Pharma Master

Linearity Graph, Correlation Coefficient, Slope & Intercept

2016-11-06T13:56:00.001+06:00

An easy MS-Excel calculation sheet

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Linearity Graph, Correlation Coefficient, Slope & Intercept.

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Taking the Scientific Method Approach to Root Cause Analysis

2015-09-18T15:04:00.000+06:00

Taking the Scientific Method Approach to Root Cause Analysis

Reference/Credit: ASQ

You probably take it for granted that root cause analysis should be empirical-that is, verifiable by observation or experience rather than just theory. In "real life," organizational approaches to finding a root cause don't always pan out this way because people are anxious for answers. However, author and expert Matthew Barsalou suggests that the scientific method may be a good approach to root cause analysis

Click Here to Watch The Video

How To Operate ElabDisso Software

2015-02-04T09:48:00.000+06:00

A Step By Step Video Tutorial
for
How To Operate ElabDisso Software
of
Electrolab Dissolution Tester.

Device Quality Management Systems (QMS): Similarities, Differences, and Ramifications

2015-01-25T09:59:00.001+06:00

[Ref.: Pharma Help Google+ Group]

There are two major quality system documents governing medical device development and commercialization. US devices must be compliant with 21 CFR 820. International devices must be compliant with ISO 13485, which is based on ISO 9001. These documents are similar but have distinct differences. Differences between requirements such as with design control are described. Assumptions for US FDA 510(k) submissions are discussed. Medical devices not meeting US FDA CFR 820 GMP requirements are termed “adulterated.” Part of the 510(k) submission is a “Truthful and Accuracy” statement in which a senior manager certifies the submission is truthful, accurate, and no substantial material has been purposefully omitted. FDA policy requires initial review within 15 days so that submissions should be complete at the time of submission. If incomplete, the FDA may refuse to accept a submission. Knowing which QMS is operable, under what circumstances, and in which markets, is critical to compliance and to the accuracy of subsequent documentation in meeting regulatory requirements. Understanding that though ISO 13485 and 21 CFR 820 QMS requirements have many similarities, they are different documents with different requirements and different regulatory oversight.

INTRODUCTION

In reviewing the many forums on medical devices, it becomes evident that there is still much confusion over which Quality Management Systems (QMS) are operable for medical devices. There are two major quality system documents governing medical device development and commercialization. Product sold in the U.S must be compliant with 21 CFR 820, the QMS Regulation/cGMP for medical devices. The international QMS, ISO 13485, which is based on ISO 9001, is the EU version of a QMS for medical devices. Product sold in the EU and desiring the CE mark must comply with the international QMS. Product sold in the U.S does not need to comply with ISO 13485 and vice versa for product sold in the EU.

Both 21 CFR 820 and ISO 13485 are very similar in their basic systems and documentation, and many companies develop a QMS that includes both. There are, however, differences between the two documents. With CFR 820, a company develops product under a defined design control system with prescribed documentation. Similar requirements exist in ISO 13485 under “Product Realization,” but they are somewhat more generalized as to how the requirements are documented as having been met. CFR 820 requires a Design History File (DHF) showing development over time. ISO 13485 requires that each requirement be documented, but there is no DHF requirement per se. The EU Medical Device Directives (EU MDD) requires a Technical file/Design dossier to show that the Essential Requirements of the MDD have been met. This requirement is a snapshot of the device at a point in time, not a compilation of the development history of the device under change control.

DESIGN CONTROL UNDER 21 CFR 820.30

Design control documentation under 820.30 addresses nine areas, all of which must be documented to prove compliance:

Design and Development Planning (the author recommends Gantt Chart to address this requirement)
Design Input
Design Output
Design Reviews
Design Verification
Design Validation
Design Transfer
Design Changes—all compiled into the
Design History File (DHF).

The goal of these requirements, implemented in 1996–1997, is to ensure that device R&D, from a reasonable company-defined start date, is performed using change control. The FDA correctly reasoned that many device problems are design problems and that uncontrolled changes during R&D in the past were the cause of many of the device non-conformances. These changes in turn lead to field problems once the device entered the marketplace.

510(k) ASSUMPTIONS

When the device has been developed, if US 21 CFR 8XX-defined as Class II, a 510(k) must be submitted to the US FDA for review and marketing clearance. In the 510(k), the submitter certifies that they have complied with the CGMPs as defined by CFR 820, including 820.30 Design Controls in the design/development of the product. Such certification strongly implies that the applicable elements of CFR 820.30 have been completed/documented prior to design transfer and manufacture. The submitting company is not audited against them, however, at the time of submission. The US FDA may not perform compliance audits such as these until some later date (a year or longer); however, the FDA requires compliance from the start of serious development (CFR 820.30) and from design transfer/manufacture for lots destined for sale in the US.

Thus, devices must comply with 21 CFR 820 (not ISO 13485) as far as sale in the US is concerned. The FDA 510(k) is an FDA review process for mainly Class II medical devices, as defined by the US CFR, not the EU Medical Device Directive—Council Directive 93/42/EEC, for marketing clearance in the US. The device must be manufactured under the US CGMP as spelled out in CFR 820, whether by a US company or offshore company for products for sale in the US. One of the 21 required sections of the “traditional” 510(k) submission, among other things, must indicate such. Some of the CFR 820 requirements are the Design History File (DHF); Device Master Record (DMR); Device History (batch record) (DHR); Production and Process Control (P&PC); Corrective and Preventive Action (CAPA), including complaints and Non-Conforming Material Report (NCMR); verification and validation (V&V), and so on. Much of the aforementioned is also addressed in ISO 13485 but often using different terminology. While CFR 820.30 requires a DHF (documenting product development and change control over time, meeting requirements of 820.30; classified under 21 CFR 8XX-series), the EU MDD requires proof of compliance in the form of a Design Dossier or Technical File showing device status as currently marketed and classified under the Annex IX Rules of the MDD.

While there are many similarities between these two major QMS, there are important differences in each QMS and related device requirements and classification. The US FDA does not currently accept ISO 13485 audits as indicating compliance to 21 CFR 820 and vice versa. Notified-Bodies, hired or contracted by the device manufacturer, audit for ISO 13485 compliance, while US FDA personnel, supported by the US taxpayer and device manufacturers in the form of fees, audit for 21 CFR 820 compliance, and so on.

TRADITIONAL 510(k)

The traditional 510(k) must address 21 elements (see FDA.gov) with data submitted or summarized (or N/A) under each of the 21 elements. Some of the FDA forms required in the 510(k) submission help the submitter through specific documentation requirements by means of checklists or data completion forms. US FDA Guidance documents exist for many devices and their requirements including specific software / firmware documentation requirements. These provide helpful information when involving similar products. The FDA 510(k) database on fda.gov can provide information on the predicate devices. Both the EU and US require hazard analysis with both using ISO 14971 as the de facto standard. Both require biocompatibility studies per ISO 10993 if applicable. The same applies to device sterilization if applicable. Other ISO standards are also accepted/required as applicable by both. When using an outside consultant to generate or review 510(k) documentation or CGMP QMS system, it must be done in accordance with 21 CFR 820 (not ISO 13485) for medical devices for sale in the US.

While some contend that CFR 820 is not relevant to the 510(k) process, the author strongly disagrees. All product for sale in the US must be manufactured under the FDA CGMPs, which is 21 CFR 820 and not ISO 13485. The device must be developed under CFR 820.30, and documented under the documentation/records requirements of CFR 820, which defines the company QMS for US marketed product. The test samples used for the testing required under the 510(k)—functional, predicate comparisons, biocompatibility, shelf life, sterility, and similar—must be so manufactured and documented. All of this is understood by the FDA and should also be understood by the submitter. Those documents must then be retained for the life of the product and at least two years beyond the last date of shipment. The documents are subject to future FDA auditing after that device is marketed in the US since it has been cleared in the 510(k) review process.

ADULTERATED MEDICAL DEVICES

Anything less than meeting the above documentation requirements leads the FDA to term the resultant device "adulterated," i.e. not proven/documented to have been manufactured in accordance with CFR 820 CGMP requirements. In fact, if a company had developed a US Class III (PMA) device, that company would have to provide the FDA a detailed description of its QMS, as defined by 820, in its pre-market approval (PMA) submission. In support of this, see the FDA’s general reference at:

http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/premarketapprovalpma/ucm050384.htm, which in part states the following:

All manufacturers (including specification developers) of Class II and III devices and select Class I devices are required to follow design controls [§820.30] during the development of their device. The design control requirements are basic controls needed to ensure that the device being designed will perform as intended when produced for commercial distribution.

