Equipment Qualification outline in light of regulatory

Regulatory requirements significantly influence the equipment qualification process in the pharmaceutical industry. The key regulatory bodies, such as the FDA and EMA, provide guidelines and regulations that outline the requirements for equipment qualification and process validation. These regulations ensure that equipment is properly installed, operated, and maintained to ensure the quality and safety of the final product.

The FDA's 21 CFR Title 211.63 emphasizes that equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance[1][3]. Similarly, the EU's EudraLex – Volume 4 – Good Manufacturing Practice (GMP) provides detailed guidance on qualification under Annex 15: Qualification and Validation[1][2].

The FDA's Process Validation Guidance explicitly states that equipment qualification is an integral part of the process validation programme[3]. This means that equipment qualification is not just a standalone process but is closely tied to the overall process validation lifecycle, which includes process design, process qualification, and continued process verification[2].

The regulatory requirements also emphasize the importance of proper documentation and reporting. Manufacturers must maintain detailed protocols, reports, and standard operating procedures (SOPs) to document the qualification and validation activities. These documents serve as a comprehensive record of the qualification and validation processes, providing evidence of compliance with regulatory requirements[2][4].

In summary, regulatory requirements play a crucial role in shaping the equipment qualification process in the pharmaceutical industry. They ensure that equipment is properly installed, operated, and maintained to ensure the quality and safety of the final product, and that the process is thoroughly documented and validated[1][2][3][4].

Citations:

[1] IQ, OQ, PQ: Essential Steps for Equipment Qualification https://zamann-pharma.com/2024/04/22/iq-oq-pq-essential-steps-for-equipment-qualification/

[2] Introduction to Equipment Qualification and Process ... https://www.linkedin.com/pulse/introduction-equipment-qualification-process-industry

[3] What are the FDA Requirements for Equipment Qualifications? https://www.gmp-compliance.org/gmp-news/what-are-the-fda-requirements-for-equipment-qualifications

[4] What You Need To Know About Equipment Qualification https://boracdmo.com/what-you-need-to-know-about-equipment-qualification/

[5] Qualification of manufacturing equipment. | PPT - SlideShare https://www.slideshare.net/slideshow/qualification-of-manufacturing-equipment/248915750

Advancements and knowledge gaps in ICH Q2(R2)

Starting with the relationship between ICH Q14 and Q2(R2), the authors take a critical look at the new aspects incorporated in ICH Q2(R2). The concepts of selectivity and specificity, range and response, as well as accuracy and precision are discussed in more detail. The authors also identify areas needing additional guidance and compare how the latest ICH Q14/Q2(R2) guidelines align with US pharmacopeial approaches.

The authors conclude that "the revised ICH Q2(R2) guideline updates terminology and broadens the scope of techniques/products applicable, improving validation requirements for uni- and multivariate analytical procedures, while maintaining traditional approaches." It also says that "while both Q14 and Q2(R2) align with principles outlined in USP <1220>, further clarity and alignment between the two guidelines are needed to promote a comprehensive lifecycle approach."

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why two different batches key starting material can't be mixed to produce active Pharmaceutical Ingredient

Mixing batches of starting materials to produce an active pharmaceutical ingredient (API) is generally not recommended for the following reasons:

1. **Traceability**: Each batch of starting material has its own unique history, including the source, manufacturing process, and quality control testing. Mixing batches makes it difficult to trace the origin of the API back to the individual starting material batches, which is important for regulatory compliance[2].

2. **Consistency**: Combining batches with potentially different properties, such as particle size, density, or impurity profile, can lead to inconsistencies in the final API. This can impact the quality, safety, and efficacy of the drug product[1][3].

3. **Contamination**: There is a risk of cross-contamination when mixing batches, especially if the starting materials have different grades or are used for different products. This can compromise the purity of the API[2].

4. **Regulatory requirements**: Regulatory guidelines, such as the FDA's Q7A Good Manufacturing Practice (GMP) guidance, recommend against mixing batches of starting materials for API production. The guidance states that "in-process mixing of fractions from single batches is generally acceptable, but combining fractions from different batches is not considered acceptable practice"[2].

In summary, while it may be tempting to mix batches of starting materials to save time or resources, the potential risks to product quality, consistency, and regulatory compliance outweigh any potential benefits. It is best to process each batch of starting material separately to ensure the highest quality and safety of the final API.

