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.

Understand ICH Q7 S11

What is expected in terms of impurities for APIs extracted from herbal or animal tissue origin [ICH Q7, 11.2]?

In cases where the API itself is the extract from an herbal or animal tissue preparation, all constituents of this extract (concomitant constituents) might be considered to be part of the API. Therefore, a production process-related impurity profile (except, for example, solvents used in the process), would generally not be expected. However, for all APIs derived from herbal or animal sources, tests and limits for possible contaminants originating from these sources (e.g., pesticides, mycotoxins, viruses, herbicides, elemental impurities and wrong species) should be established, based on a risk assessment. In cases where herbal or animal sources provide material that is further processed to yield a chemically-defined API, all constituents other than the API are considered impurities. In this situation, the API manufacturer would be expected to establish an impurity profile as well as an API release specification that would include impurity limits. In any case, it is the API manufacturer’s responsibility to establish batch release specifications for APIs to ensure that they are safe and of high quality, consistent with appropriate regulatory requirements, applicable compendial specifications and regional expectations [ICH Q7, 11.21;  ICH Q9; ICH Q11

In cases where an API test method is changed, which method should be used for stability studies already in progress?

The company should decide and justify the decision of which method to use. All test methods for stability studies [ICH Q1A] should be validated and demonstrated to be stability indicating prior to use [ICH Q7, 11.51]. Any changes to stability test methods should be documented. Applicability of the changes to the existing stability studies should be assessed and may require filing in accordance with regional requirements for post-approval changes [ICH Q7, 13.11]. 

Understand ICH Q7 S10

What is meant by ‘appropriate specifications (of each batch) prior to blending’ [ICH Q7, 8.41]? 

As a principle, no batches with Out of Specification (OOS) results should be blended [ICH Q7, 8.41]. Blending is defined in [ICH Q7, 8.40]. Individual intermediate and/or API batches should demonstrate conformance with the filed specifications prior to blending. In regions or circumstances where there are intermediates and/or APIs that do not require filing, conformance with the release specification should be demonstrated. 

What is meant by ‘APIs and intermediates can be transferred under quarantine to another unit under the company’s control when...’ and is this applicable to contract manufacturers?

ICH Q7, 10.20] states ‘APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company’s control when authorized by the quality unit(s) and if appropriate controls and documentation are in place’. The second sentence in [ICH Q7, 10.20] describes transport situations that are not considered distribution. It provides for physical movement (transfer but not release) of quarantined material to another unit. This unit can be on the same site, different site (within the same company), or a contract manufacturer (see final paragraph below). The goal of transfer under quarantine is to allow transportation and testing in parallel. Material that is transferred under quarantine is not to be used for further processing until all testing and quality review is complete and the material is released by the quality unit as defined in [ICH Q7, 2.22]. This provision for transfer under quarantine is included in ICH Q7 for situations where a company is shipping APIs or intermediates from one unit to another and has both the need to expedite the shipping and the material management system in place to prevent use of the material before full release. Examples of circumstances where transfer under quarantine may be needed include extraordinary supply chain requirement(s) (e.g., short shelf-life), and materials with a lengthy timeframe for required test(s) (e.g., some microbiological tests, etc.). With appropriate oversight as described in [ICH Q10 2.7], including a written agreement as described in [ICH Q7, 16.12], and appropriate ongoing controls, a contract manufacturer may be considered a ‘unit under the company’s control’. There is a joint responsibility by both parties to clearly justify and document the need to transfer the unreleased intermediate or API, and to ensure appropriate control is maintained to prevent use before full 

Understand ICH Q7 S9

Which tests are considered to be identity tests? 

For incoming production materials, identity tests and related methods should be used as described in the relevant sections of a Pharmacopoeia monograph, in an approved regulatory filing or in an in-house specification (including method/analytical procedure) [ICH Q7, 7.30]. When available, a discriminating test should be considered for identification testing. The visual examination of a label or the material is not considered sufficient except in the cases described in [ICH Q7, 7.32]. 

Is it possible to extend the expiry date or retest date of a raw material and what is the acceptable practice to determine how

Manufacturing and labelling of raw materials for use by API manufacturers is outside the scope of ICH Q7. As such, retest and expiry dates, as defined in ICH Q7, do not strictly apply to raw materials and may be used in a different manner by the raw material supplier. Expiry date, as defined in the glossary of [ICH Q7, 20], applies specifically to the API. API manufacturers may re-evaluate [ICH Q7, 7.5] and then use a raw material after the ‘expiry date’ or ‘retest date’, based on an appropriate scientific and risk-based justification (e.g., understanding of material attributes, testing, and stability). Similar justifications may be used to extend the date by which the material should be reevaluated. It is the responsibility of the API manufacturer to ensure the raw materials are appropriate for the intended use at the time of use. 