TRUTHFUL AND ACCURATE

Part of the 510(k) submission is a Truthful and Accuracy statement in which a senior manager certifies the submission is truthful, accurate, and no substantial material has been purposefully omitted. While one can argue that this only applies to the data in the 510(k), this author submits that, since the FDA expects the above to have been done on the test samples and will be done for production, agreement to those facts is also included in signing such a certification. During a manufacturer’s first US FDA CGMP compliance audit after marketing, the company will be audited per FDA QSIT (Quality System Inspection Technique) on its highest risk product, including its 510(k) (or PMA) and its DHF (per 820.30) along with other applicable parts of 820. In fact, failure to follow such requirements would prevent accurate CAPA (Failure Investigation, Root Cause Analysis), P&PC (process improvements over a device's life cycle) and similar continual improvement, as well as assurance that the product in the field is safe and effective and as cleared (510[k]) or approved (PMA).

This column is not saying a 510(k) requires providing information on a company's QMS, and it does not imply any pre-approval QMS inspection for devices. The device must, however, have been developed under CFR 820.30. Proven by the test data, the data supplied in a 510(k) pertaining to its SE (substantial equivalence) to the predicate must be performed on product manufactured under such a QMS (CFR 820), as does all subsequent product. The FDA will then audit such data during a future audit.

Implied in the use of the term "certify" pertaining to the 510(k) as mentioned above, the truthful and accurate statement should be viewed as providing such certification. The author has successfully submitted numerous 510(k)s for clients to the FDA. Some FDA reviewers request copies of a submitter’s SOPs defining the manufacturing and testing requirements and proof of meeting the CGMPs for the device in the 510(k). That is not to say this approach is the only way, but it is one approach that has passed repeated tests with FDA reviewers. It is also the approach the author makes clear to clients before agreeing to accept an assignment.

KNOW WHICH QMS IS OPERABLE

While adherence to CFR 820 should be obvious, the discussion on applicable internet forums and many consultants’ experiences with clients desiring to submit a 510(k) shows that is often not the case. Further, anybody can interpret the 510(k) requirements in several ways (including different FDA reviewers/staff—see the FDA’s 510(k) Report of August 2010). A potential submitter should be aware of all the issues/expectations in such a submission—implied as well as stated.

If specification developers are separate from engineering and manufacturing, then some combination of them or the ultimate owner will be responsible to ensure that the applicable CGMP requirements are met, documented, and available for audit. These different entities are listed in the 510(k), although their respective QMS documentation responsibilities are not listed but are nonetheless required.

COMPLETE SUBMISSIONS

Years ago, 510(k) with a few missing data points could be submitted and the intervening 90 days could be used to "fill in the blanks" that had to be completed prior to going to market. This is no longer an option since under current FDA policy; the submission is now immediately reviewed (within 15 days). Review uses its Acceptance Checklist, filled out and included as part of the submission, and a defined time period is given to address any problems, or the submission is Refuse to Accept (RTA), the fee is lost, and a new submission is required. See the following:

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm315014.pdf

If questions pertaining to the submitted data still exist after the applicant successfully meets the RTA process, then there is usually an automatic 180-day extension granted by FDA. This means the basics have already been addressed during that initial RTA check. If such questions involve some issues with 820.30 data or other issues such as basic product verification, validation, functional testing, biocompatibility, sterilization, etc., they may not be able to be addressed acceptably within the deadlines stated by the FDA. It is much better to have all work done prior to submission so that any extra review time granted can be used to address other specific device issues.

CONCLUSION

Knowing which QMS is operable, under what circumstances, and in which markets, is critical to compliance and to the accuracy of subsequent documentation in meeting regulatory requirements. Understanding that though ISO 13485 and 21 CFR 820 QMS requirements have many similarities, they are different documents with different requirements and different regulatory oversight. Understanding these differences will prevent errors and omissions, insure a common ground for discussion, and ensure the necessary compliance as proven by the documentation.

GLOSSARY

510(k): A 510(K) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device that is not subject to premarket approval (PMA).

CDRH: US FDA Center for Devices and Radiological Health

CGMPs: Current Good Manufacturing Practices (Devices 21 CFR Part 820 Quality System Regulations; Drugs 210/211; Biologics 600- 680; and HCT/P 1271)

CFR: US Code of Federal Regulation

DHF: Design History File (21 CFR 820.30)

DHR: Device History [batch/lot] Record (21 CFR 820.184)

EU MDD: European Union Medical Device Directives

FDA: United States Food and Drug Administration

ISO: International Standards Organization

PMA: FDA Pre-Market Approval (for the majority of Class III devices, involving clinical data)

QA: Quality Assurance

RA: Regulatory Affairs

R&D: Research and Development

SOP: Standard Operating Procedure

Frequent Findings in Supplier Qualification

2015-01-24T12:49:00.002+06:00

[Ref.: Pharma Help Google+ Group]

Supplier Qualification is a hot topic in inspections. The inspectorates' summaries of their observations show that things do not always work as desired. In a presentation published by the end of last year by the U.K. authority MHRA (Medicines and Healthcare Products Regulatory Agency), it is stated that "deficiencies relating to 'Quality Systems' are by far the most prevalent observed during inspections". The report "GMP Inspection Deficiencies 2013" covers 630 inspections performed in 2013. According to the report, deficiencies in supplier and contractor audits are amongst the top 5.

Taking a closer view at the examples of the observations, one can see that problems arise and the whole area of supplier qualification like auditing, audit plan, audit report, adequate contracts and managing unapproved suppliers:

The respective audit report was not available.
There was no evidence upon which to base the approved manufacturer decision
The address of a supplier site differed from the address on the audit report
In the audit reports it was not apparent what had actually been audited
The maintenance and control of the approved supplier list was not robust
API was received although an audit specified that the supplier was no longer approved
Risk based audit planning defines no maximum time frequency
Quality Assurance Agreement was not kept up to date.
Quality Assurance Agreement failed to adequately describe transportation conditions.
Approved supplier list was inadequate, e.g. not all suppliers were listed and some suppliers were listed that should not have been.
Supplier audit SOP did not cover API suppliers and other services.
After concluding that an API supplier was not suitable for the supply, the API already received and held on stock was not quarantined and rejected.

FDA's New Quality Metrics Program To Plan GMP Inspections

2015-01-24T12:45:00.000+06:00

[Ref.: Pharma Help Google+ Group]
The US Food and Drug Administration has initiated a comprehensive new organisation of its inspection activities. One of the key elements of this initiative is the Quality Metrics Program. This program will throw a complete new light on the compliance status of each manufacturing site. So far there were only two categories: GMP compliance or non-compliance. There was no benefit for industry to improve the overall quality as long as the manufacturing site was rated to be in GMP compliance.

Chances have been good that a non compliance situation was not discovered by FDA inspectors. The frequency of inspections - especially those in foreign countries - was not meeting internal FDA standards. Instead of inspecting at least every two years, some facilities have not been inspected for a long period of time. As a result some major GMP deviations have been discovered at manufacturing sites and have caused comprehensive compliance actions such as FDA Warning Letters and Import Alerts. This has resulted in some serious drug shortages because medicinal products were only manufactured at very few manufacturing sites.

The FDA Quality Metrics initiative aims at asking each production site (APIs, medicinal products, Biotech, OTC etc) to provide data about the "quality level" in the manufacturing site. By this, FDA will be able to see from the data how well the quality system is maintained and how successful the quality system will affect the quality of the medicinal products.

At the 17th APIC Conference on APIs FDAs Russel Wesdyk presented details on how FDA will collect data from the companies. The Food and Drug Administration Safety and Innovation Act (FDASIA) Title VII, section 706 gives US FDA the authority to collect Quality Metrics. Over the last year a number of meetings have been organised in order to discuss potential Quality Metrics with stakeholders. As an outcome of these meetings the following Quality Metrics are of high interest for FDA:

Lot Acceptance Rate = the number of lots rejected by the establishment in a year divided by the number of lots attempted by the same establishment in the same year.

Right First Time Rate = the number of lots with at least one deviation by the establishment in a year divided by the number of lots attempted by the same establishment in the same year.

Product Quality Complaint Rate – the number of complaints received by the manufacturer of the product concerning any actual or potential failure of a unit of drug product to meet any of its specifications, divided by the total number of lots released by the manufacturer of the product in the same year.

Invalidated Out-of-Specification (OOS) Rate – the number of OOS test results invalidated by the establishment, or contracted establishment in a year divided by the total number of tests performed by the establishment in the same year.

Annual Product Review (APR) on Time Rate – the number of APRS generated within 30 days of annual due date at the establishment divided by the number of products produced at the establishment

Management Engagement – the most senior manager that signed each annual product review, reported as one of the following: (1) none specified, (2) line quality manager, (3) site operations manager, or (4) corporate executive manager.
- Performance Question 1 – A “yes” or “no” value of whether the establishment calculated a process capability or performance index for each critical quality attribute as part of that product’s APR.
- Performance Question 2 - A “yes” or “no” value of whether the establishment has policy requiring a CAPA at some lower process capability or performance index.
- Performance Question 3 – If “yes” to question 2 – what is the process capability or performance index that triggers a CAPA. If “no” to question 2 – please do not respond.

Corrective and Preventative Action (CAPA) Rate – the number of corrective or preventative actions that were initiated due to an APR, divided by the total number of APRs generated.

