A Systematic Approach to Implementing Statistical Methodologies

Focusing exclusively on qualification efforts without understanding the manufacturing process and associated variations may not lead to adequate assurance of quality.

In Guidance for Industry Process Validation: General Principle and Practices, process validation is defined as, “”…the collection and evaluation of data, from the process design stage through commercial production..” The guidance further delineates the ‘process design stage through commercial production’ into three distinct stages of the product lifecycle:

Stage 1: Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.

Stage 2: Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.

Stage 3: Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

The first stage of process validation is process design. The Process Validation guidance document states, “A successful validation program depends on information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of a manufacturing process that results in products with desired quality attributes:

Manufactures should:

  • Understand the sources of variation
  • Detect the presence and degree of variation
  • Understand the impact of variation on the process and ultimately on product attributes
  • Control the variation in a manner commensurate with the risk it represents to the process and product.”

The second stage of process validation is process qualification. Although stage 2 has two elements, this course will focus on recommendations for the second element, PPQ. PPQ “combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches.” Additionally, the process validation guidance document that “Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product. Focusing exclusively on qualification efforts without understanding the manufacturing process and associated variations may not lead to adequate assurance of quality.”

The third stage of process validation is continued process verification. The process validation guidance document defines the need for this stage: “After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.” Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate the state of control of the process. These programs may identify process or product problems or opportunities for process improvements that can be evaluated and implemented through some of the activities described in Stages 1 and 2.”

This course focuses on how to establish a systematic approach to implementing statistical methodologies into a process validation program consistent with the FDA guidance. It begins with a primer on statistics, focusing on methods that will be applied in each remaining chapter. Next, it teaches the application of statistics for setting specifications and assessing measurement systems (assays), two foundational requirements for process validation. Lastly, the course applies statistic through the three stages of process validation defined by requirements in the process validation regulatory guidance documents. Methods taught through all three stages are recommended by regulatory guidance documents; references to the specific citations in the guidance documents are provided.

Areas covered by the Instructor:

  • Apply statistics to set specifications and validate measurement systems (assays)
  • Develop appropriate sample plans based on confidence and power
  • Implement suitable statistical methods into a process validation program for each of the three stages
  • Stage 1, Process Design: utilize risk management tools to identify and prioritize potential critical process parameters; and define critical process parameters and operating spaces for the commercial manufacturing process using design of experiments (DOE)
  • Stage 2, Process Qualification: assess scale effects while incorporating large (pilot and/or commercial) scale data; develop process performance qualification (PPQ) acceptance criteria by characterizing intra and inter-batch variability using process design data and batch homogeneity studies; and develop an appropriate sampling plan for PPQ
  • Stage 3, Continued Process Verification: develop a control plan as part of a risk management strategy; collect and analyze product and process data; and ensure your process is in (statistical) control and capable.

Who will benefit by this:

  • Process Scientist/Engineer
  • Design Engineer
  • Product Development Engineer
  • Regulatory/Compliance Professional
  • Design Controls Engineer
  • Six Sigma Green Belt
  • Six Sigma Black Belt
  • Continuous Improvement Manager

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How to interpret and use more than just a standard tool-box

Metrology: QC Sampling Plans the statistical analysis of measurement uncertainty, and how it is used to establish QC specifications.

How to apply statistics to manage risks and verify/validate processes in R&D, QA/QC, and Manufacturing, with examples derived mainly from the medical device design/manufacturing industry. The flow of topics over the 2 days is as follows:

  • ISO standards and FDA/MDD regulations regarding the use of statistics.
  • Basic vocabulary and concepts, including distributions such as binomial, hypergeometric, and Normal, and transformations into Normality.
  • Statistical Process Control
  • Statistical methods for Design Verification
  • Statistical methods for Product/Process Qualification
  • Metrology: QC Sampling Plans the statistical analysis of measurement uncertainty, and how it is used to establish QC specifications
  • How to craft “statistically valid conclusion statements” (e.g., for reports)
  • Summary recommendations

The various statistical methods used to support such activities can be intimidating. If used incorrectly or inappropriately, statistical methods can result in new products being launched that should have been kept in R&D; or, conversely, new products not being launched that, if analyzed correctly, would have met all requirements. In QC, mistakenly chosen sample sizes and inappropriate statistical methods may result in purchased product being rejected that should have passed, and vice-versa.

