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

Understand ICH Q7 S13

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]. 

Is a retrospective approach to validation still acceptable?

Prospective validation is normally expected for processes introduced since the publication of ICH Q7. The concept of retrospective validation remains acceptable as an exception for existing, well established products prior to the implementation of ICH Q7 [ICH Q7, 12.44]. If regulatory discussions redefine a step as critical, which had previously been considered non-critical, a protocol describing retrospective analysis of data together with the commitment for concurrent or prospective validation may be an option. Regardless of the type of validation, the quality system should confirm the ongoing robustness of the process (e.g., product quality review). 

Who is responsible for notifying the drug product manufacturer about relevant changes in API manufacturing?

Each party in the supply chain is responsible for transferring information related to quality or regulatory changes to the next customer in the supply chain. The intention is that the information is transferred along the supply chain to the drug product manufacturer in a timely manner [ICH Q7, 13.17, 17.60]. 

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. 

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]. 

Now Cannabis will be used for medical purposes ???

Introduction:

Cannabis, often associated with recreational use, has emerged as a fascinating subject in the realm of medicine. Its medicinal properties have been acknowledged for centuries, yet in recent years, there has been a resurgence of interest in harnessing its therapeutic potential. From alleviating chronic pain to managing symptoms of epilepsy, cannabis is increasingly being recognized as a valuable tool in modern healthcare.

Understanding Cannabis:

Cannabis contains hundreds of chemical compounds, but two primary ones stand out: tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is responsible for the psychoactive effects commonly associated with cannabis, while CBD is non-intoxicating and is known for its potential therapeutic benefits. These cannabinoids interact with the body's endocannabinoid system, a complex network of receptors involved in regulating various physiological processes.

Pain Management:

One of the most well-known uses of medical cannabis is in the management of chronic pain. Studies have shown that cannabinoids can effectively reduce pain associated with conditions such as arthritis, multiple sclerosis, and neuropathy. Unlike traditional pain medications, which can be addictive and have serious side effects, cannabis offers a safer alternative for long-term pain management.

Epilepsy:

In recent years, CBD has gained attention for its potential to treat epilepsy, particularly in children with severe forms of the condition. Clinical trials have demonstrated that CBD can significantly reduce the frequency and severity of seizures in patients with conditions such as Dravet syndrome and Lennox-Gastaut syndrome. This has led to the approval of CBD-based medications for epilepsy in several countries.

Mental Health:

While further research is needed, preliminary studies suggest that cannabis may have therapeutic benefits for various mental health conditions, including anxiety, depression, and post-traumatic stress disorder (PTSD). CBD, in particular, has shown promise in reducing anxiety and improving sleep quality without the intoxicating effects of THC.

FDA Warning Letter Missing Ongoing Stability Studies for APIs

Company Antaria Pty. Ltd, Australia

Synopsis 

1.Inadequate Investigation 

2.Own Analytal Methods used but proved to equivalent to USP methods

3.Annual Stability missed

1.Failure to adequately investigate and document out-of-specification results and implement appropriate corrective actions.

Your firm manufactures API (b)(4) USP, labeled in part to be the active ingredient used in (b)(4). You failed to adequately investigate out-of-specification (OOS) test results. Specifically, your firm lacked adequate investigations and corrective actions for numerous OOS results obtained during laboratory testing of your API, including assay and loss on ignition (LOI) testing. The root causes were not clearly defined nor adequately documented, and lots with OOS results were released by your quality unit (QU).

In your response, you state that staff turnover and insufficient staff training attributes to the lack of competency in good laboratory practices. Additionally, you state that you will revise your OOS procedures. You also state that you will review historical LOI OOS to identify a root cause and retrain your laboratory staff. Your response is inadequate because you failed to describe a holistic review of all investigations’ root cause analyses and corrective actions for adequacy. In addition, you did not inform your customers who received OOS lots for assay nor perform a retrospective assessment of retain samples.

Inadequate investigations can lead to unidentified root causes, ineffective corrective action and preventive action (CAPA), and recurring problems that compromise the ability to manufacture safe and effective drugs.

Own Analytal Methods used but proved to equivalent to USP methods

2.Failure to ensure that, for each batch of API, appropriate laboratory tests are conducted to determine conformance to specifications.

Based on review of your laboratory results, you failed to appropriately perform analytical testing (assay and LOI) of your (b)(4) USP in accordance to the current version of United States Pharmacopeia (USP) monograph, nor did you have data to support that your test method was equivalent or better than the USP method. In your response, you state that you will revise your (b)(4) USP assay and LOI test methods to better align with the USP.

Without adequate testing, there is no scientific evidence to assure that your APIs conform to appropriate specifications before release.

Annual Stability missed

3.Failure to design an adequate documented, on-going stability testing program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates.

Your firm’s stability program is inadequate. Your firm failed to place at least one lot of your API manufactured in 2019, 2020, or 2021 on stability annually.

In your response, you acknowledge that your stability procedure lacks specificity regarding appropriate testing. Additionally, you acknowledge that your stability study only consists of lots manufactured in 2015 and that you only establish your annual, ongoing stability program in 2022. Your response is inadequate because you did not discuss a retrospective review of API lots in distribution that were manufactured without appropriate stability testing.

Without an adequate stability program, you cannot ensure that your APIs meet established specifications and all pre-determined quality criteria throughout the APIs’ assigned shelf-life.

In response to this letter provide:

A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:

    o Stability-indicating methods.

    o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.

    o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.

    o Detailed definition of the specific attributes to be tested at each station (timepoint).

All procedures that describe these and other elements of your remediated stability program.