The FDA will use the Quality Metrics in a learning period of approx. one year. After that learning period serious compliance actions will be the consequence for not reporting to FDA. The next steps will happen very soon. The FDA is planning to publish the Draft Guide on Quality Metrics in the next months to come.

How To Create A Method On Electrolab Dissolution Tester

2015-01-20T15:58:00.006+06:00

A Step By Step Video Tutorial

for

How To Create A Method On Electrolab Dissolution Tester

ElabDisso Software

Top Tips On How to Calibrate a Thermo Hygrometer

2014-12-13T12:10:00.000+06:00

Article By Edward Simpson

[Ref.: Pharma Help Google+ Group]

Precision is important in all aspects of human life. Evolution could have been a result of mankind becoming more and more precise with passing time. We have equipment to measure everything in life. These instruments need to work at optimal condition.

One such instrument is a Hygrometer. It is a device used to measure the moisture content in the atmosphere. As per the requirements of the customer, the calibration is done at the specific humidity points. The measurements used to calculate the humidity inside the hygrometers are:

Data-acquisition application (used to measure the temperature and pressure of the saturator).
The pressure inside the hygrometers, and the wet-gas.
The wet-gas and dry-gas flows.

These measurements are then recorded in a spreadsheet and assembled in a workbook once all the data requested for the humidity points are requested. Then the new check standard data and the previous standard are compared to check the performance of the generator during the particular set of measurements. The final results in which the customer hygrometer humidity and HHG humidity are compared and placed in a calibration report.

Before the Start

The hygrometers are checked for cleanliness before they are connected to the hybrid generator. The hygrometer can be rejected for calibration is there is any dirt inside or on its fittings. If the chilled mirror hygrometers are used, then the hygrometer mirrors are cleaned with ethanol. The hygrometer is then tested for measurements.

By exposing the two gauges to the vaccum to measure their offset values, the pressure gauges of the hybrid generator are prepared for operation. It is done by correcting the zero offset of their readings.

Connection to Hybrid Generator

When the hygrometer is connected to the generator, a bypass tube which has an outlet to the room is connected parallel with the hygrometers. The proportion of the output gas which is bypassing the hygrometer is controlled using the valve which is on the bypass tube.
Measuring the pressure: The hygrometer pressure is measured by gauge which is located between the hygrometers and the bypass valve. If the humidity values exceed 15 °C (x = 1.6 × 10−3), the hygrometers are connected directly to the output of the 2-P generator, at a point downstream of the expansion valve. A heater tape is wrapped around the tubes which connect the output of the generator to the hygrometer if the desired dew points are above ambient temperature. The divided flow system with the multiplexer attached to the saturator is used if the desired humidity values are below a frost point of −15 °C.

Data Acquisition

To achieve the highest efficiency, the order has to be planned so that as many points as possible can be taken at one saturator temperature.
A computer application opens the spreadsheet after the hybrid generator is set to generate the desired humidity. It records the measurements for the hybrid generator, check standard and customer hygrometers in the spreadsheet at 30 s intervals for a total of 30 min.
The application is run again if the data readings are not stable. The computer application is run twice to check the repeatability of the hygrometer for the calibration points with the highest and lowest humidity rates.
The historical repeatability is assigned to the customer hygrometer if the first measurement s agree with the repeated measurements. The hygrometer is rejected or uncertainty is added and it all depends of the degree of the disagreement. The hygrometer repeatability is established after the first calibration is completed.

The Quality Check

If the stability and/or repeatability of the hygrometer is much s worse than the values which were given by the hygrometer specifications and the problems are unable to be corrected the hygrometer is rejected for calibration and returned to the customer.

Comparisons of at least two check standard points are made during the hygrometer calibration. If there is no check history of the lowest or highest standard customer calibration points, additional data which is closest to check standard point is taken. The new check standard data is compared to previous check standard data after the check standard data acquisition is complete.

Cross checks are made on the temperature and pressure measurement systems for the final saturator so that their measurements are within the stated uncertainties. This is done every four months.

Conducting an Effective Failure Investigation: Going Deep Enough to Hit Root Cause

2014-11-15T14:44:00.000+06:00

[Reference: Article by Christine Park collected from pharmahelp google group. For more than 30 years, she has held key positions that drive cultural change and growth for several large corporations. Her expertise and ability to create lasting change for corporations of all sizes has been recognized throughout her career and her contributions have had a significant impact on the development of sustainable compliance and quality systems, while reducing or managing costs. For further information contact Christine at chris@QualityArchitech.com]

The FDA has increased focus on the effectiveness of failure investigations during recent inspections. A review of recent 483 observations and warning letters clearly demonstrate the agency’s current concern about the adequacy of failure investigations to really identify root cause. Effective failure investigation to true root cause is the heart of the CAPA (corrective action preventive action) system.

In an effort to simplify the analysis of data, failures are often grouped into generic categories (human error, inadequate training, procedure not followed, etc.) Unfortunately investigations often stop at this point until the actual cause gets lost in this attempt at simplification. Too often a “band aid” fix is put in place (re-train, change the procedure, etc.)

Most text books on failure investigation identify key steps in the process:

Identify the general problem - the problem statement should be as clear and concise as possible.
Gather data or samples as necessary.
Investigate the failure through experiment and/or examination as necessary - can you re-create the failure? Is it repeatable?
Brainstorm the causal factors - this is a great place to use tools (fishbone, affinity diagram, 5 whys, etc.).
Define the root cause based on the data and analysis.
Develop the hypothesis - based on the data and analysis, what do you think is the real problem? What do you need to do to prevent it from happening?
Test the hypothesis - design the experiment to demonstrate you have eliminated the source of failure.

How do you choose which tools work best when starting a failure investigation? Some organizations try to force-fit all investigations into the same tools. We all know that there is no "one size fits all." A co-worker recently shared this chart from a Minitab training session:

Probability Plot

This chart was used to demonstrate a process that is out of control at both ends of the process. But is it really? As I look at this chart there are many unanswered questions that come to mind:

What are the specifications for the test being performed?
How were the acceptable limits determined?
Was the process validated?
How much variation can be due to employees and technique?
Was there any characterization of the material and process as part of the design development activity?

We could assume these are the only issues and start jumping in to answer them immediately but there are many unanswered questions that proper failure investigation techniques could help address.

In this case a fishbone diagram might be the most appropriate place to start. A fishbone diagram – also known as Ishikawa diagrams or cause-and-effect diagrams, can help identify the causes related to a certain event. The diagram got its name because it looks like a fishbone when drawn.

Fishbone diagram

Here's how to interpret the diagram:

People: identify the individuals in the process. Person-to-person variation is another great area to investigate. What is the actual process for performing the pull test? Is it something that can have great variability between the individuals performing the test? A gauge R&R should be performed to understand the variation involved. Another suggestion would be to certify the employees performing the procedure to be sure it is done properly.
Methods: describe how the process is performed. What are specific requirements for the process? Are any critical-to-quality (CTQ) steps involved? When considering the various methods involved, don't forget to consider the design development activities related to the item being manufactured. Is it possible that something was modified in the manufacturing process that is actually crucial to the final output? For example, if the item was properly characterized and validated, the specifications should reflect acceptable tolerances of the pull test. Maybe he data points at both ends of the analysis are actually out of spec because they were outside the original design.
Machines: identify any special equipment, computers, tools, etc. required to accomplish the job. Be sure to look at calibration and maintenance records for the equipment and/or tools used in the process.
Materials: what raw materials, consumables, etc. were used to produce the final product?
Measurements: what data are generated from the process that are used to evaluate its quality.
Environment: identify the conditions for operations. Consider location, time, temperature and culture in which the process operates.

The real key to a good failure investigation is to understand the various tools available and what you might get from using the tool selected. Other tools you might consider in the failure investigation include:

5 whys – This is a question asking method used to explore the cause and effect relationships of a particular issue. The goal of the 5 whys is to determine root cause of the defect or problem. Unfortunately there is a tendency for investigators to stop at symptoms rather than getting to the lower level causes. The investigator may not have enough technical knowledge to get to the real answer. Additionally, the results are not always repeatable. Different individuals performing the analysis may come to different conclusions. When using this tool it is best to work as a team of subject matter experts rather than having one individual try to get to the answer.
Affinity diagrams - a business tool used to organize ideas and data. It is one of the Seven basic quality tools. This is often used with project management allowing a lot of ideas to be generated as a result of brainstorming sessions. The ideas are then sorted into groups for further review and analysis.
Is/Is not analysis – this is another very subjective tool and is best completed with a team of subject matter experts. This tool generates the documentation of the circumstances leading to the problem as well as those not associated with the issue at all. It may be helpful with the use of the fishbone analysis diagram.