This provides a practical approach to understanding how to interpret and use more than just a standard tool-box of statistical methods; topics include: Confidence intervals, t-tests, Normal K-tables, Normality tests, Confidence/reliability calculations, Reliability plotting (for extremely non-normal data), AQL sampling plans, Metrology (i.e., statistical analysis of measurement uncertainty ), and Statistical Process Control. Without a clear understanding and correct implementation of such methods, a company risks not only significantly increasing its complaint rates, scrap rates, and time-to-market, but also risks significantly reducing its product and service quality, its customer satisfaction levels, and its profit margins.

  • FDA, ISO 9001/13485, and MDD requirements related to statistical methods
  • How to apply statistical methods to manage product-related risks to patient, doctor, and the designing/manufacturing company
  • Design Control processes (verification, validation, risk management, design input)
  • QA/QC processes (sampling plans, monitoring of validated processes, setting of QC specifications, evaluation of measurement equipment)
  • Manufacturing processes (process validation, equipment qualification)

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  • QA/QC Supervisor
  • Process Engineer
  • Manufacturing Engineer
  • QC/QC Technician
  • Manufacturing Technician
  • R&D Engineer

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200+ followers. WOWWWWWW…

followed- 200

Hello Everyone,

Today we have the pleasure of celebrating the fact that we have reached the milestone of 200+ followers on WordPress. Since we started this blog, we have had such a great time connecting with everyone.  we never expected to actually to connect with other people in the blogging community.

we are so incredibly thankful for each and every one of you who follows and comments on my blog posts. Please know that!

we would continue our blogging in these areas FDA Regulation, Medical Devices, Drugs and Biologics, Healthcare Compliance, Biotechnology, Clinical Research, Laboratory Compliance, Quality Management ,HIPAA Compliance ,OSHA Compliance, Risk Management, Trade and Logistics Compliance ,Banking and Financial Services, Auditing/Accounting & Tax, Packaging and Labeling, SOX Compliance, Environmental Compliance, Microsoft Excel Spreadsheet, Geology and Mining, Human Resources Compliance, Food Safety Compliance and etc.

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Digital Marketing for Pharmaceutical companies offers tremendous opportunities

There is enormous potential for digital marketing for pharmaceutical companies. Proper exploitation of the social media can take pharmaceutical companies to their market in a more pinpointed and accurate manner than traditional marketing.

Gone are the initial days of reluctance on the part of pharmaceutical companies to embrace social media as a powerful marketing medium. That was in the past, when the concept of social media was new, and regulations in the pharmaceutical industry had yet to catch up with explosive pace at which the social media grew.

More and more pharmaceutical companies are on the social media

Today, one is likely to see any pharmaceutical company worth its name being active on YouTube, Facebook and Twitter to interact with its customers. Changes brought about by digital marketing in the pharmaceutical industry have seen companies like Johnson and Johnson and Pfizer being among the several majors associated with YouTube lately for creating and promoting their image. This is a result of the realization that social media can, far from being unconducive to the industry, can be quite amiable to it.

  • In a study in late 2014, the New England Journal of Medicine estimated that leading pharmaceutical companies spend up to a quarter of their marketing budgets on the social media
  • The study pointed out that the social media were as powerful and effective as EHRs and mobile applications as marketing tools, signaling a new dynamic for digital marketing in the pharmaceutical industry.

Social media as a key differentiator

The defining area in which the social media can be different and more effective than traditional marketing tactics for pharmaceutical companies is this: earlier methods such as trade conferences, promotions, gifting doctors for prescribing a company’s brands were effective, but were carried out outside the healthcare setting and in isolation of the patient. The reach and intervention of the social media has made digital marketing for pharmaceutical companies so much more effective that they can get right into the arena of treatment and be of assistance with valuable inputs and suggestions.