Can yield ranges defined for the first batch differ from latter batches within a campaign? 

Yes. Differing yield ranges [ICH Q7, 8.14] may be described and justified in the manufacturing procedure/master batch record explaining the ranges [ICH Q7, 6.41]. For example, the first batch in the series of production of batches of the same material (campaign) may leave residual material in the equipment, resulting in a low yield in the first batch and contributing to an increased yield in a subsequent batch of the campaign. 

Understand ICH Q7 S8

What is expected in terms of evaluation of suppliers of materials? 

Different phrases are used to describe the expectation for evaluation of suppliers of materials [ICH Q7, 7.11, 7.12, 7.31], including traders, if any. [ICH Q7, 7.12] states that all materials are purchased against a specification and from suppliers approved by the quality unit [ICH Q7, 7.31]. Prior to approval of any supplier, an evaluation should be conducted using a riskbased approach [ICH Q9, Appendix II.5; ICH Q7, 7.31].  More extensive evaluation is needed for suppliers of those materials classified as ‘critical’ [ICH Q7, 7.11].

What is meant by ‘full analysis’ [ICH Q7, 7.31] on batches of raw materials to qualify a supplier? 

A ‘full analysis’ should include all tests specified by the user of the raw material in the regulatory filing. In cases where no filing is required, the full analysis should include tests in other formal written specifications issued by the user of the raw material [ICH Q7, 7.31]. A raw material supplier’s Certificate of Analysis (CoA) may not necessarily align with the user’s specifications. 

Are on-site audits required in the evaluation of suppliers? 

No. An on-site audit is not required; however, an on-site audit could be a useful tool in the evaluation of a supplier. A risk assessment of the material or the service provided can be used to develop an audit strategy and manage the ongoing evaluation of suppliers [ICH Q7, 7.11, 7.31]. 

Understand ICH Q7 S7

What is meant by ‘completely distributed’ in [ICH Q7, 6.13], which states that ‘records should be retained for at least 3 years For APIs with a retest date, [ICH Q7, 6.13] states that after the batch is completely distributed’? 

For APIs with a retest date, [ICH Q7, 6.13] states that records related to production, control and distribution should be retained for at least 3 years after the API batch is ‘completely distributed’, which is understood as the complete distribution of the entire batch of the API by the API manufacturer to the next party in the supply chain. In the case of APIs handled by agents, brokers, traders, distributors, repackers, and relabellers [ICH Q7, 17], ‘completely distributed’ refers to distribution of the received quantity of the batch of API. The intent of ICH Q7 is to retain records for the period of time that the API could be on 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. However, the use of ‘at least three years’ in this section of ICH Q7 covers longer record retention periods, which is in alignment with the basic GMP principle and/or regional requirements that records be retained for the entire period the material is available on the market. It is good industry practice to consider retaining records for the period of time the drug product(s) in which the API was used may be available on the market. 

Does a batch numbering system need to be sequential? 

No, [ICH Q7, 6.51] says only that batch production records should have a unique batch or ID number. ds? [ICH Q7, 2.3] does not specify who is responsible for the issuance of batch production records [ICH Q7, 6.5] as long as the issuance process is described in writing and approved by the quality unit [ICH Q7, 2.21]. 

Does the phrase ‘grouping of containers’ have the same meaning in [ICH Q7, 7.20 and 7.24]? 

The phrase ‘grouping of containers’ should be read in the context of each sentence. A grouping of containers refers to multiple containers physically secured by the supplier (e.g., shrink-wrapped pallet, etc.) usually intended for ease of shipment and reconciliation. [ICH Q7 7.20] is referring to incoming visual examination of materials before acceptance into the facility under quarantine. The phrase in [ICH Q7, 7.24], ‘grouping of containers (batches)’ contains an additional word ‘batches’ because this section is addressing the need to establish batch traceability for the incoming material. 

USP plans new Chapter on Process Analytical Technology (PAT)

The United States Pharmacopeia (USP) is developing a new General Chapter dedicated to Process Analytical Technology (PAT), aiming to provide guidance on its definition, attributes, enablers, and practical applications in the pharmaceutical industry.

The chapter will focus on aligning with current scientific and regulatory standards, emphasizing real-time monitoring, control, and assurance of product quality throughout the manufacturing process. According to a General Chapter Prospectus published on 29 March 2024, "the scope extends to the use of PAT for process understanding and optimization, including applications in Continuous Process Verification (CPV) and Real-Time Release Testing (RTRT). The chapter will address the regulatory impact of PAT and its role in complying with quality standards."