While everything in this document is important in a true failure investigation, here are a few points to keep in mind:

Use common sense
Don't overlook the obvious. Look for the most likely causes first
The problem should dictate the too, not the other way around
Avoid analysis paralysis. Don't make a problem more complicated than it is.
Most problems can have more than one cause. Remember, this is an integrated system. There are many touch points within processes. If you have identified those critical to quality, you can be proactive in preventing failures.
Tools are generic. You may need to modify the tool to fit the situation.
Don't generalize the investigation. Ask more "why" questions. Be as specific as possible

Change Control-A Key Element of A Quality System

2014-11-02T09:40:00.000+06:00

A pdf file of a PPT

"Change Control- A Key Element of A Quality System"

By Jerry Lanese

To Download
1) Click Here & Then
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Dissolution Concepts and Applications

2014-10-23T11:29:00.002+06:00

Addressing Compliance Concerns During Dissolution Method Development, Validation, and Transfer

By Gregory P. Martin and Vivian A. Gray

Dissolution is an important test for pharmaceutical products. Dissolution is the only test that addresses product performance. While most dissolution tests are used for quality control purposes, there are several potential applications for dissolution methods that are vital during the entire product lifecycle. These include activities such as aiding in formulation selection, developing a correlation between in vitro data and in vivo data (IVIVC), or justifying post-approval product changes. Dissolution method development should be linked to the intended purpose of the method. Once method conditions have been established and an understanding of method ruggedness generated, the method must be validated. When sufficient data have been generated with the validated method, a specification can be proposed. The product dissolution specification will ultimately require regulatory approval. Over the lifetime of the method (from development to production to site transfer to generic product), there are likely to be multiple changes to both the drug product and the testing laboratory. With each change, the validity of the method may be challenged and must be reestablished.

To Read More Details Or Download PDF File
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Guidelines for using the Test for Bacterial Endotoxins

2014-10-23T11:22:00.002+06:00

In September, the European Directorate for the Quality of Medicines & HealthCare (EDQM) published in Pharmeuropa online the information about their new policy for bacterial Endotoxins, which was approved by the Ph. Eur. Commission at its 149th Session in June 2014. Amongst others they announced for existing monographs:

"BET specifications are kept in individual monographs for substances for pharmaceutical use. Existing limits remain in individual monographs to maintain the use of well-established limits.

In order for the policy to be applied, the following changes are proposed to existing Ph. Eur. texts:

General chapter 5.1.10 is expanded with further considerations regarding the setting up of limits.

General monograph Substances for pharmaceutical use"

In consequence it is up to the users of these EP chapters to determine whether compliance to BET is needed or not for a given substance. Where a test is included in the monograph with no specific limit, it is up to the user to set the limit for the substance, based on the following considerations: use of the substance (route of administration, patient population); calculation according to the formula given in general chapter 5.1.10; process capability; or any other considerations raised by the competent authority.

Recently, on 26 September, a revision of Chapter "5.1.10. Guidelines for Using the Test for Bacterial Endotoxins" was issued and open for comments until 31 December 2014. The revision now includes possible alternative methods to the Limulus amoebocyte lysate (LAL) test, like testing with recombinant factor C.

Following a short overview of the additions and changes:

"The monocyte-activation test (2.6.30) is a suitable method to be used to rule out the presence of non-endotoxin pyrogens in substances or products."

"Hence, the analyst who wishes to implement a test for bacterial endotoxins or to replace the pyrogen test by a test for bacterial endotoxins has to demonstrate that a valid test can be carried out on the substance or product concerned; this may entail a procedure for removing interference"

"Replacement of the rabbit pyrogen test required in a pharmacopoeial monograph by an amoebocyte lysate test, or by other methods such as the monocyte-activation test or a test using recombinant factor C as a replacement for the amoebocyte lysate, constitutes the use of an alternative method of analysis and hence requires demonstration that the method is appropriate for the given substance or product and gives a result consistent with that obtained with the prescribed method as described in the General Notices"

The additions under paragraph 13. "Replacement of Methods prescribed in Monographs" are of particular importance. In section 2, you can find information about the replacement by methods not described in the PH.EUR:

"The use of alternative reagents such as recombinant factor C as a replacement to the amoebocyte lysate eliminates the use of live animals. Replacement of a rabbit pyrogen test or a bacterial endotoxin test prescribed in a monograph by a test using recombinant factor C or any other reagent as a replacement of the amoebocyte lysate is to be regarded as the use of an alternative method in the replacement of a pharmacopoeial test, as described in the General Notices: “The test and assays described are the official methods upon which the standards of the Pharmacopoeia are based. With the agreement of the competent authority, alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative.”

The complete revision can be found in Pharmeuropa, Issue 26.4.

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Safety in the workplace

2014-10-21T14:48:00.003+06:00

Safety In The Workplace/Occupational Health And Safety
An excerpt from the GMP MANUAL
By Dr. Michael Hiob

Good practical knowledge of the workplaces and processes used in the company and regular communication with personnel are a prerequisite for professional and efficient preventive healthcare. The assessment of the working conditions should be carried out in close cooperation with the expert for safety in the workplace.

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GMP MANUAL Update No. 19

2014-10-18T09:38:00.001+06:00

What is new on GMP MANUAL Update No. 19 ? [Date: 9 October, 2014]

GMP in Practice

New Chapters:

Chapter 4 Facilities and Equipment

4.A: Facility Planning
4.B: Materials
4.H: Cleaning of Facilities

Updated Chapters:

Chapter 4 Facilities and Equipment

4.C Hygienic Design in Solids Handling (formerly 4.L, still under revision)
4.D System Controllers and Process Control Systems (formerly 4.C and 4.K)
4.E Technical Documentation (formerly 4.F)
4.F Calibration (formerly 4.G)
4.G Maintenance (formerly 4.H)
4.I Containment (personnel protection) in Solids Handling
(formerly 4.J, still under revision)

GMP Regulations

New Chapters:

Chapter C EU Directives and Guidelines

C.18 Guidance for the template for the qualified person’s declaration concerning GMP compliance of active substance manufacture “The QP declaration template”
C.18.1 Qualified Person’s declaration concerning GMP compliance of the active substance manufacture “The QP declaration template”

Updated Chapters:

Chapter C EU Directives and Guidelines

C.4 Part I Basic Requirements for Medicinal Products
C.4.3.1 Chapter 3 Premises and Equipment (entry into force 1 March 2015)
C.4.5.1 Chapter 5 Production (entry into force 1 March 2015)
C.4.8.1 Chapter 8 Complaints, Quality Defects and Products (entry into force 1 March 2015)
C.5 Part II Basic Requirements for Active Substances used as Starting Materials
C.8.5.1 Importation of Active Substances for Medicinal Products for Human Use – Questions and Answers Version 5.0

Chapter D.1 Code of Federal Regulations

D.1.1 21 CFR Part 210
D.1.2 21 CFR Part 211
D.1.3 21 CFR Part 11
D.1.4 21 CFR Part 820
D.1.5 21 CFR Part 4
D.1.6 21 CFR Part 606
D.1.7 21 CFR Part 606

Chapter F PIC/S Guidelines

F.9 PIC/S PE 009-11 GMP Guide Introduction
F.10 PIC/S PE 009-11 GMP Guide Part I
F.11 PIC/S PE 009-11 GMP Guide Part II
F.12 PIC/S PE 009-11 GMP Guide Annexes

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GMP Updates_October 2014

2014-10-12T09:50:00.001+06:00

[Ref. & Thanks: Pharmahelp Group of Google Plus]

WHO publishes New Version of Guide regarding the Principles of GMP

The draft for comment of this superordinated Guideline was already published in the middle of 2013 (we reported). Since then, nothing has fundamentally changed. Only changes to the following chapters have been made:

1. Pharmaceutical quality system (formerly "quality assurance")
2. Good Manufacturing practices for pharmaceutical products
7. Contract production, analysis and other activities
17. Good practices in quality control

Compared to the draft from 2013, the new document contains an extended description of the pharmaceutical quality system. In Chapter 1, the ultimate responsibility of senior management has been strongly emphasized. Likewise, the aspect of qualification has been complemented. In Chapter 2, the required review of processes has been extended to the scientific aspect (so far only review based on experience only).

The Guideline "Good Manufacturing Practices for Pharmaceutical Products: Main Principles" has been published as Annex 2 of the Technical Report 986.

WHO publishes second Draft on the Revision of its Process Validation Guideline

In April 2014 WHO published a first draft to revise their Non-sterile Process Validation Guideline. Comments to the first draft from April 2014 have now flowed into the second one. This is obvious at one point or another.

The table of contents and the scope have remained unchanged. Yet, the definition of process validation contains the life-cycle approach in the glossary already. Compared to the first draft, the new version now also explains the matrix approach or bracketing.

Still, the introduction mentions different possibilities for process validation (traditional vs. life-cycle approach vs. hybrid). A flow diagram "may" be helpful. At the end of the introduction, a flow diagram intends to illustrate the process validation life-cycle. Now, the diagram mentions "validate process" already at the process design stage.

The chapter on process design contains no major changes compared to the first draft.

In the chapter "process qualification", a risk assessment is required for the change in batch size from scale up to commercial batch size. Explicitly, manufacturers are requested to implement the new validation approach. However, it is mentioned that full implementation may take time. In the interim, the traditional approach or concurrent validation may be accepted. Also a hybrid approach (based on a scientific basis and risk management principles) may be an alternative.