Citations:

[1] Batch versus continuous blending of binary and ternary pharmaceutical ... https://www.sciencedirect.com/science/article/pii/S2590156721000402

[2] Guidance for Industry, Q7A Good Manufacturing Practice ... - FDA https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-q7a-good-manufacturing-practice-guidance-active-pharmaceutical-ingredients

[3] Batch versus continuous blending of binary and ternary pharmaceutical ... https://www.pharmaexcipients.com/continuous-manufacturing/batch-versus-continuous-blending/

[4] 3 Critical Things for Dry Blending Process in Pharmaceutical Industry https://www.customprocessingservices.com/blog/critical-things-to-know-about-pharmaceutical-blending-process

[5] Impact of excipients on batch and continuous powder blending https://www.sciencedirect.com/science/article/pii/S0032591021001170

can I mix two different raw material batches activity pharmaceutical ingredient

It is generally not recommended to mix two different raw material batches when producing an active pharmaceutical ingredient (API). Here are a few key reasons why:

- Raw material variability can significantly impact the quality and consistency of the final API[2]. Mixing batches with different properties like particle size, flowability, or surface energy could lead to inconsistencies in the API.

- Strict regulations like ICH Q7 require thorough consideration of raw material variability during API manufacturing[3]. Mixing batches may introduce uncontrolled variables that could violate good manufacturing practices (GMP).

- The API manufacturing process is designed and validated based on specific raw materials. Introducing different raw materials could impact the chemical reactions, purification steps, and final API quality attributes[4].

- Traceability and documentation are critical for APIs. Mixing batches makes it harder to track the origin and history of the raw materials used in each API batch[3].

- Acceptance criteria and specifications are set for each raw material batch. Mixing batches could result in a composite that does not meet the required specifications[3].

In summary, while it may be possible to mix raw material batches in some cases, it is generally not recommended due to the potential impact on API quality, consistency, and regulatory compliance. The safest approach is to use a single qualified raw material batch for each API manufacturing run[1][4][5].

Citations:

[1] Pharmaceutical raw materials - FUJIFILM Wako Chemicals https://labchem-wako.fujifilm.com/us/pharmaceutical-raw-materials/medicine/material.html

[2] Raw material variability of an active pharmaceutical ingredient and its ... https://www.sciencedirect.com/science/article/abs/pii/S0939641117312882

[3] Guidance for Industry, Q7A Good Manufacturing Practice ... - FDA https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-q7a-good-manufacturing-practice-guidance-active-pharmaceutical-ingredients

[4] Active Pharmaceuticals Ingredients and Excipients in Pharmaceuticals https://veeprho.com/active-pharmaceuticals-ingredients-and-excipients-in-pharmaceuticals/

[5] What is an API？Difference among API, raw material and intermediate https://www.katsura-chemical.co.jp/en/drugs/

ICH Q3C: New Version of the Guideline for Residual Solvents published

The essence of the update is if in any manufacturing process contains only Class 3 solvents and the manufacturer measures residual solvents through LOD then it is essential to The impact of solvent volatility on the test method should be

considered in the validation.

Full details are as follows 

Since the end of April 2024, the ninth revision of the "IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS Q3C(R9)" of the ICH (INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE) has been available on the ICH website under the heading "Quality Guidelines". This version includes revisions and adjustments in section 3.4 Analytical Procedures.

The updated section 3.4 Analytical Procedures now states as follows:

"Residual solvents are typically determined using chromatographic techniques such as gas chromatography. Any harmonised procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure for a particular application. If only Class 3 solvents are present, a non-specific method such as loss on drying may be used, if the method is properly validated. The impact of solvent volatility on the test method should be

considered in the validation. Validation of methods for residual solvents should conform to the current version of ICH guideline Q2 on Validation of Analytical Procedures."

Understand ICH Q7 S13

Is the lifecycle approach to process validation acceptable for APIs under ICH Q7?

Yes, ICH Q7 does not preclude the lifecycle approach [ICH Q7, 12.10, ICH Q10, ICH Q11]

Can the range of a process parameter be expanded based only on a process deviation(s)? 