The preliminary outline is as follows:

Introduction

Definition and Core Attributes of PAT

Key Enablers of PAT

Regulatory Considerations

Implementation Strategies

Applications of PAT

Emerging Trends and Technologies

USP invites early input from stakeholders on this proposed General Chapter, which is expected to be published for comment in the Pharmacopeial Forum. Comments on the proposed outline are due to the USP by 28 April 2024.

Do GMP inspectors no longer go to China?

Counter-Espionage Law

This law also known as counterintelligence, is a type of activity that protects an agency's intelligence program from another agency's. It involves detecting, destroying, neutralizing, exploiting, or preventing espionage activities. Counter-espionage can include: identification, penetration, manipulation, deception, and repressionp

China has revised its counter-espionage law. Compared to the previous version, the new version expands the government's powers to combat espionage and emphasises the role of the public in this task. In theory, activities carried out as part of an audit or inspection can now also be punishable by law. Espionage suspects may be prevented from leaving China by order of the national security authorities at provincial level or higher. This provision also applies to foreigners.

Now, following the German Medicines Manufacturers Association (Bundesverband der Arzneimittel-Hersteller, BAH), the Handelsblatt (a German business and financial newspaper) has also taken up the matter. The article "Antibiotics: Pharmaceutical inspectors no longer dare to visit China" ("Antibiotika: Pharma-Inspekteure trauen sich nicht mehr nach China"), Handelsblatt, 10 April 2024, reports on the potential impact of the stricter security laws in China on inspections and audits by German authorities and pharmaceutical companies. These laws, in particular the anti-espionage law, are quite vaguely worded, meaning that any information gathering could potentially be criminalised, causing uncertainty among foreign companies. In particular, this may affect inspection and audit activities in China. And inspections and audits that are not carried out could further exacerbate bottlenecks in the supply of medicines in the EU.

According to research by Handelsblatt, German GMP inspectors, who normally inspect production facilities on site in China and then issue GMP certificates, have already partially suspended their activities due to fears of problems.

The German Medicines Manufacturers Association (BAH) has appealed to Federal Chancellor Olaf Scholz to address the problem during his visit to China and find a solution. One possible solution could be a "Letter of Intent" in which the Chinese government clarifies that the data collected during GMP-inspections does not fall under the anti-espionage law.

Understand ICH Q7 S6

Is it expected that campaign manufacturing be addressed in cleaning validation? 

Yes. The cleaning validation section [ICH Q7, 12.7] does not specifically address campaign manufacture. However, sections [ICH Q7, 5.23, 8.50] set forth the expectations that equipment be cleaned at appropriate intervals (e.g., time or number of batches) to prevent build-up and carryover of contaminants so that they do not adversely alter the quality of the API. The appropriate interval is confirmed during cleaning validation. 

At product changeover, are both visual examination and analytical testing necessary to verify that equipment is clean? 

Appropriate cleaning validation verifies that the cleaning process is effective. During cleaning validation, both visual examination and analytical testing should be used to verify cleaning effectiveness [ICH Q7, 12.72-75]. Once the cleaning process is validated, routine monitoring of cleanliness of equipment at product changeover should include visual inspection [ICH Q7, 12.76]. Frequency of analytical testing to verify ongoing effectiveness of the validated cleaning process is determined by the API manufacturer using a risk-based approach. In situations where the cleaning process is not yet validated, both visual examination and analytical testing are expected. For APIs with a retest date, [ICH Q7, 6.13] states that records related to production, control and distribution should be retained for at least 3 years after the API batch is ‘completely distributed’, which is understood as the complete distribution of the entire batch of the API by the API manufacturer to the next party in the supply chain. In the case of APIs handled by agents, brokers, traders, distributors, repackers, and relabellers [ICH Q7, 17], ‘completely distributed’ refers to distribution of the received quantity of the batch of API. The intent of ICH Q7 is to retain records for the period of time that the API could be on 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. However, the use of ‘at least three years’ in this section of ICH Q7 covers longer record retention periods, which is in alignment with the basic GMP principle and/or regional requirements that records be retained for the entire period the material is available on the market. It is good industry practice to consider retaining records for the period of time the drug product(s) in which the API was used may be available on the market. 

Understand ICH Q7 S5

To what extent can quality risk management be used in establishing appropriate containment measures to prevent cross-contamination? 

The principles of quality risk management [ICH Q9, Annex II.4] should be applied to the design of buildings, facilities and controls for the purpose of containment, taking into consideration the pharmacological/toxicological/chemical/biological properties of the raw material, intermediate and/or API to be handled or manufactured. Appropriate containment measures and controls [ICH Q7, 4.42] include but are not limited to the following: • Technical controls (e.g., dedicated production areas, closed/dedicated HVAC system, closed manufacturing systems, use of disposable technologies, design of facility and equipment for containment and ease of cleaning) 

Procedural (organisational) controls (e.g., cleaning, personnel flow, environmental monitoring and training) Monitoring systems are important to check the effectiveness of the containment controls. 

