Understanding the calibration curve

To get an understanding of instrument calibration, we can think of it as being an essential phase in most measurement procedures. The calibration curve is a set of operations with which the relationship between the outputs of the measurement system (for example, the response of an instrument) and the accepted values of the calibration standards (for instance, the amount of analyte it has) can be established. Understanding the calibration curve is important because this is required in a large number of analytical methods.

How to go about a calibration curve?

At its most basic form, understanding the calibration curve has to begin with the preparation of a group of standards which contain a known amount of the analyte of interest. In this, the instrument response for each standard has to be measured. In addition, the relationship between the instrument response and analyte concentration has to be established. This relationship is then used to transform measurements made on test samples into estimates of the amount of analyte present.

The calibration process

In understanding the calibration curve, we have to know that a number of stages go into calibrating an analytical instrument. This is how a logical sequence of steps would look:

• Planning of the experiments;
• Making the relevant measurements;
• Plotting the results;
• Carrying out regression analysis on the data, which will help obtain the calibration function;
• Assessing the results of this regression analysis;
• Using the calibration function to estimate the values of the test samples;
• Evaluating the ambiguity of the values obtained

References:

http://www.nmschembio.org.uk/dm_documents/lgcvam2003032_xsjgl.pdf

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Technical file vs design dossier

One of the important points that a medical device professional encounters is this: the technical file vs design dossier. The reason for the confusion about these two is that there are different names of the same concept and vary according to the class of device and the Notified Body that approves it. This is what has given rise to the technical file vs design dossier.

Depends on class of device

At a basic level, there is a difference between the two: the medical device manufacturer must have technical documentation for each device. Called the conformity assessment annex of the MDD, IVD and AIMD directives; this is a basic requirement of these regulatory bodies and statues. The important element of the technical file vs design dossier aspect is that the terminology technical file/design dossier sometimes varies depending on whom the directive has come from, and the annex in which it is placed. This is why there is some confusion on this technical file vs design dossier matter.

The two terms are interrelated

The following description should give a perspective: by the term “technical file” is meant the description of the documentation that demonstrates the ways by which the device complies with essential requirements. Among these devices, some devices require a design examination. The Technical Construction File (TCF) of such devices is called a design dossier. This explains the fundamentals of the technical file vs design dossier debate.

Depends on the Notified Body

To recap, the technical file, which the MDD refers to as “technical documentation”, is a bunch of documents that the medical device manufacturer has to put in place and furnish to their Notified Body for assessment. This is to show that the medical device conforms to the Essential Requirements of the directive. While this much is clear, some Notified Bodies require different methods of documentation for certain class of medical devices. These are to be presented as a design dossier. This is what has given rise to some confusion about the technical file vs design dossier issue.

Reference:

http://www.tuvamerica.com/tuvnews/newsletters/searchdetail.cfm?ID=552

http://elsmar.com/Forums/showthread.php?t=28968

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Supplier quality audit training

Most medical device companies have auditors that assess the quality of the product from the supplier. This is the supplier quality audit. Supplier quality audit training is the training that is needed to be qualified to assess the quality of a product from the supplier. Auditors, regardless of whether they are from inside the organization or are external; have a need for this kind of training.

What are the attributes of an effective supplier quality audit training?

For a supplier quality audit training to be effective, it has to ideally combine theoretical and practical aspects of supplier quality audit. Auditing staff that undergo training must ideally be made to carry out a number of assignments in the area of regulatory compliance relating to supplier quality audit. This will give them enough knowledge of how the course aspects of supplier quality audit training work in real life.

What types of audits can supplier quality audit training help an auditor perform?

When proper supplier quality audit training is imparted, auditors in the organization or outside can perform the following types of audits:

• New supplier audits
• Existing supplier audits
• Time cycled audits
• Internal audits
• Audits specific to a task or cause

Areas of supplier audits

There are specific areas that supplier audits work in. The aim of supplier quality audit training is to identify these and help auditors carry the audits out in their respective areas:

• Regulatory
• Quality
• Operations
• Business
• The supplier audit process

Effective supplier quality audit training will help auditors carry out two important types of audit:

• Top-down, which is an ISO-type of audit that is concerned with recordkeeping and Quality System documentation
• Bottom up, a style of audit in which specific quality deficiencies are identified and rectified. This is usually referred to as the FDA type.

