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.

Harm, Hazard and Risk Part 1

Harm is an adverse outcome or impact, hazard is a potential source of harm, and risk is the likelihood of harm occurring under certain circumstances. Risk is a combination of the chance that a hazard will cause harm and how serious that harm could be. Risk is usually described as being "high", "medium", or "low".

For example, when crossing a road, the cars and other traffic are the main hazards, and the risk is a combination of how likely it is that you'll be hit by a vehicle, along with how seriously you might be injured. 

Ref

ISO 14971, the International Standard for Risk Management

Flying is a routine activity and there are thousands of commercial flights every day. Yet, despite a strong track record of safety, commercial aviation is a hazardous activity. Last year, we were reminded of the risk by two nearly back-to-back fatal crashes of the Boeing 737 Max 8 aircraft that led to a combined 346 fatalities and the worldwide grounding of the entire fleet. In both of these crashes, a sequence of events unfolded due to the interaction between pilot actions and a software control called the Maneuvering Characteristics Augmentation System (MCAS). The trigger event was faulty sensor data from the Angle of Attack (AOA) sensor which caused the MCAS to activate in an effort to stabilize the plane by lowering the nose. When the pilots tried to counter by trying to manually get the plane to nose-up, the MCAS continued to issue the nose-down commands. This sequence of events is shown in the top right of the graphic above. The hazardous situation in this case, as shown in the bottom right of the graphic above, is the failure to achieve altitude after take off due to these events. The result is a disastrous fatal crash with no survivors.

Harm, Hazard and Risk Part 2

ISO 14971 Basic Concepts – Hazard, Hazardous Situation and Harm

1) Hazard

ISO 14971 defines a hazard as a potential source of harm. What does that mean? Is it a “thing”, an “action”, or an “activity”? Well, it could be anything that could result in any harm. It doesn’t have to, but it can. 

Driving a car is a hazard even though we do it every day. 

Surgery is a hazard because it could result in all kinds of complications. 

At the most basic level, use of a medical device itself is a hazard. 

Remember, we are not yet talking about the type of harm or if it is just a small injury or something more serious. We will consider that when we get to the definition of harm later in this blog. 

One problem we have seen in practice is when people look at failure modes associated with a medical device as part of their risk analysis. This is usually done during engineering risk analysis using tools such as an FMEA, or Failure Mode Effects Analysis. A failure mode is a way in which a device can fail to meet specifications or its intended function. Engineers try to think ahead of all possible failure modes so they can control them and improve the reliability of the device. 

But a failure mode, in itself, is not a hazard. It could act as a trigger event that could lead to harm by activating exposure to one or more hazards. This difference is subtle, but important. Controlling failure modes is important for reliability, but it is not sufficient for analyzing safety risks within the context of ISO 14971. That is why using an FMEA for risk analysis is useful, but not sufficient for safety risk assessments. Yet, we have frequently seen FMEAs used as the only tool for this purpose. 

Instead, it is better to look at different types of hazards within the context of the device and its use scenarios. ISO 14971 provides guidance on different classes of hazards such as energy hazards, biological or chemical hazards, information hazards and functional hazards. It is helpful to make a master hazards list under different categories so you can evaluate them holistically within the scope of a given medical device. A failure mode may be associated with one or more hazards, and this standard list can help mapping of failure modes to applicable hazards. In this way, the FMEA can be used exclusively for failure analysis and implementing controls for reliability, and the mapping of failure modes to hazards can facilitate a connection with safety risk analysis. 

2) Hazardous Situation

A hazardous situation is a circumstance that exposes people, property or environment to one or more hazards. 

A related concept to understand in this context is “foreseeable sequence of events”. There is usually a sequence of events that lead to a hazardous situation where people are exposed to hazards. Exposure to hazards through these situations is needed for harm to occur. Again, it may not always happen, but it could. 

As an example, if a medical device is supposed to be sterile, any breach of sterility due to packaging issues, or how it is handled in the use environment, may expose the patient to infection causing microorganisms. The hazard in this case is biological – for example, bacteria, viruses or other infection agents. The foreseeable sequence of events is defective packaging leading to breach of sterility and presence of infection agents. The hazardous situation is this device being used by or on the patient, thereby exposing the patient to these infection agents. 