Compared to the first draft, the chapters "continued process verification" and "change control" haven't changed significantly.

Conclusion: The second draft is considerably more stringent than the first one. The document is a bit of a mix of FDA's Guidance on process validation and EMA's process validation guideline where the terms used come from the FDA Guidance. Both documents are also listed under references. A few inconsistencies remain. The topics risk assessments, QRM, and risk-based approaches are seen in very different ways in the document. The chapter "background and scope" recommends a risk-based approach. Risk assessments are referred to as "should" requirements, QRM rather as "nice to have" ("when applying QRM..."). A flow diagram shouldn't be only named as "may" requirement. Naming process validation under process design in the flow diagram for the process validation life-cycle (background/objective) is against the definition in the glossary according to which process validation include the whole life-cycle. Moreover, mentioning concurrent validation as an alternative to the life-cycle approach could be misunderstood.

It is astonishing that ICH Q10 hasn't been referred to although some elements of this document (e.g. continuous improvement, product life cycle) have been used.

ECA SOP: Methods for the Identification of Trends in Production and QC

After the creation of an SOP on Out-of-Specification results, ECA Working Group on Analytical Quality Control's next objective is the elaboration of an SOP on methods for statistical process control with regard to the statistical evaluation of the variability of production processes. The analysis of trends in stability studies will also be part of this SOP. Moreover, the handling of Out-of-Expectation (OOE) results will be addressed in this SOP, too.

Among other things, the following methods and working examples will be considered:

1. Investigation of trends for statistical process control:
Statistical process control for continuous data:
    a. Shewhart Charts
    b. CuSum & Zone Charts
    c. Post Mortem CuSum Analysis

2. Statistical process controls for discrete data: p and c Charts

3. Trend analysis for stability testing:
   a. Simplified procedure
   b. More complex procedure using the "Random Coefficients" approach.

All delegates of the OOT Forum on 22 - 23 October 2014 in Prague, Czech Republic, will receive the outline of the draft version of ECA Working Group on Analytical Quality Control's SOP on OOE and OOT Results. The outputs from the workshops at the OOT Forum will provide the scope for the content of the draft guidance. The participants will receive the draft guidance after the team has put it together sometime after the Forum as defined as the next steps for this project.

New FDA Interim Guidance for Human Drug Compounding Outsourcing Facilities

In the USA, the compounding of medicinal products was not regulated very well. The compounding of medicinal products can be outsourced to specific compounders (Compounding Pharmacies) bypassing the authority and GMP regulations. Also quantitative limitations don't play any role so that those compounders could produce at industrial scale and thus also win a substantial share of the medicinal products market.

So far, they have been in a sort of no man's land in the USA. Manufacturers of medicinal products are regulated at federal level by the FDA, whereas pharmacies - including also Compounding Pharmacies - face a respective heterogeneous regulation at the level of the 50 federal states. In 2002, the Supreme Court refused FDA's attempts to intervene with regulations.

The inglorious culmination of this situation was the case New England Compounding Center (NECC) in 2012. A steroid solution for epidural injection had a fungal contamination and had been administered to approx. 14,000 patients. About 50 patients died of meningitis and over 700 had to be treated against fungal infection.

In 2013, the regulations in the USA were adjusted - DQSA Pub. L 113-54 - to transfer to the FDA the monitoring of outsourced compounding facilities. The subsequent inspections with a lot of Warning Letters issued to the compounders (partly with outrageous quality deficiencies) clearly showed the consequences of inexistent inspections over many years.

The FDA has recently announced that it will regulate this area in the future in accordance with the cGMP. Until appropriate regulations have been developed, the FDA has - in the meantime - expressed its expectations for this transitional period in a Guidance for Industry - Current Good Manufacturing Practice - Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. This Guidance is based on the 21 CFR parts 210 and 211 with regard to cGMP. The FDA has tried to take into consideration the differences between industrial medicinal products manufacturing and compounding, and to adjust the specific aspects of the compounders. The FDA has announced that it will focus its inspections efforts to the points which present the highest danger for patient safety. One should thus not be surprised - also in view of the past incidents - that these efforts will particularly address the securing of sterility. Decidedly, the following topics are addressed:

Facility Design
Control Systems and Procedures for Maintaining Suitable Facilities
Environmental and Personnel Monitoring
Equipment, Containers, and Closures
Components
Production and Process Control (General Production and Process Control / Aseptic Drug Processing)
Release Testing
Laboratory Controls
Packaging and Labels
Quality Assurance Activities / Complaint Handling

One interesting thing is that the FDA itself isn't quite sure about certain aspects, whether its requirements will be suitable for compounders. In the chapters "Components" and "Laboratory Controls", an "Alternative Approach for Comment" is respectively presented in the Guidance to both topics "Reducing the Need for Laboratory Testing of Incoming Components" and "Minimize Need for Facilities to Have an In-House Laboratory".

All in all, this is an interesting development, and most of all has been a necessary evolution in the regulation of compounders which comes a few years too late.

Sources:

Guidance for Industry - Current Good Manufacturing Practice - Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act

Guidance - Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act

Saudi Food and Drug Authority publishes Drug Master File Guidance

This year in August, the regulatory authority of Saudi Arabia published a guideline entitled "Drug Master File (DMF): Guidance for Submission". The document describes the formal prerequisites to be fulfilled to ensure the successful submission of a DMF. The following elements have to be part of a DMF:

Cover letter - This letter shall include all technical-formal information like for example the name of the API, trade name, name and address of both the manufacturer and the DMF holder, registration or reference number.
Letter of access: authorisation to review and reference the DMF.
The same information as in the cover letter should also be indicated here. If the API is manufactured at different manufacturing sites, all sites have to be listed.
Formal requirements for the DMF: the DMF must be written either in English or Arabic. Only one electronic-based copy - a CD - should be submitted. If the data volume exceeds 750 MB, a DVD should be used.

In the context of this DMF Guideline, there is another important document entitled "Guidance for Submission" published by the SFDA in March 2014 in the updated version 4.0. The document contains further technical details about the storage media to be used for all submissions made to the SFDA, e.g. security requirements, password and virus protection, etc. These requirements should also be considered for the submission of Drug Master Files.

Further regulations and guidelines of the Saudi Authority relevant for authorisation can be found on the website of the SFDA

EU GMP Inspectors find 26 GMP Deficiencies at Chinese API Manufacturer Hebei Dongfeng Pharmaceuticals

EU GMP Inspectors from the competent authority in Romania identified several GMP deviations during a GMP inspection at HEBEI DONGFENG PHARMACEUTICAL Co., Ltd, Mingjiao Road Western Yongnian County, Handan, 057 150, China. As a consequence, a GMP Non-Compliance Report has been issued and entered into the European database EudraGMDP.

The products concerned are doxycycline hyclate and doxycycline monohydrate. According to EudraGMDP, a total of 26 deficiencies were found during the inspection. Six of them were rated as major:

1) not fully implemented Quality Assurance system
2) problems related to the documentation management
3) deviation related to material management and qualification of the approved supplier
4) risk of contamination in the production area
5) risk of contamination and cross-contamination of testing samples
6) data recording and integrity in the QC laboratory not in compliance

It is very interesting to see that for the first time the GMP Non-compliance Report also lists known customers of the API manufacturer. The report states: "Known customers Doxycycline hyclate: Sintofarm, Industria, P.S.P. ,Chemifarma, Zetercoop Italy; Ofichem, ORFFA, ALC Netherlands; Divasa Spain; Wins Czech Republik, Remedica Cyprus, Farmabase Brasil, many others in rest of the world. Doxycycline monohydrate: only local market. Finished dosage forms: only local market"
European manufacturers of medicinal products are not allowed to use the APIs concerned from Hebei Dongfeng Pharmaceuticals.

Source: EudraGMDP

ICH endorses new Working Groups on Clinical Trials

The ICH Steering Committee approved the establishment of four new ICH Efficacy Expert Working Groups:

E6(R2) EWG will work on the development of an Addendum to the current E6(R1) Guideline on Good Clinical Practices

The approach is to enable implementation of innovative approaches to clinical trial design, management, oversight, conduct, documentation, and reporting that will better ensure human subject protection and data quality.

E11(R1) EWG will work on the development of an Addendum to the current ICH E11 Guideline on Clinical Investigation of Medicinal Products in the Pediatric Population

This Addendum is proposed to address new scientific and technical knowledge advances in pediatric drug development.

E17 EWG will develop a new Guideline on General Principle on Planning/Designing Multi-Regional Clinical Trials (MRCTs)

The goal is a harmonised international Guideline to promote conducting MRCT appropriately, especially focusing on scientific issues in planning/designing MRCTs. This new Guideline will complement the guidance on MRCTs provided in ICH E5(R1) Guideline and facilitate MRCT data acceptance by multiple regulatory agencies.