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Design Control for Medical Devices

Design Control for Medical Devices 3

Design Control for medical devices is of utmost importance to the medical device industry. In order to get a grasp of its importance, one needs to get an understanding of what Design Control is. In simple terms, Design Control for medical devices is a set of logical and linear steps that medical device manufacturers have to take to ensure that:

  1. The medical device being manufactured is safe
  2. The medical device manufacturer follows all the steps and procedures for ensuring that the device it develops is what was meant to be developed
  3. Design controls for medical devices have to be put in place to ensure that the final product – the medical device – meets all the required and prescribed regulatory procedures and guidelines and meets the customer’s expectation

In short and simple terms, design controls for medical devices are verifiable and provable assurances that medical device manufacturers have taken adequate steps to guarantee that a medical device meets its set of required standards and procedures to ensure its safety and meet customer requirements.

FDA and ISO expectations of design controls for medical devicesBoth the FDA and the ISO have regulatory requirements from medical devices that expect some Design Control standards. The FDA’s requirements for design controls for medical devices are spelt out in FDA 21 CFR 820.30, while ISO 13485 is the standard for design controls for medical devices. Although formed by different regulatory or standards bodies; both the FDA 21 CFR 820.30 and the ISO 13485 are essentially similar. Their purview of the areas of design controls for medical devices is almost identically similar to each other. Sections of the FDA 21 CFR 820.30 and the ISO 13485 speak of requirements relating to the following in their various sections:

In just one area of design controls for medical devices, namely Design History File, there is a small difference, in that while the FDA’s regulatory requirements for design controls for medical devices include DHF; in the case of the ISO 13485, this is treated separately.

There is thus near total convergence between the FDA 21 CFR 820.30 and the ISO 13485 when it comes to design controls for medical devices.

Basic requirements of FDA 21 CFR 820.30 and ISO 13485Both the FDA 21 CFR 820.30 and the ISO 13485 have expectations for design controls for medical devices. These are the core areas:

designControlForMedicalDevices

Aspects of Regulatory History in the US

The beginnings of all that the USFDA regulates can be traced right to the early decades of the founding of the nation. In a sense, the FDA, even if came to be called by that formal name much later; embodies the discipline and value set that the new created nation sought to represent. Regulation of all aspects of American life was deeply ingrained very early in the nation’s history, and the FDA was one of prime institutions that played a part in making this happen.

How has the FDA evolved and shaped up over the years? What are the important milestones of this history? This makes interesting reading, because the USFDA has had the kind of history whose colorfulness is matched by few other regulatory agencies around the world.

aspectsOfRegulatoryHistoryAn indication of the extent to which the FDA attaches importance to ensuring the wellbeing of the American people can be gauged from the fact that the food and other products that this agency regulates account for a fifth of the total money that the nation’s consumers spend. Just its budget – well over four billion in 2014 – is a good indicator to the way in which the FDA has spread its influence in the various spheres of American life. It regulates almost all food items with the exception of meat and poultry.

This situation has not been reached accidentally or overnight. The FDA has by and large kept pace with the developments in the areas it regulates. This was largely true till the advent of very recent technology-led areas such as biotechnology and the social media, where too, the FDA has been trying to put its best foot forward.

The start of formal regulation 
aspectsOfRegulatoryHistoryA look at the history of the FDA points to the year 1848 as the start of the first formal aspects of regulatory history. That was the year in which Lewis Caleb Beck took his appointment with the Patent Office. His mandate was to chemically analyze agricultural products. This is considered as the first task that was aimed at regulating a product that people consumed. This function rolled over to the Department of Agriculture, which was created in 1862.

The Act of 1906The next step in solidifying the regulatory aspects of life in the US was taken in 1906, with the promulgation of the Pure Food and Drugs Act in 1906. Stretching to some two decades of wrangling between the American Congress and the food industry to formulate, the Act of 1906 sought to prohibit adulterated and misbranded food and drugs from interstate commerce.

The 1938 Food, Drug, and Cosmetic ActThe next major milestone in the aspects of regulatory history in the US took place in 1938. The 1938 Food, Drug, and Cosmetic Act prescribed and detailed the legal requirements for products the FDA – which this Act created – regulated. In this Act, one can trace the earliest tidings of a major activity that the FDA has been carrying out since then: Prescribing the requirements for ensuring quality by prohibiting false claims by manufacturers and advertisers.

aspectsOfRegulatoryHistoryPresident Franklin D. Roosevelt signing the 1938 Food, Drug, and Cosmetic Act.