One problem we have seen is that a clear statement of the sequence of events and resulting hazardous situation is generally missing. Sure, there is a lot of discussion during risk analysis about how a hazard may result in harm, but such discussion is not usually captured accurately to provide a clear understanding of sequence of events and hazardous situation. The reality is that engineers usually do a bottoms-up analysis from device failures, while medical experts focus on a top-down analysis starting from harms and working backwards to hazards. Although these are complimentary analyses, often they are done in isolation by different teams of experts. The result is generally incorrect or missing relationships between hazards and harms, which makes it difficult to properly estimate and evaluate the resulting risks. Inaccuracies in risk evaluation is a common reason for low effectiveness of the risk management process. 

It is through an iterative back and forth bottoms-up and top-down analysis that we can come to a clear understanding of hazardous situations.

ISO 14971 provides guidance on events and circumstances that can lead to hazardous situations. It is a good practice to prepare a master table that clearly shows hazards and statements of sequence of events leading to hazardous situations. 

3) Harm

In the context of safety risk management under ISO 14971, harm is defined as injury or damage to the health of people, or damage to property or the environment. 

It is a very broad definition. Harm could be as simple as a minor inconvenience from a health point of view, or as serious as a life-threatening emergency or even death. In this way, harm has two components – the type of harm, and the severity of the harm.

We have seen two problems in defining harms during risk analysis. The first is not using a standard terminology. Harms should be defined in medical terms, and should ideally be done in consultation with a medical professional. Typically, people have used different complaint codes over the years to describe harms that have been reported. These complaint codes are not standardized and often evolve over time. It is not unusual to see “Other” as one of the most frequently used complaint codes because a reported condition may not always fall under any of the exiting categories. One good resource is MedDRA, or Medical Dictionary for Regulatory Activities. It is a recognized source of medical terms which can be used to create a master harms list for your product portfolio.

The second problem we have seen is inconsistent, and often incorrect, assignment of severity levels to harms. In our experience, the underlying problem is the lack of clear statements of sequence of events and hazardous situations. It is possible that the same condition, let us say a bacterial infection, could have different levels of severity. It is the link between a hazard and hazardous situation that can help us identify the appropriate severity level. In practice, this is not done and the result is inconsistent assignment of severity levels for the same harm because different teams come up with a different analysis of sequence of events and hazardous situations.

It is a good practice to build a Master Harms Severity table that has multiple lines of clear statements reflecting different scenarios. This work is best done in a cross functional team environment with engineers, medical professionals and risk management experts. 

In conclusion, these three terms – Hazard, Hazardous Situation and Harm – are inter-related. It is really important to clearly understand each term and how they relate to each other. It requires a lot of work upfront to build a master table of hazards, hazardous situations and harms relevant to a product or product family. But once you do this work, your risk analysis will be more accurate which will help you manage these risks more effectively. 

What is there in Revised ICH Q9 Part 1

1.High levels of subjectivity in risk assessments and in QRM outputs

Subjectivity is commonly present in a QRM process, as it can be introduced in the many risk assessments, especially in how hazards, harms and risks are perceived. With the revision of the ICH Q9, in a risk assessment, the terminology of the first step has been altered from “Risk Identification” to “Hazard Identification”, for improved alignment with the current definition of Risk Assessment in the guideline. 

The hazards must be identified and later proceed with the analysis and evaluation of risk, regarding the exposure. No further alterations in the risk assessment suggested flow were implemented. Nonetheless, subjectivity in a QRM process can never be fully eliminated – it may be restricted by acknowledging partiality, the application of proper QRM tools and a maximization of the use of relevant data and sources of knowledge.

2. Failing adequately management supply and product availability risk

Quality/manufacturing issues, including noncompliance with Good Manufacturing Practice (GMP), have been a frequent cause of product availability issues. Despite the guideline addressing this topic in its definition of harm as a form of “loss of product availability”, an effective pharmaceutical quality system should empower supply chain robustness and sustainable GMP compliance.

 QRM can help design monitoring systems for detection in departures from a state of control regarding product availability of the supplier, robustness of manufacturing facilities in the process, and acceptability of supply chain partners over the lifecycle. The new revision of Q9 addresses different factors that could affect reliability, such as the Manufacturing Process Variation and State of Control, Manufacturing Facilities and Oversight of Outsourced Activities and Suppliers.