For dedicated equipment, is ‘visually clean’ acceptable for verification of cleaning effectiveness, (i.e., no expectation for specific analytical determination)?

Visually clean’ may be acceptable for dedicated equipment based on the ability to visually inspect and sufficient supporting data from cleaning studies (e.g., analytical determination to demonstrate cleaning effectiveness) [ICH Q7, 12.76]. Equipment should be cleaned at appropriate intervals (e.g., time or number of batches) to prevent buildup and carryover of contaminants (e.g., degradants or objectionable levels of microorganisms) so that they do not adversely alter the quality of the API [ICH Q7, 5.23, 12.7].

Should acceptance criteria for residues be defined for dedicated equipment? 

Yes. Regardless of whether equipment is dedicated or not, it is expected that acceptance criteria for residues be defined and that the equipment be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants. Intervals can be based on number of batches, product change-over, time, etc. [ICH Q7, 5.22, 5.23, 5.24, 5.25, 8.50]. Cleaning intervals and acceptance criteria should be established based on an understanding of the process/reactions/degradation, taking into account solubility, potency, toxicity, etc. Establishment of acceptance criteria does not necessarily imply sampling and testing after every cleaning. Visual inspection of equipment for cleanliness is an expectation of [ICH Q7, 5.21]. Where validation data has confirmed effective cleaning, cleaning procedures should be monitored at appropriate intervals [ICH Q7, 12.76]. 

Understand ICH Q7 S4

What is the intent of the statement in [ICH Q7, 3.12] ‘training should be periodically assessed’? 

In [ICH Q7, 3.12], the statement ‘training should be periodically assessed’ refers to a system to evaluate if personnel remain proficient and competent in their job tasks and responsibilities, and whether more frequent, additional, or new training is needed and recurring training is up to date. 

Does ICH Q7 expect the use of a consultant and can a company delegate tasks and/or responsibility to a consultant?

ICH Q7 does not expect the use of a consultant. Consultants may perform delegated tasks and/or provide advice. However, the ultimate responsibility for API quality must not be delegated [ICH Q10 2.7, ICH Q7 2.2, 3.3]. 

When are dedicated production areas expected? 

ICH Q7 expects dedicated production areas for highly sensitizing materials such as penicillins and cephalosporins because of the patient risk (e.g., anaphylactic shock to penicillin-allergic patients) from trace amounts of these compounds in other medicines [ICH Q7, 4.40]. For materials of an infectious nature or high pharmacological activity or toxicity, a risk-based approach should be used to determine appropriate containment measures, which may include validated inactivation, cleaning and/or dedicated production areas [ICH Q7, 4.41]. While ICH Q7 does not define high pharmacological activity

or toxicity, these are generally determined by evaluating relevant animal and human data collected during research and development. Important considerations in this evaluation of pharmacological activity or toxicity may include Occupational Exposure Limit (OEL), Permitted Daily Exposure (PDE), Acceptable Daily Exposure (ADE), Threshold for Toxicological Concerns (TTC), No Observed Adverse Effect Level (NOAEL) [ICH S-guidelines, ICH E2E, 2.1.1], and the consequences of cross-contamination [ICH Q9, 4.3]. 

Quality Metrics US FDA

FDA's current approach to overseeing pharmaceutical manufacturing emphasises the importance of quality metrics in ensuring product safety and efficacy. These metrics, which are an integral part of the FDA's inspection and compliance strategies, aim to promote continuous improvement and innovation within the industry. While the FDA focuses primarily on Quality Metrics, the concept of Key Performance Indicators (KPIs) also plays a critical role as it provides a broader perspective on operational efficiency and strategic management.

The effective use of metrics is essential for robust quality management at a site. They also play a crucial role in selecting suppliers, monitoring contract activities and minimising supply chain disruptions. The FDA itself uses metrics to develop compliance and inspection guidelines, improve the prediction and mitigation of drug shortages, and optimise risk-based inspection planning.

The FDA is also working on a Quality Metrics Reporting Programme to support its quality monitoring activities, with the goal of obtaining more quantitative and objective measures of manufacturing quality and reliability. In addition, the FDA's Center for Drug Evaluation and Research (CDER) is implementing a programme to promote Quality Management Maturity (QMM) in drug manufacturing facilities. The QMM programme promotes the adoption of quality management practices that go beyond CGMP requirements and aims to foster a strong quality culture, recognise advanced quality management practices, identify areas for improvement and minimise risks to product availability.

