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

Frequently asked questions FDA

Q1: When is an FDA Form 483 issued?
A: An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgment, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.
Q: What is the purpose of an FDA Form 483?
A: The FDA Form 483 notifies the company’s management of objectionable conditions. At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously.

Q2: What is the purpose of an FDA Form 483? A: The FDA Form 483 notifies the company’s management of objectionable conditions. At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously. Q3: Is the FDA Form 483 intended to be an all-inclusive list of every possible deviation from law and regulation? A: No, it’s not. The FDA Form 483 is a report which does not include observations of questionable or unknown significance at the time of the inspection. There may be other objectionable conditions that exist at the firm that are not cited on the FDA Form 483. FDA investigators are instructed to note only what they saw during the course of the inspection. Companies are responsible to take corrective action to address the cited objectionable conditions and any related non-cited objectionable conditions that might exist. Q2: How is the FDA Form 483 shared with the company? A: FDA Form 483s are discussed with a company’s management at the conclusion of the inspection. Each observation is read and discussed so that there is a full understanding of what the observations are and what they mean. Q3: What are the implications of the FDA Form 483 for agency enforcement and what happens next? A: The FDA Form 483 does not constitute a final Agency determination of whether any condition is in violation of the FD &C Act or any of its relevant regulations. The FDA Form 483 is considered, along with a written report called an Establishment Inspection Report, all evidence or documentation collected on-site, and any responses made by the company. The Agency considers all of this information and then determines what further action, if any, is appropriate to protect public health

Court Ruling: Suspended Sentence and Heavy Fine for Falsifying Stability Data

A London court has sentenced a pharmaceutical company and its former director to heavy fines. The defendant had admitted to knowingly submitting falsified data to the Medicines and Healthcare products Regulatory Agency (MHRA) in order to obtain a Marketing Authorization for a product. This was preceded by extensive investigations by the authority, during which thousands of scientific data files were analyzed and reviewed. The defendant was sentenced to eight and seven months on two counts. He will not have to spend time in prison as the sentence was suspended for 18 months. However, both the defendant and the company must pay a fine of £50,000. The defendant must also pay the prosecution costs of over £80,000. A confiscation order of over £1 million, reflecting the profit from the crime, have already been confiscated. What happened? A press release dated 15 March 2024 states that "Evotrox Oral Solutions (a liquid solution containing the active ingredient levothyroxine) was licensed in 2006 in three strengths for the treatment of hypothyroidism (underactive thyroid)." As usual, the manufacturer also had to submit stability data as part of the licence application. Back in 2008, reports emerged that the product was not stable for the whole duration of the shelf-life claimed in the original licence application. The MHRA took this as an occasion to launch an investigation. During this investigation, "the company continued to submit falsified data to the MHRA to try to support the medicine’s stability and effectiveness." A comprehensive series of independent analyses by the MHRA and a detailed evaluation of the data seized from laboratory computers brought the falsifications to light. This culminated in the termination of the marketing authorisations by the MHRA in 2013 and subsequent criminal prosecution. Statement of the MHRA In the press release, Andy Morling, MHRA Deputy Director (Criminal Enforcement), emphasizes the complexity of the investigations. "Whilst the MHRA found no evidence that patients were harmed, the fact that the manufacturers were prepared to put them at risk by knowingly supplying a substandard product is very concerning." All in all, "this is a shocking case of a pharmaceutical company that thought it was above the law and was not required to uphold our stringent standards for safety, quality and effectiveness."

What is a standard operating procedure (SOP)?

in this blog I would like to share my thought process on what is standard operating procedure and containing to this blog what are the components that are needed to be considered while writing an efficient standard operating procedure A standard operating procedure is a set of written instructions that describes the step-by-step process that must be taken to properly perform a routine activity. SOPs should be followed the exact same way every time to guarantee that the organization remains consistent and in compliance with industry regulations and business standards. Standard operating procedures provide the policies, processes and standards needed for the organization to succeed. They can benefit a business by reducing errors, increasing efficiencies and profitability, creating a safe work environment and producing guidelines for how to resolve issues and overcome obstacles.

cGMP Basic Introduction

Quality of Pharmaceutical effects either positively or negatively on each citizen of every nation. 

Therefore every nation configure its own regulatory authority for example United States has regulatory authority with the name us FDA and Australia please having the name asTGA, India is having the name as CDSCO, UK is having MHRA, European is having EDQM and etc.

While speaking from business perspective the customer base in US is very high and the cost of the drugs that is manufacturers can sell for the maximum margin in US.

In this blog we will mainly focus on how us-fda things about cgmp.

Which regulatory body of the country regulates the quality of pharmaceuticals very carefully. The main regulatory standard for ensuring pharmaceutical quality is the Current Good Manufacturing Practice (CGMPs) regulation for human pharmaceuticals. Consumers expect that each batch of medicines they take will meet quality standards so that they will be safe and effective. Most people, however, are not aware of CGMPs, or how FDA assures that drug manufacturing processes meet these basic objectives. Recently, FDA has announced a number of regulatory actions taken against drug manufacturers based on the lack of CGMPs. This paper discusses some facts that may be helpful in understanding how CGMPs establish the foundation for drug product quality.

CGMP refers to the Current Good Manufacturing Practice regulations enforced by the FDA. CGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. This includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories. This formal system of controls at a pharmaceutical company, if adequately put into practice, helps to prevent instances of contamination, mix-ups, deviations, failures, and errors. This assures that drug products meet their quality standards.

The CGMP requirements were established to be flexible in order to allow each manufacturer to decide individually how to best implement the necessary controls by using scientifically sound design, processing methods, and testing procedures. The flexibility in these regulations allows companies to use modern technologies and innovative approaches to achieve higher quality through continual improvement. Accordingly, the "C" in CGMP stands for "current," requiring companies to use technologies and systems that are up-to-date in order to comply with the regulations. Systems and equipment that may have been "top-of-the-line" to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today's standards.

It is important to note that CGMPs are minimum requirements. Many pharmaceutical manufacturers are already implementing comprehensive, modern quality systems and risk management approaches that exceed these minimum standards.

A consumer, in pharmaceutical industry case the consumer would be a patient, usually cannot detect (through smell, touch, or sight) that a drug product is safe or if it will work. While CGMPs require testing, testing alone is not adequate to ensure quality. In most instances testing is done on a small sample of a batch (for example, a drug manufacturer may test 100 tablets from a batch that contains 2 million tablets), so that most of the batch can be used for patients rather than destroyed by testing. 

Therefore, it is important that drugs are manufactured under conditions and practices required by the CGMP regulations to assure that quality is built into the design (As it was discussed in previous blog)and manufacturing process at every step. 

Therefore the main principle of any quality system which depends majorly on 4M system that is man, machine, method, mother nature (environment).

To understand more of 4M system please go through the following paragraph

Facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and fully trained, and processes that are reliable and reproducible, are a few examples of how CGMP requirements help to assure the safety and efficacy of drug products. 

Any regulatory body of any nation inspects pharmaceutical manufacturing facilities worldwide, including facilities that manufacture active ingredients and the finished product. Inspections follow a standard approach and are conducted by highly trained FDA staff. FDA also relies upon reports of potentially defective drug products from the public and the industry. FDA will often use these reports to identify sites for which an inspection or investigation is needed. Most companies that are inspected are found to be fully compliant with the CGMP regulations.

What happens website is not following cgmp regulations can be seen next blog.