References:

http://www.nixonpeabody.com/files/Supplier_Quality_Mailhot.pdf

 

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Supplier qualification program

In the pharmaceutical and life sciences industries, a sound supplier qualification program is a must. It is an indispensable element of their very reputation. Many pharmaceutical organizations contract several of their manufacturing processes or even products to third parties. For this reason, the FDA considers the supplier as a logical extension of the manufacturer. In fact, it attaches so much importance to this area that it holds the pharmaceutical organization (the contracting company) responsible for the supplier’s behavior in relation to the manufacturer’s product

The FDA can inspect the supplier’s facility too

Since the supplier is considered a part of the manufacturer’s operations, the FDA reserves the right to inspect the supplier’s facility too, at the time of carrying out an inspection of the pharmaceutical organization. This being the importance of the supplier, it is imperative to chalk out an effective supplier qualification program that meets regulatory requirements.

Supplier evaluation

A supplier qualification program starts with supplier evaluation. Obviously, the supplier and his facilities have to be inspected according to predefined parameters. This will enable the pharmaceutical organization to clearly state the terms of the contract. The contract should ideally specify the conditions in which the pharmaceutical product is going to be made.

Key elements of a sound supplier qualification program

All the important aspects of a supplier qualification program have to be put in place, as should the kind and nature of control. There should be proper checking up of data that goes into the supplier qualification program. These are some of the aspects that need to be implemented:

• Establishment and maintenance of data that clearly describe or reference the specified requirements, among which quality requirements are very important
• Identification of the key elements of a strong, sustainable and successful supplier qualification program
• Signing of terms of the contract and making written agreements of the same, in which all the conditions of work will be clearly specified and ensure that the supplier meets the quality requirements consistently
• Ensuring that the supplier qualification program has processes that are important to quality. This should also define how conformance to manufacturer requirements will be monitored and verified.

Reference:

http://www.eventbrite.com/event/5766556927/eorg

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SOX compliance training

SOX compliance training is a new requirement that publicly held companies and other CPA’s have to comply with. The SOX Act (Sarbanes Oxley Act) was a landmark legislation passed by the Congress in 2002. The primary purpose of this Act was to bring about greater accountability among businesses, especially publicly held companies and their auditors.

As a result of this legislation, organizations are required to bring in enhanced accountability by implementing the provisions of Act, which pertain to being in compliance with its provisions as set out in the Public Company Accounting Oversight Board (PCAOB), an SOX creation.

Compliance with relation to important company activities

Companies are now required to ensure compliance with the provisions of SOX in a number of ways. These relate to increased monitoring of the regulatory environment, scrutinizing prospective audit clients with a committee, and increasing staffing as workloads go by. The exact ways in which each organization needs to audit these call for sound SOX compliance training. It usually consists of training capsules that are measured in terms of hours spent on training staff on SOX compliance. These range from introductory five-hour packs to detailed 40-hour packs.

Aims of SOX compliance training

SOX compliance training is aimed at equipping companies, especially publicly held one, to implement the provisions of the SOX Act. This has to be carried out by a person appointed by the company. This person has to be a senior employee, preferably a senior manager, director or partner, who will monitor all changes in standards and implement them. Whenever there is a change in standards activity in the company, this person has to report this to PCAOB. The company has to also make sure that this person communicates these developments to the employees and gives them the information and support needed for ensuring compliance.

One of the principal aims of SOX compliance training is to make sure that the provisions of the SOX Act, which relate to items such as internal audit controls and increase in staffing needs are adhered to. SOX compliance training has to impart the method by which a company’s board rotates its partners, another important SOX requirement. There are different rotation plans for different kind of companies.

References:

http://www.journalofaccountancy.com/Issues/2004/Jun/TipsForTheSarbanesOxleyLearningCurve.htm

http://www.ehow.com/how_5955087_train-perform-sox-compliance-auditing.html?ref=Track2&utm_source=ask

http://www.grcg.com/sox-training/

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Software vendor qualification

Since many of the present generation’s medical devices are run by software; a practical approach is to have this software validated. This validation, also known as software vendor qualification, is a means to ensuring that the software, the heart of the medical device, is compliant with set standards. The principles of this qualification are set out in 21 CFR Part 11.

Why is software vendor qualification needed?

It is generally more economical for medical device companies to buy commercial off-the-shelf software (COTS) than having it developed in-house. Software vendor qualification is the means to ensuring this. This is not only cost-saving; it also saves manpower resources and the time taken to bring the product out into the market. When companies install software that is not built in-house; they need to have COTS that meets some regulatory requirements.