No. However, information from the investigation into a process deviation(s) can be used to support expanding the range of a process parameter. Additional work and studies are normally needed to adequately demonstrate that the expanded range for the process parameter consistently produces API of the necessary quality [ICH Q7, 2.16, 12.11, 13.13]. 

Would additional process validation studies be needed to support a change in the source of an API starting material?

Any change in the API starting material should be assessed for impact on the API manufacturing process and the resulting API quality [ICH Q7, 7.14]. Additional validation studies of the API process may be warranted if the change in the API starting material is deemed significant. In most cases, validation would be expected for a different source of the starting material unless otherwise justified [ICH Q7, 12.1, 13.13]. 

Understand ICH Q7 S12

When is it acceptable for an API manufacturer to extend an API retest date [ICH Q7, 11.6]? 

The purpose of a retest date is to ensure that the API is still suitable for use. The API manufacturer can extend the retest date of a specific batch based on good science and longterm stability results for that API and testing of the specific batch that has been stored according to the label conditions. In some regions, regulatory authority approval of the retest date extension for the batch may be required. If an API manufacturer wants to change (i.e., extend) the retest date for future batches of an API, then it should conduct stability testing sufficient to support the change, and include the new retest date and supporting data in a regulatory filing, as determined by regional requirements. 

What is meant by ‘completely distributed’ in [ICH Q7, 11.71], which indicates reserve/retention samples should be retained for 3 years after the batch is completely distributed by the manufacturer? 

Completely distributed’ refers to the distribution of the entire batch of the API by the API manufacturer to the next party in the supply chain. It should be noted that this applies to all parties that physically process or repackage the API [ICH Q7, 20 – see Glossary for definition of ‘manufacture’). The intent of ICH Q7 is to retain samples for the period of time that the API could be in the market in order to investigate any problems and/or product complaints. Based on accepted industry practice at the time ICH Q7 was written, it was not anticipated that a manufacturer would set a retest date longer than 3 years. It is a basic GMP principle that reserve samples be retained for the entire period the material is available on the market. For example, if a company sets a retest date of 5 years and the API is completely distributed immediately after manufacturing, it was never intended that the reserve sample be destroyed before the 5 year retest date was reached. 

Why does ICH Q7 permit the use of a packaging system for reserve/retention samples that is ‘more protective than the marketed packaging system’ [ICH Q7, 11.72]? 

Unlike stability samples, the purpose of the reserve/retention sample is not to represent the quality of the batch in the market place but to allow future evaluation of the quality of the original API batch (e.g., in evaluation of potential counterfeits, etc.). Therefore, reserve/retention samples may be stored in packaging (and conditions) that better preserve the original state of the API. 

My New Artificial intelligence Assistant talking on cGMP

Over view of Lean Management

Lean management is a business approach focused on maximizing customer value while minimizing waste. It originated from the Toyota Production System (TPS) and emphasizes continuous improvement in all aspects of an organization.

Here's a breakdown of the core concepts of lean management:

Value: The core principle is identifying what truly adds value for the customer in a product or service. Non-essential activities that don't contribute to customer value are considered waste.

Waste Elimination: Lean management strives to eliminate waste in all its forms. This can include overproduction, excess inventory, unnecessary transportation, waiting times, defects, and unused employee creativity

Continuous Improvement: A core aspect of lean is the idea of constantly seeking ways to improve processes and eliminate waste. This involves employee empowerment, where everyone is encouraged to identify and suggest improvements.

By implementing lean principles, organizations aim to achieve several benefits:

Increased Efficiency: Reduced waste leads to smoother workflows, less wasted time and resources, and overall higher efficiency.

Improved Quality: By focusing on eliminating defects, lean manufacturing helps produce higher quality products.

Reduced Costs: Less waste translates to cost savings in areas like materials, labor, and inventory management.

Enhanced Customer Satisfaction: By focusing on value and eliminating waste, lean practices can lead to products and services that better meet customer needs.

Lean management is not just applicable to manufacturing. Its principles can be adapted and implemented across various industries, from healthcare to software development, to improve operational performance and overall effectiveness.

Lean GMP: is "right-sizing" GMP and Compliance possible?