Key Performance Indicators (KPIs) are important metrics used in pharmaceutical manufacturing to measure and evaluate the effectiveness of operations and processes against defined goals. While the FDA emphasises quality metrics to monitor the product and process lifecycle in pharmaceutical manufacturing, KPIs can complement these by providing insights into compliance and operational efficiency.

Supplier or Vendor Qualification

Supplier Qualification Overview 

The "Best practices guide for managing suppliers of API manufacturers" was finalised by the "APIC Supplier Management Task Force" in March 2024 and is now available on the APIC website. It emerged from the document "Supplier Qualification and Management Guideline", which was first published in 2009, and now replaces it in its entirety. The previous document has been completely revised, although the original annexes have been retained and an additional Annex 2 entitled "Commitment declaration (template)" has been added.

The new guide contains the following chapters and sub-chapters:

1. General Section
    1.1 Introduction 
    1.2 Objectives
    1.3 Scope
    1.4 Overall Process for Supplier Management

2. Supplier Management
    2.1 Selection Phase
    2.2 Qualification Phase
    2.3 Operational Phase
    2.4 Termination Phase

3. Risk Management applied to Supplier Management
    3.1 Risk management process
    3.2 Risk Identification and Analysis
    3.3 Risk Evaluation and Risk Review
    3.4 Risk control

4. Auditing
    4.1 General
    4.2 Audit organisation
    4.3 Audit Types
    4.4 Audit rating
    4.5 Refusal of audits

5. Quality agreements
    5.1 General
    5.2 Refusal or partial acceptance of agreements

6. Definitions and abbreviations
7. References
8. Annexes
9. Version History

US FDA Warning Letter 09.04.2024

Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

Your firm manufactures over-the-counter (OTC) (b)(4) drug products, such as, (b)(4). Your firm failed to adequately test your (b)(4) drug product for identity and strength of active ingredients prior to release and distribution.

In your response, you state that you will perform an assay test of your (b)(4) for (b)(4) with a validated analytical method. Your response is inadequate. You failed to provide sufficient details such as your testing procedures or a risk assessment of products released without appropriate assay testing.

Because you lacked adequate testing of each batch of your drug product, you do not know whether they conform to all appropriate finished product specifications and are suitable for release and distribution.

2. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure the following:

Appropriate production and process controls, including an adequate process validation program designed to assure drug products manufactured have the identity, strength, quality, and purity purported or represented to possess (21 CFR 211.100(a)).

Scientifically sound and appropriate test methods and standards used for testing your drug products (21 CFR 211.160(b)).

Complete data derived from standard preparation, sample preparation, and assay testing of your drug products was properly documented and retained (21 CFR 211.194(a)).

Adequate investigations and deviations (21 CFR 211.192).

Adequate cleaning and maintenance procedures, including an appropriate cleaning validation program for your non-dedicated manufacturing

Natco Pharma Ltd received a Warning Letter

Natco Pharma Ltd, a leading Indian pharmaceutical company, announced today that it has received a Warning Letter from the United States Food and Drug Administration (USFDA) regarding its manufacturing facility located in Kothur, Telangana.

The letter, dated April 8, 2024, follows a routine current Good Manufacturing Practices (cGMP) inspection conducted by the USFDA at the facility in October 2023.

The Kothur facility produces various pharmaceutical products for the company. While the company did not disclose specific details about the products manufactured at this site, it stated that the warning letter is not expected to disrupt supplies or impact existing revenues from the facility.

However, the letter may result in delays or withholding of pending product approvals from the Kothur site, it added.Hit Follow

Insufficient CAPA turned into Non-compliance

CAPA is a promise from the manufacturer that provide assurance to regulatory over a documentation. Failing to meet such promise will turn into a non compliance report by regulatory authority here is the example.

A follow-up GMP inspection was carried out at Cubit Lifesciences in India by the Malta Medicines Authority (MMA), an EU Competent Authority, early 2024. This inspection was in line with the recommendations from a previous inspection conducted about one year earlier, which had identified "2 critical, 3 major and a total of 17 other observed issues."

The main goal of the recent follow-up inspection was to "assess and validate the effective incorporation, spanning the entirety of the facility and the pharmaceutical quality system, of the documented Corrective and Preventive Actions (CAPAs) and commitments presented by Cubit Lifesciences in response to the February 2023 inspection."

However, the follow-up inspection revealed that some issues identified in the initial inspection were "not fully addressed and implemented," leading to the finding of "two critical, four major and twelve other findings." This indicated a lack of proper implementation of the necessary CAPAs.