COTS could include software packages like display managers, peripheral interfaces, communications protocols or operating systems. The medical device company needs to have processes that evaluate software packages for their ability to meet intended needs. The companies also need to have processes for software vendor qualification, which will help their products meet strict regulatory requirements.

When should software vendor qualification be done?

An important question that arises with this issue is about when to do the software vendor qualification. If the software is bought from outside, it is understood that it should already have been built to meet standards. What happens once the software starts getting implemented into the company’s systems?

A thumb rule that many medical device companies follow to avoid getting cited from the FDA is this: they ensure that the vendor’s validated system demonstrates “systematic, high quality software specification, development and testing methodologies, together with documentary evidence that they have been followed”. This is the yardstick by which FDA measures software vendor qualification, because to it, any validated system that fails to demonstrate this is considered as not valid.

References:

http://ieeexplore.ieee.org/xpl/login.jsp?tp=&arnumber=263005&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Farnumber%3D263005

http://tech.groups.yahoo.com/group/21cfrpart11/message/10728

 

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Quality by Design (QBD) and analytical methods

Quality by Design (QBD) and analytical methods have come into focus because of an inherent limitation in the guideline used for validation of analytical methods. The International Conference on Harmonization (ICH)’s Q2 guideline, Validation of Analytical Procedures: Text and Methodology serves as the guiding document for validation of analytical methods for pharmaceutical products. Since the most common approach to method validation is a one-time affair, there is need for guidance on how to implement continuous and consistent method performance.

Methods fail to perform as required or intended in the receiving laboratory because there is always the absence of an effective process for capturing and transferring the knowledge of those involved in the development. With too much emphasis on validation of the methods to meet regulatory requirements, the focus on what to do to make the process work during actual application seemed to be lost. It is to address this bottleneck that Quality by Design (QBD) and analytical methods took shape.

How do Quality by Design (QBD) and analytical methods make a difference?

QBD, in being “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management”; emphasizes the importance of having predefined objectives built into the development process. An analytical method, which is an analytical procedure that includes all steps in the procedure, constitutes an important step in the QBD lifecycle approach. Together, Quality by Design (QBD) and analytical methods become an important component of the three-stage process of method validation, which are:

• Stage one, which relates to method design
• Stage two, which relates to method qualification, and
• Stage three, which is about continued method verification

 Reference:

http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=791903

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Process validation for medical devices

The FDA introduced the idea of process validation for medical devices with the idea of improving the quality of pharmaceuticals and medical devices. From its rudimentary form that was conceived in 1987, process validation for medical devices has undergone changes to accommodate more types of devices and more processes into the validation.

Why is process validation for medical devices necessary?

In simple terms, validation is the ability of a medical device to demonstrate that a procedure, process and activity will consistently lead to the expected results. For the FDA; process validation for medical devices is all about establishing documented evidence which will offer a high degree of assurance that a specific process will consistently produce a medical device product that meets its pre-determined specifications and quality characteristics.

Process validation for medical devices is a requirement of the current GMP regulations for medical devices, 21 CFR Part 820 and is applicable to the manufacture of medical devices.

Factors

A host of factors influences the quality of a product in medical device manufacturing. Some of these are:

• Adequate product and process design
• Control of the process
• In-process and end-product testing
• Selection of quality parts and materials

The guidelines published by the FDA provide a framework for medical device manufacturers to build a holistic approach to process validation for medical devices. This is broad in nature, since the particulars of process validation vary from one manufacturer to the other because of many factors, such as

• The nature of the medical product (e.g., sterile vs. non-sterile)
• The complexity of the process
• The local regulatory requirements
• The age of the product (e.g., new invention vs. similar to an existing product)

The FDA recommends that the manufacturer:

1. Prepare a written validation protocol  which specifies:
   1. The procedures to be conducted and the data to be collected
   2.  Purpose of data collection
   3. A sufficient number of process repetition to demonstrate reproducibility
   4. An accurate measure of variations during repeated process runs
   5. The test conditions that include best case and worst case scenarios called as “most appropriate challenge” conditions
   6. Validation documentation requirements to include evidence of the suitability of materials and the performance and reliability of equipment and systems
   7. Monitor and document key process variables and analyze the data collected to establish:
      1. The variability of process parameters for individual runs
      2. Whether or not the equipment and process controls are adequate to assure that product specifications are met
      3. Utilize finished product test data and in-process test data to obtain quality attributes and in establishing variability
      4. Where finished (or in-process) testing cannot adequately measure certain attributes, process validation should utilize the details of each system in production and by document the observed results