E18 EWG will develop a new Guideline on Genomic Sampling Methodologies for Future Use

Although ICH E15 Guideline describes definition of sample coding, there is currently no harmonised ICH Guideline on genomic samples collection in clinical trials or other studies. Harmonisation across regions on this topic will maximise the information gathered from the studies for e.g., sample collection and analysis (including ethical considerations) and facilitate implementation of pharmacogenomics for the benefit of all stakeholders.

Source: ICH Newsroom

HPLC Solutions #122

2014-10-11T13:10:00.001+06:00

How to Measure Noise (Part 1)
By John Dolan

This installment of HPLC Solutions begins a series on different measurements that we make on chromatograms. Measuring the baseline noise generated by an HPLC system may seem like a singularly boring subject. But if you think about it, noise can be a critical factor in the results of our analytical work. It is directly related to the limit of detection and limit of quantification, it can be used to determine the health of the detector, noise is a great diagnostic tool for problems, and can be a limiting factor in the precision of a method.

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Free Webinar_February 2014

2014-02-15T14:43:00.000+06:00

Reducing Risks and Costs of Analytical Instrument Qualification for Successful Regulatory Compliance
WEBINAR INVITATION from Agilent Technologies

Overview:
Ensuring that your analytical laboratory is in compliance with U.S. FDA and other regulatory agency requirements is not an easy task. In this webinar you will review the basics of lab instrument qualification, hear about the latest regulatory requirement updates, and learn best practices of how to reduce risks and costs in keeping your lab compliant.
Date(s):
Thursday, February 27, 2014
Time:
Broadcast #1: 10:30 am Mumbai /1 pm Singapore / 2 pm Tokyo/ 4 pm Sydney
Broadcast #2: 8:00 am PST/ 11 am EST / 4 pm UK / 5 pm CET
Speaker:
Gary Powers
Global Compliance Program Manager
Agilent Technologies, Inc.

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Basic Titration

2014-02-08T15:05:00.001+06:00

New Guide ABC of Basic Titration

Released By METTLER TOLEDO

This booklet is intended as a first introduction to the theory and practice of potentiometric and Karl Fischer titration and gives an overview about the following topics:

●The basic knowledge that is needed to understand a titration

●Different kinds of chemical reactions, indication principles and titration types for potentiometric titration are explained and manual titrations are compared to automated titrations

●The Karl Fischer titration, as a special variant of titration for water content determination, is discussed in a separate chapter

●Practical tips & hints are given for potentiometric and Karl Fischer titration

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Introduction to HPLC

2013-10-05T16:16:00.002+06:00

Chromatography equipment look rather intimidating to anyone who has not handled them before, but on a closer look and as you get familiar with the equipment you realize that behind the network of wires, complex plumbing and circuitry is a simple machine with only a few major parts. Different combinations of these parts namely pumps, detectors and injectors yield a infinite number of configurations based on the application.

Just like an understanding of human anatomy makes you conscious of the vital role of each and every body organ towards your well being and vitality. Similarly you need to have a good understanding of the parts of your HPLC system to generate data of highest reliability. A conceptual understanding of the function of each component will add to your comfort level with your HPLC system. You will ensure long time usage with high reliance on output data. The present module is intended to serve this very purpose and in simple terms you will appreciate the role of each part and its contribution to overall system efficiency.

HPLC is a technique for separation, identification and quantification of components in a mixture. It is especially suitable for compounds which are not easily volatalised, thermally unstable and have high molecular weights.

The liquid phase is pumped at a constant rate to the column packed with the stationary phase. Before entering the column the analysis sample is injected into the carrier stream. On reaching the column the sample components are selectively retained on the basis of physico-chemical interactions between the analyte molecules and the stationary phase. The mobile phase moving at a steady rate elutes the components based on the operating conditions. Detection techniques are employed for detection and quantification of the eluted components.

We now introduce you to the significance and role of each component part of the HPLC system.

Mobile Phase
Mobile phase serves to transport the sample to the system. Essential criteria of mobile phase are inertness to the sample components. Pure solvents or buffer combinations are commonly used. The mobile phase should be free of particulate impurities and degassed before use.

Mobile Phase Reservoirs
These are inert containers for mobile phase storage and transport. Generally transparent glass bottles are used so that so as to facilitate visual inspection of mobile phase level inside the container. Stainless steel particulate filters are provided inside for removal of particulate impurities in the mobile phase if any.

Pumps
Variations in flow rates of the mobile phase effect elution time of sample components and result in errors. Pumps provide constant flow of mobile phase to the column under constant pressure.

Injectors
Injectors are used to provide constant volume injection of sample into the mobile phase stream. Inertness and reproducibility of injection are necessary to maintain high level of accuracy.

Column
A column is a stainless steel tube packed with stationary phase. It is a vital component and should be maintained properly as per supplier instructions for getting reproducibility separation efficiency run after run.

Column Oven
Variation of temperature during the analytical run can result in changes of retention time of the separated eluting components. A column oven maintains constant column temperature using air circulation. This ensures a constant flow rate of the mobile phase through the column

Detector
A detector gives specific response for the components separated by the column and also provides the required sensitivity. It has to be independent of any changes in mobile phase composition. Majority of the applications require UV-VIS detection though detectors based on other detection technique are also popular these days.

Data Acquisition & Control
Modern HPLC systems are computer based and software controls operational parameters such as mobile phase composition, temperature, flow rate, injection volume and sequence and also acquisition and treatment of output.

These are the main parts of a basic HPLC system more specialized equipment might also have solvent selection valves, vacuum degasser, auto samplers, column switchers, pre or post column derivatization and fraction collectors.

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2011-09-14T12:41:00.001+06:00

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Laboratory Equipment Qualification

2011-05-29T00:25:00.000+06:00

Article of Kenneth W. Sigvardson,* Joseph A. Manalo,Robert W. Roller, Fatieh Saless, and David Wasserman

The main goal in qualifying laboratory equipment is to ensure the validity of data.The current equipment qualification programs and procedures used within the pharmaceutical industry are based on regulatory requirements, voluntary standards, vendor practices, and industry practices.The result is considerable variation in the way pharmaceutical companies approach the qualification of laboratory equipment and the way they interpret the often vague requirements.The authors summarize the conclusions of the PhRMA Workshop on Acceptable Analytical Practices for the topic “Qualification of Laboratory Equipment.”They describe the areas of agreement and offer options for areas in which there is variation on what is appropriate

The concept of Acceptable Analytical Practices (AAPs) was developed by the Analytical Research and Development Steering Committee of the Pharmaceutical Research and Manufacturers of America to share information about how the pharmaceutical industry has implemented the CMC and Quality Guidances of the International Conference on Harmonization and worldwide regulatory authorities.AAPs were designed

to provide a process by which one could learn from the experience of experts in pharmaceutical research and development and enhance the understanding of analytical practices that reflect good science

and sound regulatory compliance. The process of discussing and publishing AAPs also is intended to identify and address critical issues in which guidance is lacking, ambiguous, or contradictory.

Initially, the process adopted for the development of the first four AAPs involved a two-and-a-half-day workshop held 19–21 September 2000. The four topics discussed were Laboratory Equipment and Instrument Qualification; Out-of-Specification Results: How to Conduct Laboratory Investigations; Forced Degradation Studies: Issues and Controversies; and Analytical Methods Transfer. This article presents the

first of these presentations. The three remaining topics will be covered in future issues of this magazine. Regulations regarding the qualification of laboratory equipment often are vague and subject to interpretation. The good manufacturing practice requirements state that “the calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met” (1). The good laboratory practice regulations impose similar requirements, stating that “equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated, and/or standardized” (2).

Terminology and definitions

In this industry, considerable variation ex-ists in the terminology used in the qualification of equipment. The “Equipment qualification definitions” commonly used terms with their definitions. Throughout this document the term equipment is used to represent both instruments and equipment as they are defined

in the “Equipment qualification definitions”.

General requirements

The equipment qualification program must be defined and documented. The program must contain provisions for the qualification, maintenance, and documentation of failures of all equipment used to collect data for regulatory submissions.This is usually accomplished by using a standard operating procedure (SOP) that describes the overall program. Individual procedures, specific to the equipment used, also must be documented. Specific procedures for equipment qualification can be documented in one of two ways: First, separate SOPs can be written that contain the procedures used for qualifying and maintaining each type of equipment. Alternatively, master SOPs can be used to describe the compliance

requirements for a variety ofequipment, and specific equipment procedures can be created as separate documents similar to test methods. This second approach minimizes the repetition of the compliance requirements in many SOPs, and it provides additional flexibility in documentation practices. In addition to the documentation of the program and its associated procedures, all equipment used to generate reportable

data must be tagged or labeled and have records maintained. The labeling serves as a way to identify equipment that is unqualified or does not meet performance requirements. It prevents the use of such equipment while it is in its normal operating location. Records usually are maintained through some form of log book that documents all critical activities such as failures, maintenance, qualification testing, location, custodian, and so forth.