Good Manufacturing Practices (GMP) in the pharmaceutical industry are designed to ensure that products are consistently produced and controlled according to defined quality standards. However, it's common for companies to overinterpret regulations, leading to unnecessary processes that can inflate costs and reduce efficiency. To right-size GMP and compliance, and move towards lean GMP-systems while still adhering to regulations, companies can consider several strategies:

Risk-Based Approach: Implement a risk-based approach to quality management, where the focus is on the processes and areas that have the most significant impact on product quality and patient safety. This allows companies to allocate resources more effectively and prioritize areas that require strict compliance, reducing unnecessary controls in lower-risk areas.

Continuous Improvement: Adopt continuous improvement methodologies such as Six Sigma or Lean Manufacturing to streamline processes, eliminate waste, and enhance efficiency. These methodologies can help identify non-value-adding activities and reduce complexity in GMP systems.

Employee Training and Engagement: Ensure that employees are well-trained and understand the intent behind GMP regulations. An informed workforce can make better decisions about what is necessary for compliance and what might be an overinterpretation of the rules.

Simplify Documentation: Review and simplify documentation processes. While documentation is a critical aspect of GMP, overly complicated or excessive documentation can be counterproductive. Ensure that documents are clear, concise, and only as detailed as necessary to meet compliance requirements.

Utilize Technology: Leverage technology and automation to reduce manual errors and improve efficiency. Digital solutions can help manage documentation, track compliance, and streamline quality management processes.

Benchmarking and Best Practices: Look to industry benchmarks and best practices to understand how other companies are efficiently meeting GMP requirements. Learning from others can provide insights into how to streamline your own processes.

Regulatory Dialogue: Engage in open dialogue with regulatory authorities to gain a clearer understanding of compliance expectations.

Outsourcing Non-Core Activities: Consider outsourcing non-core activities to specialized partners that can perform them more efficiently and in compliance with GMP. This allows the company to focus on its core competencies while ensuring compliance in all areas of operation.

By focusing on these strategies, companies can develop lean GMP-systems that are not only compliant but also optimised for efficiency and effectiveness. It's about finding the right balance between ensuring product quality and safety while eliminating unnecessary costs and processes.

Warning letter to South Korea - from process validation to analysis of starting and raw materials

The US Food and Drug Administration (FDA) recently issued a Warning Letter to FirstCham Co, Ltd. due to significant violations of Current GMP guidelines. The agency identified a number of deficiencies during an inspection of the company's drug production facility from 23 to 27 October 2023. In summary, the Warning Letter contains the following findings.

CGMP violations

The company did not perform tests to verify the identity of each component of one of your drug products and also failed to verify or, validate the reliability of supplier analyses at appropriate intervals. Particularly critical is the lack of the necessary tests for raw materials such as glycerine, which must be tested for contamination with diethylene glycol (DEG) and ethylene glycol (EG). FirstChem thus joins the list of companies that have been reprimanded in the recent past for failing to test for EG and DEG.

Deficiencies in the laboratory

Also inadequate was the documentation in the company's laboratory, These records did not contain all the necessary data to ensure compliance with established specifications and standards. There was a lack of information on the test methods used and the results compared to the defined specifications.

Production and process control procedures

In addition, there was no evidence that the manufacturing processes were properly validated to ensure that the medicinal products were consistently of the desired quality and purity. There was also a lack of adequate validation of the water system used to manufacture the products.

Quality control

The company's quality control function did not adequately fulfil its responsibilities to ensure that the medicinal products manufactured met CGMP standards. There were numerous deficiencies, including lack of procedures for process validation, equipment qualification and supplier qualification.

Misleading labelling

The product "Soo'Ae Hand Sanitising Wipes" was misleadingly labelled because the labelling gave the appearance of being approved or endorsed by the FDA, which was not the case. The labelling and advertising of the product as "FDA registered" and the presentation similar to the FDA logo on the product website were criticised as misleading.

As part of the Warning Letter, the FDA is requiring the company to take extensive corrective and preventive actions, including a detailed risk assessment for products that may contain ingredients contaminated with DEG or EG, a comprehensive review and validation of manufacturing processes and water systems, and a comprehensive review of quality assurance and documentation practices.

FirstCham Co., Ltd. has been placed on Import Alert 66-40 for these deficiencies, which means that company products imported into the U.S. that appear to be adulterated or mislabelled may be detained or denied importation until the company demonstrates compliance with CGMPs.

Access Warning Letter here