Statistical Process Control in Pharmaceutical Quality Assurance

Statistical Process Control in Pharmaceutical Quality Assurance 

1.Control Charts: X-bar, R-chart, S-chart, and p-chart keep process variation in check.
2. Pareto Analysis: Pinpoint significant quality influencers for targeted improvements.
3. Histograms: Illuminate data distribution aiding in process stability assessments.
4. Scatter Diagrams: Visualize variable relationships to enhance quality mechanisms.
5. Cause-and-Effect Diagrams: Uncover quality issue roots with Fishbone Diagrams.
6. Process Capability Analysis: Evaluate if processes meet quality benchmarks.
7. Regression Analysis: Probe variable relationships crucial for quality optimization.
8. FMEA: Prevent quality issues by identifying potential failure modes.
9. ANOVA: Compare means across groups to ensure quality consistency.
10. Trend Analysis: Proactively manage quality by spotting data patterns.
11. Control Plan: Outline steps to uphold quality standards throughout production.

FDA Requirements for Process Validation

Synopsis of the US FDA 483on Process Validation 

In the Warning Letter, the FDA criticised the fact that no microbiological tests were named in the validation protocol and that the active ingredient specification did not correspond to the current process. Process validation studies were also missing for other medicinal products with regard to different active ingredients and dosage forms.

In the company's response letter, the FDA lacked a detailed description of how the company will ensure in future that the manufacturing process consistently produces medicinal products of suitable quality. The FDA refers to the validation life cycle and specifically mentions the importance of developing the manufacturing process and monitoring after the actual validation. Each significant stage of a manufacturing process must be adequately developed and ensure the quality of the starting materials used, the in-process materials and the finished drug product. Process qualification studies include intensive monitoring and testing of all significant process steps to characterise within-batch variation and evaluate batches to determine whether an initial control state has been achieved.

Successful process qualification studies are required prior to commercial distribution, according to the FDA. Referring to its process validation guidance, the FDA writes that without adequate process validation that considers all production factors and parameters that may affect product quality, the company lacks the basic assurance that it can reproducibly deliver products that meet specifications.

Specifically, the FDA requires:

A detailed summary of the validation programme to ensure that a "state of control" is maintained throughout the product life cycle, together with the associated procedures.

A description of the Process Performance Qualification (PPQ) programme

A description of the monitoring activities to assess intra-batch and inter-batch variability to ensure state of control

A schedule for the implementation of PPQ for each of the marketed medicinal products.

A detailed programme for the development, validation, maintenance, control and monitoring of each manufacturing process, with regard to intra- and inter-batch variability, with the aim of achieving a state of control

A programme for the qualification of facilities and equipment.

A comprehensive, independent assessment of the change management system. This assessment should include procedures to ensure that changes are justified, reviewed and approved by your quality unit. Your change management programme should also include requirements for determining the effectiveness of changes.

US FDA 483 2024 Alkem Laboratories

The authority has issued a new Form 483 following an inspection of Alkem Laboratories Limited, a drug manufacturer located in Baddi, Himachal Pradesh, India. The document was published on 09 April 2024 and goes back to an inspection from 19 to 27 March 2024.

The FDA observed several deficiencies during the inspection, particularly related to the quality system. The 17-pages report lists a total of 10 observations.

One significant observation (Observation 1) relates to the failure to thoroughly review unexplained discrepancies and failures of batches to meet specifications. Specifically, there was a failure in the preventive maintenance of a Perkin Elmer UV Spectrophotometer, resulting in its retirement without conducting an investigation or impact assessment on previously generated test results. Batches tested with this malfunctioning instrument were released into the US market, raising concerns about the accuracy and reliability of the test results.

The other observations include the following aspects:

No shipping studies of finished products shipped to US markets were performed.

Change Controls are not managed and closed within the specified timeframe.

The company failed to adequately perform and assess the GxP impact for computerized system/software.

Appropriate controls governing computer acquired data have not been established.

The firm failed to handle and store drug product containers at all times in a manner to prevent contamination.

Analytical results were not documented according to the SOP.

No annual visual examination of reserve samples was performed.