Qualification life cycle

It is not necessary to formally document any equipment prepurchase activities. These activities normally are referred to as design qualification, or DQ, and they lead to the selection of equipment. Once the equipment arrives, the installation phase begins. The first part of the qualification cycle requiring formal documentation occurs with the installation qualification (IQ). In addition to specific installation activities, a key part of IQ is to enter the equipment into inventory maintained as part of the program by labeling it and creating the equipment log. In some cases, vendors may require that they perform the installation themselves, resulting in shared documentation of IQ activities. The qualification life cycle also includes components commonly referred to as operational qualification (OQ) and performance qualification (PQ). Although no requirement exists to separate qualification components into IQ,OQ, and PQ, these terms often facilitate the qualification activities when complex equipment is involved. The OQ testing ensures that the equipment is capable of meeting performance criteria within the ranges used for all of the testing. The selection of OQ tests is based on good science and the intended use of the equipment. The purpose of such tests is to ensure the validity of the data. Suggestions of specific OQ tests for various equipment types are listed in the sidebar “Examples of operational qualification tests for common analytical equipment.”Depending on the specific use of each type of equipment, the appropriate tests and frequency of testing should be incorporated into the qualification program. Performance qualification involves the testing of the equipment using the specific method or assay to ensure that the method is producing valid data. PQ may consist of method validation testing, system suitability testing, and analysis and trending of control samples. PQ supplements the OQ by adding checks of the specific method used.Again, like OQ, PQ

testing procedures should be based on good science and will depend on the specific method being used. In summary, the procedures used throughout the entire qualification life cycle must be documented, be based on good science, and ensure the integrity of the data generated by the equipment. The procedures and the functions or components qualified also should be based on the intended use of the equipment. Some qualification should be performed on a periodic basis, and this practice should be defined in the written qualification procedures. The regulations and the supporting science offer no distinction between a manufacturing quality control laboratory and an R&D laboratory. The same quality standard applies in each situation.

Equipment maintenance

Some OQ testing should be performed following equipment maintenance. The testing should be limited to the operational functions that are affected by the specific maintenance procedure. This usually involves repeating the OQ tests that evaluate the component that has been repaired or replaced. Components that are subject to wear and require routine replacement are best handled with a preventive maintenance program. The preventive maintenance intervals should be defined, be documented, and be an integral part of the qualification life cycle. Intervals can be defined or adjusted on the basis of the actual equipment qualification or maintenance history. Preventive maintenance is performed mainly for business reasons because it represents the most cost-effective method of maintaining equipment that requires frequent service.

Computers and software used to control laboratory equipment

Current regulations require the validation of computers and software that are used to control laboratory equipment or process data. Systems that acquireprocess, or store data also have additional requirements defined by 21 CFR 11. Although qualification is considered a subset of validation, validation requires additional documentation and change control procedures. Guidance for validation of computers and software for general computer-related systems and data acquisition systems have been described in Parenteral Drug Association technical reports (3,4). These guidance documents offer procedures for the documentation, qualification, and change control aspects of validation. When multiple laboratory computers are maintained with the same configuration of hardware and software, complete validation on a single representative unit can be performed. All other identical configurations would require only the IQ portion of the qualification. All such computers must be maintained in the same system of change control, which requires the appropriate revalidation when any change in configuration is made.

Summary and conclusion

The state of equipment qualification practices in the pharmaceutical industry is evolving and is subject to much variation. Although more extensive guidance exists for computerized systems than for non computerized components of laboratory equipment, the additional validation requirement of the computerized systems present many new challenges. Some commercially available software may not completely meet current requirements. A need exists for greater consistency in the qualification and maintenance practices for common analytical instruments used within the pharmaceutical industry. In today’s environment, there is a tendency to harmonize practices by simply incorporating new procedures into existing programs. In an atmosphere of growing regulatory expectations, this approach is common but not recommended as a means of upgrading qualification programs. The overall program should be evaluated periodically to ensure that current requirements are met and that excessive or inefficient practices are eliminated or changed. Although variations in equipment qualification practices never can be eliminated within the industry, it is recommended that the industry be consistent in meeting core requirements. This article outlines the core requirements that now are widely accepted. It also offers the rationale for making decisions about topics that are not widely accepted and that will continue to evolve in the industry.

References

1. “Laboratory Controls, General Requirements,”

Code of Federal Regulations, Part

211.160, Title 21, Rev. April 2000.

2. “Maintenance and Calibration of Equipment,”

Code of Federal Regulations, Part 58.63,

Title 21, Rev. April 2000.

3. PDA, Validation of Computer-Related Systems,

Technical Report No. 18, PDA J. Sci.

Technol. 49 (1), S1–S17 (1995).

4. PDA, Validation and Qualification of Computerized

Laboratory Data Acquisition Systems,

Technical Report No. 31, PDA J. Sci.

Technol. 53 (4), 1–12 (1999).

5. National Conference of Standards Laboratories,

Establishment and Adjustment of Calibration

Intervals, NCSL RP-1 (1996).

6. J.Agalloco, “Master Planning of Validation,”

PDA Training and Research Institute, April

1998.

7. M. Dorfman and R. Thayer, Standards,

Guidelines, and Examples on Software Requirements

Engineering (IEEE Computer Society

Press,Washington, DC, 1990).

8. P. Bedson, “The Development and Application

of Guidance on Equipment Qualification

of Analytical Instruments,”Accred. Qual.

Assur. 1 (6), 265–274 (1996).

9. P.A. Cloud, “Validating a Laboratory Incubator,”

BioPharm 10 (11), 30–42 (1997).

10. The Rules Governing Medicinal Products in

the European Community,Volume IV (Office

for Official Publications for the European

Communities, Luxembourg, 1992).

11. FDA, “Guidelines on General Principles of

Process Validation,”Rockville,MD,May 1987.

12. Department of Defense,“Definition of Terms

for Testing,Measurement, and Diagnostics,”

MIL-STD-1309D, PAR 3.1.326 (1983).

13. J.K. Taylor, “Standard Reference Materials:

Handbook for SRM Users,” National Technical

Information Services Publication

260–100 (1993).

14. National Conference of Standards Laboratories,

“General Requirements for the Competence

of Testing and Calibration Laboratories,”

ANSI/ISO/IEC 17025 (2000). PT

Definition of Pharmaceutical Terms

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Design Qualification (DQ) :

The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.

Installation Qualification (IQ) :

The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.

Operational Qualification (OQ) :

The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

Performance Qualification (PQ) :

The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

Ref: Qualification and validation, Annex 15 to the EU Guide to Good Manufacturing Practice

Audit checklist for who GMP guideline compliance in pharmaceuticals_Part 5

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Equipment/Line/Area Cleaning, Preparation, and Clearance

Do written procedures detail how equipment is to be checked immediately prior to use for cleanliness, removal of any labels and labeling from prior print operations? Check here YES / NO
Do written procedures detail any disconnection and reassembly required to verify readiness for use?

Operational Process Validation and Production Change Order Control,

Have production procedures been validated? (Review selected procedures for validation documentation. Adequate?) Check here YES / NO
Does the process control address all issues to ensure identity, strength, quality and purity of product? Check here YES / NO
Does the procedure include formulation that is written to yield not less than 100% of established amount of active ingredients? Check here YES / NO
Are all weighing and measuring preformed by one qualified person and observed by a second person? Check here YES / NO
Have records indicated preceding policy been followed by presence of two signatures? Check here YES / NO
Are actual yields calculated at the conclusion of appropriate phases of the operation and at the end of the process? Check here YES / NO
Are calculations performed by one person? Is there independent verification by a second person? Check here YES / NO

In-Process Inspection, Sampling, and Laboratory Control

Are written procedures established to monitor output and validate the performance of manufacturing procedures that may cause variability in characteristics of in-process materials and finished drug products? Check here YES / NO
Are in-process materials tested at appropriate phases for identity, strength, quality, purity and are they approved or rejected by Quality Control? Check here YES / NO
Are there laboratory controls including sampling and testing procedures to assure conformance of components, containers, closures, in-process materials, and finished product specifications? Check here YES / NO
Reprocessing/Disposition of Materials Check here YES / NO
Do written procedures identify steps for reprocessing batches? Check here YES / NO
Are quality control review and approval required for any and all reprocessing of material? Check here YES / NO
Does testing confirm that reprocessed batches conform to established specification? Check here YES / NO
Does a written procedure outline steps required to reprocess returned drug products (if it can be determined that such products have not been subjected to improper storage conditions?) Check here YES / NO
Does Quality Control review such reprocessed returned goods and test such material for conformance to specifications before releasing such material for resale?
Check here YES / NO

Finished Product Control

Finished Product Verification, Storage, and Handling Check here YES / NO
Do written procedures indicate how and who verifies that correct containers and packages are used for finished product during the finishing operation? Check here YES / NO
In addition, do written procedures require that representative sample of units be visually examined upon completion of packaging to verify correct labeling? Check here YES / NO
Are expiration dates stamped or imprinted on labels? Check here YES / NO
Are expiration dates related to any storage conditions stated on the label? Check here YES / NO
Are all finished products held in quarantine until QC has completed its testing and releases product on a batch to batch basis for sale? Check here YES / NO
Is finished product stored under appropriate conditions of temperature, humidity, light, etc. Check here YES / NO