As a consequence, the Inspection Review Group (IRG) at the Malta Medicines Authority has decided to issue a "Statement of Non-Compliance with the principles and guidelines of Good Manufacturing Practice laid down in Directive 2003/94/EC" for the site, reflecting ongoing concerns about compliance and quality management at Cubit Lifesciences.

Also for inspection observations, the causes of the problems identified would need to be thoroughly investigated and corrective and preventive actions (CAPA) should be defined to prevent recurrence. The implementation of CAPA following a root cause analysis (RCA) is crucial as it ensures that the identified causes are addressed through appropriate actions. The report emphasises the need for an in-depth root cause analysis and the implementation of effective CAPA.

Understand ICH Q7 S3

Can other departments outside of the quality unit be held responsible for releasing raw materials and intermediates? Yes. The quality unit is responsible for establishing a system Yes. The quality unit is responsible for establishing a system to release or reject raw materials, intermediates, packaging, and labelling materials. This responsibility cannot be delegated [ICH Q7, 2.22(2)]. The system established by the quality unit may allow ‘other departments’ to release raw materials and intermediates (except intermediates that are for use outside the control of the manufacturer [ICH Q7, 2.22(1)]) as long as oversight and the overall responsibility of this system remains with the quality unit. Does ICH Q7 expect that sampling be performed by the quality unit? No. ICH Q7 does not prescribe specifically who should perform the sampling [ICH Q7, 2.22]. However, the quality unit has responsibility for reviewing and approving sampling plans [ICH Q7, 11.12] and procedures. Sampling should be performed by adequately trained personnel [ICH Q7, 3.10] and be appropriately documented as per [ICH Q7, 6.52]. What should be the frequency of a product quality review? A product quality review is generally expected annually. Review timeframes can be appropriately adjusted based upon manufacturing and campaign duration with adequate justification. Even if no manufacturing has occurred in the review period, the quality review should be conducted as per section [ICH Q7, 2.50] and include stability, returns, complaints, and recalls. For example, a product quality review may encompass more or less than 12 months depending upon product campaign duration [ICH Q7, 2.50; ICH Q10, 2.6].

Technical Documents Writing Tips

Know your audience: Before you even start writing, consider who will be reading your document. Are they experts in the field, or do they need a more basic explanation? Tailor your language and level of detail accordingly. Clarity is key: Strive for clear, concise, and easy-to-understand language. Avoid jargon and technical terms whenever possible. If you do need to use them, define them clearly the first time you use them. Structure your document logically: Organize your information in a logical and easy-to-follow way. Use headings, subheadings, bullet points, and numbered lists to break up your text and make it visually appealing. Use visuals effectively: Charts, graphs, diagrams, and screenshots can be powerful tools for explaining complex concepts. Make sure your visuals are clear, well-labeled, and relevant to the text. Write in active voice: Active voice makes your writing more concise and engaging. For example, instead of saying "The experiment was conducted by the researchers," say "The researchers conducted the experiment." Focus on the benefits: When explaining a technical process or product, focus on the benefits for the reader. What problem does it solve? How will it make their life easier? Use examples: Examples can help illustrate complex concepts and make your writing more relatable. Proofread carefully: Once you've finished writing, proofread your document carefully for typos, grammatical errors, and formatting inconsistencies. Get feedback: Ask a colleague or friend to review your document and provide feedback

Understand ICH Q7 S2

Should GMP according to ICH Q7 be applied for manufacturing steps before the defined ‘API starting material' i.e. steps not identified in grey in Table 1? ICH Q7 does not apply to steps prior to the introduction of the API starting material. However, there is an expectation that an appropriate level of controls suitable for the production of the API starting material should be applied [ICH Q7, 1.3]. Normally, the ‘API-starting material’ is defined in the regulatory filing by the applicant and approved in the regulatory reviewing process. Additional guidance is provided to define and justify ‘API starting material’ derived from various sources [ICH Q11, 5]; for master cell banks, see [ICH Q5B; ICH Q5D]

Understand ICH Q7

What is meant by ‘quality unit(s) independent from production The intent of the term ‘independent’ is to prevent any conflict of interest and ensure unbiased decision-making regarding quality-related decisions in the organization structure. The person in the quality unit who is responsible for final decision-making (e.g., batch release decision) should not have responsibilities for production activities [ICH Q7, 2.13]. Does ICH Q7 expect that the quality unit performs API release testing While the quality unit has responsibility for the release of the API, which includes oversight of the testing and results, ICH Q7 does not prescribe specifically who performs testing. ‘Quality control’ in the ICH Q7 Glossary [ICH Q7, 20] refers to the activities, not the organisational structure. For examples of quality responsibility related to testing and release, refer to [ICH Q7, 2.13, 2.22, and 11.12]. Appropriate laboratory controls should be followed [ICH Q7, 11.10, 16.10] regardless of who performs the testing.