Reference:

http://www.fda.gov/downloads/Drugs/…/Guidances/UCM070336.pdf

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/QualitySystemsRegulations/MedicalDeviceQualitySystemsManual/ucm122439.htm

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Pharmacovigilance signaling

Pharmacovigilance signaling is an important aspect of pharmacovigilance. In simple terms, it is the detection of a new safety finding within a set of safety data which requires further investigation. The World Health Organization (WHO) defines pharmacovigilance signaling thus: ““reported information on a possible causal association between an adverse event and a drug, the relationship being unclear or incompletely documented previously”.

Why is pharmacovigilance signaling important?

For a drug to enter the market, it should have gone through a series of clinical trials and tests that establish its intended use and effect. These are very stringent and should take all aspects of the drug development into consideration. They are essentially aimed at making the drug and its manufacturing process documentable, verifiable, reproducible and predictable. These trials involve the collection of a huge amount of data pertaining to important aspects of the drug. Adverse events are one of them. Pharmacovigilance signaling establishes the link between an adverse event and the data, and hence is of pivotal importance to the clinical trial.

Categories of pharmacovigilance signaling

Pharmacologists usually classify these findings into three categories:

a)     Confirmed signals: in this scenario, data indicate that there is a causal relationship between the drug and the adverse effect (AE);

b)     Refuted (or false) pharmacovigilance signaling: this is a type of signaling in which the investigation shows no causal relationship between the drug and the AE;

c)      Unconfirmed signals: this is a type of finding in which the pharmacologists decide that there is need for further investigation. This investigation is done using more data. A prime example of this is the data that is got from carrying out a post-marketing trial to study the relationship between the drug and the AE.

Data mining

Having said this; pharmacovigilance signaling goes beyond just data used at the clinical trials. Since at least the 1990’s, statistical data mining emerged as a method of pharmacovigilance signaling. These are some of the kind of databases that are used for pharmacovigilance signaling:

• Spontaneous reporting system (SRS) databases
• Prescription event monitoring databases
• Electronic medical records (EMR) databases
• Large linked administrative databases, or electronic health records (EHR) databases

The main aim of mining databases for pharmacovigilance signaling is that they help researchers have a broader set of data for reference, leading to more accuracy of their tests.

References:

http://en.wikipedia.org/wiki/Pharmacovigilance#Signal_Detection

http://isif.org/fusion/proceedings/Fusion_2011/data/papers/200.pdf

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Pharmaceutical production batch record review

We can understand pharmaceutical production batch record review as meaning the controls and processes that pharmaceutical organizations have to build into the batch records of pharmaceutical products they manufacture. This is a means to ensuring that products meet compliance standards and are easy to detect whenever a problem arises from a sample in the batch or in the entire batch.

What does the 21 CFR 211.100 (a) say?

21 CFR 211.100 (a) is clear in its expectations. This and related subsections lay out the process by which pharmaceutical production batch record review has to be done. It states that all requirements have to written down in a prescribed format. The aim is to ensure that the core qualities of the drug relating to its molecule, such as the strength, quality, purity and identity are adhered to in every batch.

WHO requirements

The World Health Organization (WHO) lists the requirements for pharmaceutical production batch record review. These are the main points that go into it:

Pharmaceutical production batch record review consists of reviewing production and quality control records being made part of the approval process of batch release. Whenever there is the slightest deviation or failure on the part of any batch to meet its specifications; this should be properly and completely investigated. To ensure the quality of pharmaceutical production batch record review; the WHO states that the investigation can extend to other batches of the same product if necessary. On any observation and action taken, there should be a written record created of the investigation. This record should include the conclusion and details of the follow-up action that was taken.

The WHO also states that retention samples from each batch of finished product should be kept for at least one year after the expiry date. These have to be kept in the prescribed methods and conditions. Pharmaceutical production batch record review requirements state that where starting materials are concerned, the retention period is two years from the date of expiry.

References:

http://apps.who.int/medicinedocs/en/d/Js5517e/20.4.17.3.html#Js5517e.20.4.17.3

http://pharmaceuticalvalidation.blogspot.com/2010/03/batch-manufacturing-record-review.html

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