Finished Product Inspection, Sampling, Testing, and Release for Distribution

Has the formulation for each product been tested for stability based on a written protocol? (Containers must duplicate those used in final product packaging.) Check here YES / NO
Are written sampling and testing procedures and acceptance criteria available for each product to ensure conformance to finished product specifications? Check here YES / NO
Is a quantity of samples equal to at least twice the quantity needed for finished product release testing maintained as a reserve sample? Check here YES / NO
Are sterility and pyrogen testing performed as required? Check here YES / NO
Are specific tests for foreign particles or abrasives included for any ophthalmic ointments? Check here YES / NO
Do controlled release or sustained release products include tests to determine conformance to release time specification? Check here YES / NO

Distribution Controls

Does a written procedure manage stocks to ensure that oldest approved product is sold first? Check here YES / NO
Are deviations to the policy above documented? Check here YES / NO
Does a written procedure identify the steps required if a product recall is necessary? Check here YES / NO
Is the recall policy current and adequate? Check here YES / NO

Marketing Controls

The current regulation does not address marketing controls per se except that all finished products must meet their specifications. Check here YES / NO

Complaint Handling and Customer Satisfaction Program

Are complaints, whether received in oral or written form, documented in writing and retained in a designated file? Check here YES / NO
Are complaints reviewed on a timely basis by the Quality Control Unit? Check here YES / NO
Is the action taken in response to each complaint documented? Check here YES / NO
Are decisions not to investigate a complaint also documented and the name of the responsible person documented? Check here YES / NO
Are complaint investigations documented and do they include investigation steps, findings, and follow-up steps, if required? Are dates included for each entry? Check here YES / NO

Reference : WHO guideline for GMP/Internet

Audit checklist for who GMP guideline compliance in pharmaceuticals_Part 4

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Material Component Storage and Handling with respect to

Are incoming material and components quarantined until approved for use? Check here YES / NO
Are all materials handled in such a way to prevent contamination? Check here YES / NO
Are all materials stored off the floor? Check here YES / NO
Are materials spaced to allow for cleaning and inspection? Check here YES / NO
Are labels for different products, strengths, dosage forms, etc., stored separately with suitable identification? Check here YES / NO
Is label storage area limited to authorized personnel? Check here YES / NO
Are rejected components, material, and containers quarantined and clearly marked to prevent their use? Check here YES / NO

Inventory Control Program for GMP

Are inventory control procedures written? Check here YES / NO
Does the program identify destruction dates for obsolete or out-dated materials, components, and packaging materials? Check here YES / NO
Is stock rotated to ensure that the oldest approved product or material is used first? Check here YES / NO
Is destruction of materials documented in a way that clearly identifies the material destroyed and the date on which destruction took place? Check here YES / NO

Vendor (Supplier) Control Program

Are vendors periodically inspected according to a written procedure? Check here YES / NO
Is the procedure for confirming vendor test results written and followed? Check here YES / NO

Operational Control

Material/Component/Label Verification, Storage, and Handling Check here YES / NO
Do written procedures identify storage time beyond which components, containers, and closures must be reexamined before use? Check here YES / NO
Is release of retested material clearly identified for use? Check here YES / NO
Are retesting information supplements originally obtained? Check here YES / NO
Do written procedures identify steps in the dispensing of material for production? Check here YES / NO
Do these procedures include (1) release by QC, (2)Documentation of correct weight or measure, and (3) Proper identification of containers? Check here YES / NO
Does a second person observe weighing/measuring/dispensing and verify accuracy with a second signature? Check here YES / NO
Is the addition of each component documented by the person adding the material during manufacturing? Check here YES / NO
Does a second person observe each addition of material and document verification with a second signature? Check here YES / NO
Does a written procedure specify who is authorized to issue labels? Check here YES / NO
Does a written procedure specify how labels are issued, used, reconciled with production, returned when unused, and the specific steps for evaluation of any discrepancies? Check here YES / NO
Do written procedures call for destruction of excess labeling on which lot or control numbers have been stamped or imprinted? Check here YES / NO

Reference : WHO guideline for GMP/Internet

Audit checklist for who GMP guideline compliance in pharmaceuticals_Part 3

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Equipment Identification with respect to GMP

Are all pieces of equipment clearly identified with easily visible markings? Check here YES / NO
Are all pieces of equipment also marked with an identification number that corresponds with an entry in an equipment log? Check here YES / NO
Does each piece of equipment have written instructions for maintenance that includes a schedule for maintenance? Check here YES / NO
Is the maintenance log for each piece of equipment kept on or near the equipment? Check here YES / NO

Equipment Maintenance & Cleaning with respect to GMP

Are written procedures established for the cleaning and maintenance of equipment and utensils? Check here YES / NO
Are these procedures followed? Check here YES / NO
Does a written procedure assign responsibility for the cleaning and maintenance of equipment? Check here YES / NO
Has a written schedule been established and is it followed for the maintenance and cleaning of equipment? Check here YES / NO
Has the cleaning procedure been properly validated? with respect to who GMP guide for quality assurance .Check here YES / NO
If appropriate, is the equipment sanitized using a procedure written for this task? Check here YES / NO
Has a sufficiently detailed cleaning and maintenance procedure been written for each different piece of equipment to identify any necessary disassembly and reassembly required to provide cleaning and maintenance? Check here YES / NO
Does the procedure specify the removal or obliteration of production batch information from each piece of equipment during its cleaning?
Is equipment cleaned promptly after use? IS GMP FOLLOWED Check here YES / NO
Is clean equipment clearly identified as "clean" with a cleaning date shown on the equipment? Check here YES / NO
Is clean equipment adequately protected against contamination prior to use? Check here YES / NO
Is equipment inspected immediately prior to use? Check here YES / NO
Are written records maintained on equipment cleaning, sanitizing and maintenance on or near each piece of equipment? Check here YES / NO

Measurement Equipment Calibration Program for GMP

Does the facility have approved written procedures for checking and calibration of each piece of measurement equipment? (Verify procedure and log for each piece of equipment and note exceptions in notebook with cross reference.) Check here YES / NO
Are records of calibration checks and inspections maintained in a readily retrievable manner? Check here YES / NO

Equipment Qualification Program for GMP

Verify that all pieces of equipment used in production, packaging, and quality assurance are capable of producing valid results. Check here YES / NO
When computers are used to automate production or quality testing, have the computer and software been validated? Check here YES / NO
Have on-site tests of successive production runs or tests been used to qualify equipment? Check here YES / NO
Were tests repeated a sufficient number of times to ensure reliable results? Check here YES / NO
Is each piece of equipment identified to its minimum and maximum capacities and minimum and maximum operating speeds for valid results? Check here YES / NO
Have performance characteristics been identified for each piece of equipment? (May be provided by the manufacturer, but must be verified under typical operations conditions.) Check here YES / NO
Have operating limits and tolerances for performance been established from performance characteristics? Check here YES / NO

Material/Component Specification and Purchasing Control

Although purchasing is not specifically addressed in the current GMP regulation, incumbent upon user of components and materials to ensure quality of product, material or component. Check here YES / NO
Has each supplier/vendor of material or component been inspected/audited for proper manufacturing controls? (Review suppliers and audits and enter names, material supplied, and date last audited in notebook.) Check here YES / NO
Material/Component Receipt, Inspection, Sampling, and Laboratory Testing Check here YES / NO
Does the facility have current written procedures for acceptance/rejections of drug products, containers, closures, labeling and packaging materials? (List selected materials and components in notebook and verify procedures.) Check here YES / NO
Is each lot within each shipment of material or components assigned a distinctive code so material or component can be traced through manufacturing and distribution? Check here YES / NO
Does inspection start with visual examination of each shipping container for appropriate labeling, signs of damage, or contamination? Check here YES / NO
Is the number of representative samples taken from a container or lot based on statistical criteria and experience with each type of material or component?
Is the sampling technique written and followed for each type of sample collected? Check here YES / NO
Is the quantity of sample collected sufficient for analysis and reserve in case retesting or verification is required? Check here YES / NO
Verify that the following steps are included in written procedures unless more specific procedures are followed:Containers are cleaned before samples are removed. Check here YES / NO
Stratified samples are not composited for analysis. Check here YES / NO
Containers from which samples have been taken are so marked indicating date and approximate amount taken. Check here YES / NO
Each sample container is clearly identified by material or component name, lot number, date sample taken, name of person taking sample, and original container identification. Check here YES / NO
At least one test is conducted to confirm the identity of a raw material (bulk chemical or pharmaceutical) when a Certificate of Analysis is provided by supplier and accepted by QA. Check here YES / NO

If a Certificate of Analysis is not accepted for a lot of material, then additional testing is conducted by a written protocol to determine suitability for purpose.
Microbiological testing is conducted where appropriate. Check here YES / NO
Reference : WHO guideline for GMP/Internet