Out of Specification (OOS) Results in Pharmaceuticals: A Outline

In the world of pharmaceutical manufacturing, maintaining strict quality control is paramount. Every step of the process is meticulously monitored to ensure the safety and efficacy of the final product. But sometimes, things don't go according to plan, and a test result might fall outside the established specifications, known as an Out-of-Specification (OOS) result. An OOS result can be a cause for concern, but it's crucial to stay calm and follow a systematic investigation process. Here's a breakdown of what to do when you encounter an OOS See the latest updates to the Gemini Apps Privacy HubOpens in a new window Conversation with Gemini profile picture US FDA TODAY news There is no daily news section on the US Food and Drug Administration (FDA) website, but they do have a newsroom section that is updated regularly. Here's what I found for today, April 2nd, 2ˑ024: They have an upcoming public conference on medical device statistical issues (https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops). Looking at their recent press announcements, here are the highlights from March 29th: The FDA warned consumers to avoid certain topical pain relief products (https://www.fda.gov/news-events/press-announcements/fda-warns-consumers-avoid-certain-topical-pain-relief-products-due-potential-dangerous-health). You can find more information on the FDA website https://www.fda.gov/. profile picture EDQM news Here's some recent news from the EDQM (European Directorate for the Quality of Medicines & HealthCare): EDQM celebrating 60 years: 2024 marks their 60th anniversary, and they're hosting a conference on June 11th and 12th in Strasbourg to celebrate their achievements in public health protection [EDQM conference]. New monographs in European Paediatric Formulary: Two new additions were made: Clonidine hydrochloride and Furosemide oral solutions [EDQM news]. EDQM ISO 9001 certification maintained: Their quality management system was successfully audited in November 2023 [EDQM newsroom]. Temporary closure: Due to a recent public holiday, the EDQM was closed from March 29th to April 1st, 2024 [EDQM newsroom]. For more information and the latest updates, you can visit the EDQM website news section [EDQM newsroom]. profile picture What is extra polation Extrapolation is a technique used to estimate what's beyond the data you have. It's like making an educated guess about something that hasn't been observed yet, based on what you already know. Here's a breakdown: Estimating the unknown: Imagine you have data points for something, like temperature measured every day for a month. Extrapolation would be using that data to guess the temperature on a day outside that month. Going beyond the range: Extrapolation extends a trend or pattern in the data beyond the points you actually measured. Comparison to interpolation: It's different from interpolation, which is used to estimate values between known data points. Here are some real-world examples of extrapolation: Weather forecasting: Predicting next week's weather based on data from this week. Population growth: Estimating a city's population in 10 years based on current growth trends. Sales prediction: Projecting future sales figures based on historical sales data. Important to remember: Extrapolation can be risky. The further you go from your existing data, the less reliable your estimates become. New factors can emerge that throw off your predictions. So, it's a useful tool, but use it with caution! profile picture US FDA latest warning letter The FDA website doesn't provide daily updates on warning letters. However, you can find the latest ones yourself by following these steps: Go to the FDA's Warning Letters webpage: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters Look for the "Date Posted" section on the right-hand side. This will show you the dates of the most recently added warning letters. As of today, April 2nd, 2024, the most recent warning letter on the FDA website is dated November 17th, 2023. It was issued to Cipla Limited https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/cipla-limited-660904-11172023. Here are some alternative resources to find the latest FDA news: FDA News & Events: https://www.fda.gov/ This page provides a list of recent press releases and upcoming events. FDA RSS Feed: https://www.fda.gov/about-fda/contact-fda/subscribe-podcasts-and-news-feeds You can subscribe to the FDA's RSS feed to receive automatic updates on new content. FDA Twitter: https://twitter.com/us_fda?lang=en Follow the FDA on Twitter for the latest news and updates. Sources library.weill.cornell.edu/about-us/snake%C2%A0oil%C2%A0-social%C2%A0media-drug-advertising-your-health/modern-drug-advertisements-themes-fda profile picture What is an outlier in stats In statistics, an outlier is a data point that falls significantly outside the overall pattern of the data. It's a single observation that seems very different from the rest of the values in a dataset. Here's a breakdown of what makes a data point an outlier: Extremely high or low value: Outliers are usually on the very high end or very low end of the data spectrum. They deviate considerably from the average (mean) or median of the data set. Doesn't fit the pattern: Outliers disrupt the overall trend or distribution of the data. Imagine a bunch of data points clustered together, and then one point way off by itself - that's an outlier. There are two main ways to identify outliers: Visually: Box plots and scatter plots are useful tools for spotting outliers. In a box plot, outliers appear as points far away from the main box-shaped area. In a scatter plot, they'll be isolated points far from the cloud of other data points. Statistically: There are statistical methods to define outliers based on factors like interquartile range (IQR). These methods set thresholds to determine how far a data point can deviate from the rest before being considered an outlier. Here's some additional