 211.166 (Stability Testing of Drug Products). Stability data are essential to confirm that drugs remain within specifications under labeled storage conditions. By highlighting the absence of test results and investigation details, the FDA is reinforcing that manufacturers must provide transparent, evidence-based responses to demonstrate compliance. This also reflects the agency’s expectation for proactive resource planning to prevent testing backlogs, which could delay the detection of product quality issues.

3. **Systemic CGMP Failures Across Glenmark’s Network**  

   The warning letter notes that similar CGMP violations were previously identified at other Glenmark facilities, indicating systemic deficiencies in the company’s quality management system. For instance:

   - **Himachal Pradesh, India Facility (FEI 3005757050)**: A 2019 warning letter cited violations of 21 CFR 211.192 for inadequate investigations into out-of-specification (OOS) test results for critical product attributes, such as failed assays in a cream product.

   - **Goa, India Facility (FEI 3004672766)**: A 2022 warning letter highlighted inadequate investigations into OOS results for content uniformity testing of desmopressin acetate tablets.

   - **North Carolina, U.S.A. Facility (FEI 3011585599)**: A 2023 warning letter addressed various CGMP violations, further evidencing recurring issues.

   These repeated failures across multiple sites suggest that Glenmark’s executive management has not adequately overseen or controlled manufacturing operations to ensure consistent CGMP compliance.

   **FDA’s Intent**: By referencing violations at multiple sites, the FDA is underscoring that compliance is a corporate-wide responsibility. The agency expects executive management to conduct a comprehensive assessment of global manufacturing operations to identify and resolve systemic deficiencies. This aligns with 21 CFR 211.180 (General Requirements) and 21 CFR 211.192 (Production Record Review), which require robust quality systems to ensure consistent product quality. The FDA’s focus on systemic issues signals its intent to hold companies accountable for fostering a culture of compliance across all facilities.

### Broader Implications and FDA Expectations

The FDA’s warning letter serves as both a corrective directive and a broader warning to the pharmaceutical industry about the importance of adhering to CGMP standards. The violations identified at Glenmark’s Pithampur facility—cross-contamination risks, delayed stability testing, and systemic quality failures—highlight common areas of concern that can compromise drug safety and efficacy. The FDA’s intent is clear:

- **Protect Patient Safety**: Non-compliance with CGMP standards, such as inadequate contamination controls or delayed testing, can lead to substandard or unsafe drugs reaching patients. The FDA prioritizes public health by enforcing rigorous manufacturing standards.

- **Demand Accountability**: By citing violations across multiple Glenmark facilities, the FDA is holding the company’s leadership accountable for ensuring global compliance. This includes implementing effective quality systems and oversight mechanisms.

- **Encourage Proactive Remediation**: The FDA expects Glenmark to address the specific violations (e.g., cross-contamination prevention and stability testing) and conduct a holistic review of its operations to prevent recurrence. This includes submitting detailed corrective action plans within specified timelines (typically 15 working days).

### Recommended Actions for Glenmark and Pharmaceutical Professionals

To address the FDA’s concerns and restore compliance, Glenmark must take the following steps, which also serve as guidance for pharmaceutical professionals managing similar issues:

1. **Develop a Cross-Contamination Prevention Plan**: If Glenmark resumes manufacturing the implicated drug products, it must submit a detailed plan outlining cleaning validation, equipment segregation, and air handling controls to prevent cross-contamination. This should include risk assessments and scientific justification for the chosen controls.

2. **Strengthen Stability Testing Processes**: Glenmark should provide the FDA with complete stability test results, investigation reports, and a corrective action plan to prevent future backlogs. This may involve increasing QC laboratory capacity, automating testing processes, and establishing robust oversight mechanisms.

3. **Conduct a Global Compliance Assessment**: Executive management should perform a comprehensive audit of all manufacturing sites to identify and address systemic CGMP deficiencies. This includes enhancing quality systems, training personnel, and ensuring adequate resources for compliance.

4. **Respond Promptly and Transparently**: Glenmark must submit a detailed response to the FDA within 15 working days, addressing each violation with specific corrective actions, timelines, and supporting data. Transparency and thoroughness are critical to demonstrating commitment to compliance.

### Conclusion

The FDA’s warning letter to Glenmark Pharmaceuticals Limited reflects its unwavering commitment to enforcing CGMP regulations to ensure the safety, quality, and efficacy of pharmaceutical products. By identifying specific violations—such as inadequate cross-contamination controls, delayed stability testing, and systemic quality failures—the FDA is signaling to Glenmark and the broader industry that robust quality systems and proactive compliance are non-negotiable. Pharmaceutical professionals should view this letter as a call to action to strengthen their own manufacturing processes, prioritize patient safety, and maintain rigorous oversight to meet regulatory expectations. Glenmark’s response to this letter, including its corrective actions and global compliance efforts, will be closely scrutinized by the FDA to ensure alignment with CGMP standards.[](https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/glenmark-pharmaceuticals-limited-708270-07112025)

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