Over time, the 1938 Act expanded to include more areas such as cosmetics, devices and veterinary medicines, thus strengthening the foundation for regulation and making it more expansive. Since the passage of the 1938 Food, Drug, and Cosmetic Act; two major events happened on the regulatory scene. The outbreak of tetanus and diphtheria diseases in the 1960’s compelled the FDA to take a more proactive approach to vaccinations.

Another major, earthshaking event was the tragedy that thalidomide unleashed on Europe in the 1960’s, which stunted the growth of hundreds of children, which was mainly due to regulatory lapse. This did not happen in the US, mainly because of the efforts and diligence shown by Frances Kelsey, in her role as FDA reviewer. Frances plainly refused to approve thalidomide because she was not convinced about its safety, an act which made her a cult figure in FDA and American and Canadian medicinal history till her death in 2015.

aspectsOfRegulatoryHistory

Aspects of regulatory history in the US in the 1990’sFollowing the 1960’s, the next major milestone in the aspects of regulatory history in the US happened in 1990, when the Nutrition Labeling and Education Act was passed. This law was important because it changed the American perspective of labeling of products in the food and pharmaceutical industries. The Nutrition Labeling and Education Act requires manufacturers to provide nutritional information about products on their labels, with the caveat that false labeling information will lead to consequences.

 

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Good Documentation Practice Guideline is simple: just write

Good Documentation Practices are the soul of many regulated industries. The FDA, like all other regulatory agencies, makes GDP a central element of its regulations, and bases it on the principle of evidence. For the FDA and other regulatory agencies across the world, what is not documented is nonexistent.

Good Documentation Practices are essential for a number of disciplines. The soul of documentation is, naturally, the written word. What happens when something that happened is not actually written down? It is a work of no practical use, because apart from those that carried out the particular undocumented task; no one else is aware of it. And even when the people who did that task or were witness to it are prone to have their own interpretation and perception of what was done. This is why proof in the form of writing is the most important element of Good Documentation Practices.

goodDocumentationPracticesGuidelines

What to write, and how toGDP should not only be about just writing down; it is about what to write and also, how, meaning, in what manner. If there has been an intervention in any method of manufacture or any other activity in the regulated industries; the change should be noted down in the proper format as prescribed by the FDA. This enables everyone concerned, from the people in the organization to the auditors to the regulatory agencies, to clearly identify what action was carried out, by whom and when. This further leads to a discovery of the impact of the actions. This is the key to determining the effectiveness of the application of the GDP principles in the particular case.

goodDocumentationPracticesGuidelinesThis is why the FDA has very clear-cut requirements and expectations of GDP from the industries it regulates. These clearly explain the method by which to document the said document, the ways of doing it, and what actions to take when the need arises.

Quality Assurance is unthinkable without the application of GDP principles. The main reason for establishing GDP is ensure that the documentation does the following to the record in question:

goodDocumentationPracticesGuidelines
What needs to be documented?Another major element of GDP is to determine what is to be documented. The FDA and other regulatory agencies require the principles of Good Documentation Practices to be applied across a number of activities at different stages. These include:

goodDocumentationPracticesGuidelines

The EMA’s requirements
goodDocumentationPracticesGuidelinesThe EMA also has clear-cut guidelines on Good Documentation Practices. Some of its core requirements relate to

  • Specifications
  • All aspects of the manufacturing including the product’s formulae, the way in which the processing was done, the methods of its packaging, and the extent to which its testing instructions are written down
  • SOPs
  • Protocols
  • Technical agreements

Further, most regulatory agencies have their own requirements with regard to the styling, ways by which the amendments, if any, need to be jotted down, the type of ink to be used, the way in which the review, if any, needs to be entered, and who should put signatures and where, so on. Manufacturers who fall under the purview of respective regulatory agencies need to adhere to these.

And, for other reasons, as wellImplementing Good Documentation Practices is a great idea to have for meeting regulatory requirements, because companies that do not meet these requirements are in a spot of bother about a number of issues. However, in addition to this, there is also the need for maintaining GDP for business reasons, as well. A business that complies with the requirements set out by the FDA or other regulatory agencies in relation to Good laboratory practices, the CFR regulations such as 21 CFR Parts that apply to various industries, and also as required as part of national and global agencies; earns a good name in the market and is considered a reliable company.

 

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