information to consider about outliers: Not always errors: While outliers can sometimes indicate errors in data collection, they don't necessarily mean there's a mistake. They could represent genuine variations or exceptions within the data. Impact on analysis: Outliers can significantly affect statistical analyses, especially those that rely on averages or medians. It's important to acknowledge their presence and decide how to handle them (including removing them if justified) before drawing conclusions from your data. profile picture How to download WHO audit observations The World Health Organization (WHO) website doesn't directly offer downloads of individual audit observations. Here are some alternative approaches to find relevant information: List of Internal Audit Reports: The WHO publishes a list of their internal audit reports for each year. This provides an overview of the audits conducted, their titles, dates, and overall conclusions (https://www.who.int/publications/m/item/report-of-the-internal-auditor). While it doesn't include detailed observations, it can be a starting point to see if an audit was conducted in your area of interest. WHO Publications: Search the WHO publications database using keywords related to the specific program or area you're interested in, along with terms like "audit," "evaluation," or "assessment" (https://www.who.int/publications). This might lead you to reports that include summaries of audit findings. WHO Regional Offices: If your focus is on a specific region, explore the websites of the WHO regional offices, as they might publish information on audits conducted within their jurisdiction. Contact WHO: If the above options don't provide what you need, consider contacting the WHO Department of Internal Oversight and Investigations (OIOS) directly. They might be able to advise on how to access specific audit information (https://www.who.int/about/office-of-internal-oversight-services/investigations). Keep in mind: Releasing detailed audit observations might have privacy or confidentiality concerns, so access may be restricted. The WHO website focuses on publishing final reports and recommendations, rather than individual observations. profile picture I need a blog post on how to investigate out of specifications results in pharmaceutical Show drafts Out of Specification (OOS) Results in Pharmaceuticals: A Guide to Investigation In the world of pharmaceutical manufacturing, maintaining strict quality control is paramount. Every step of the process is meticulously monitored to ensure the safety and efficacy of the final product. But sometimes, things don't go according to plan, and a test result might fall outside the established specifications, known as an Out-of-Specification (OOS) result. An OOS result can be a cause for concern, but it's crucial to stay calm and follow a systematic investigation process. Here's a breakdown of what to do when you encounter an OOS result: 1. Initial Response and Documentation: Stop the process: Halt any activity that could potentially affect the product or generate misleading data. Secure the sample: Isolate and quarantine the sample associated with the OOS result to prevent contamination or loss. Document everything: Record all details of the event, including the test name, OOS value, date, time, and any observations about the sample or process. 2. Investigate the Cause: Repeat analysis: Re-run the test according to the established procedure. This helps confirm the initial OOS result and rule out potential errors during the first test. Analyze trends: Review historical data for the same product or test. Have there been any similar OOS occurrences? Identifying trends can help pinpoint potential root causes. Evaluate potential factors: Consider factors that might have influenced the result, such as: Equipment malfunction: Was the testing equipment properly calibrated and functioning correctly? Human error: Did any deviations from the standard operating procedure (SOP) occur during sample collection or testing? Raw material issues: Were there any problems with the starting materials used in the manufacturing process? Environmental factors: Could temperature, humidity, or other environmental conditions have affected the results? 3. Risk Assessment and Corrective Action: Assess the impact: Evaluate the potential health risks associated with the OOS result. How critical is the deviation from specifications? Determine disposition of the batch: Based on the investigation and risk assessment, decide whether to release, rework, or reject the affected batch. Implement corrective actions: Address the root cause of the OOS to prevent future occurrences. This might involve equipment recalibration, additional staff training, or revising SOPs.

FDA warning Letter issued 02.04.2024

Synopsis Identity testing of incoming components: The firm did not conduct adequate testing to verify the identity of each component of its drug products, including active ingredient ethanol for methanol contamination. Finished drug product testing: There was a lack of appropriate laboratory determination of satisfactory conformance to final specifications for drug products before release, including identity and strength of the active ingredients. Stability program: The firm failed to establish and follow an adequate written testing program to assess the stability characteristics for the OTC hand sanitizer drug products. Quality Unit (QU): The QU did not effectively oversee the quality of drug manufacturing operations. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)). The records and information you provided demonstrate that your quality unit (QU) did not effectively exercise its responsibilities to oversee the quality of your drug manufacturing operations. Your QU is responsible for fully exercising its authority and responsibilities. FDA is concerned that your QU may not be conducting appropriate oversight regarding CGMP operations. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download