Wednesday, December 24, 2008

IEST tutors on cleaning validation

Contamination control professionals keen to learn more about swabbing protocols for cleaning validations can boost their knowledge by attending a tutorial on the subject next month.



Developed from the Institute of Environmental Sciences and Technology (IEST), the Swabbing Protocols for Cleaning Validation tutorial aims to enhance working skills and expose professionals to real-world experiences.

The tutorial will feature hands-on demonstrations detailing proper swabbing techniques for high performance liquid chromatography (HPLC) and total organic carbon (TOC) for cleaning validation. Topics to be covered include proper methodology of sampling, review of cleaning validation challenges, and current industry practices. Participants will also learn about sampling materials requirements, swab material selection, vial handling, instrument loading, and how to improve recovery rates.

The tutorial is scheduled for 6 May during the 54th Annual Technical Meeting and Exposition, ESTECH 2008 at the Hilton Chicago/Indian Lakes Resort in Bloomingdale (Northwest Suburban Chicago), Illinois.




contact

IEST
F+1847 9814130
iest@iest.org

Wednesday, December 3, 2008

Quintiles Acquires Oak Grove Technologies, A Leading Pharmaceutical Validation And Engineering Firm

Quintiles Transnational Corp. (Research Triangle Park, NC) has acquired Oak Grove Technologies Inc., a specialist in providing current Good Manufacturing Practice (cGMP) compliance services to the pharmaceutical, biotechnology and medical device industries.

Oak Grove provides services related to manufacturing, process and system validation, concept development, design engineering, budget and procurement, program management, facility commissioning and software validation. As a result of its acquisition the firm will become part of Quintiles Consulting, which provides broad strategic consulting services throughout the product development and commercialization process.

"Regulatory commissioning and validation often are causes of delay in obtaining approval to manufacture from the Food and Drug Administration," said Jim Hamill, Executive Vice President of Quintiles Consulting. "Oak Grove has extensive experience in helping companies comply with the FDA's regulatory standards governing manufacturing. Oak Grove's compliance expertise, combined with Quintiles' industry-leading clinical research and commercialization services, can help bring products to market faster. That translates into real value for our customers and patients in need."

Oak Grove, which has about 50 employees, had been privately held. Quintiles has entered into employment agreements with Oak Grove's former president, Mitch Januszewski, and executive vice president Thomas Dzierozynski, who will continue to lead this new unit of Quintiles Consulting.

"As part of Quintiles, we'll have access to a significantly larger base of customers that could benefit from our services," Januszewski said. ``This transaction also gives us greater opportunity to address product manufacturing issues earlier in the development process. For customers, this should mean faster, more cost-effective compliance approval and production start-up."

Quintiles Transnational Corp. is the market leader in providing a full range of integrated product development and commercialization services to the pharmaceutical, biotechnology and medical device industries. Quintiles also provides healthcare policy consulting and health information management services to healthcare and governmental organizations worldwide. Quintiles is headquartered near Research Triangle Park, North Carolina. Quintiles operates through specialized work groups dedicated to meeting customers' individual needs and has more than 15,000 employees worldwide and offices in 30 countries.

For more information: Jim Hamill, Executive Vice President, Quintiles Consulting, P.O. Box 13979, Research Triangle Park, NC 27709-3979. Tel: 919-941-2888. Fax: 919-941-6258.

Thermal Validation in the Pharmaceutical Industry:

An argument against the use of thermocouples


The pharmaceutical industry is a highly regulated environment based on research, evidence, record-keeping, and validation. The term "thermal validation" is the process of validating / qualifying equipment and storage facilities to prove that they will create and maintain the temperatures they are designed for.

For those responsible, choosing the right temperature validation tool is decision #1 - and making that choice requires a thorough understanding of different sensor types. This paper will specifically focus on two common sensors: thermocouples and thermistors (see table below).

With nearly a decade of experience using both thermocouples and thermistors, Veriteq Instruments knows the advantages and disadvantages of each sensor, and will discuss them in this article as they relate to data logging in the pharmaceutical industry. This paper will also include specific references to Veriteq data loggers, which utilize internal thermistors. But first, a brief definition of thermocouples and thermistors:

  • A thermocouple is made of two dissimilar metals in contact with each other. The thermocouple works by generating a small voltage signal proportional to the temperature difference between the junctions of two metals.
  • In contrast, a thermistor is a resistive device made up of metal oxides that are formed into a bead and encapsulated in epoxy or glass. As temperature changes, so does resistance, causing a large voltage drop. Both sensors are quite small and normally encased in a protective shell, stainless probe, or wire coating, meaning that they may look very similar to the end-user.


Thermocouple Thermistor
Temp. Range -270 to 1800°C
(-454 to 3272°F)
-86 to 150°C
(-123 to 302°F)
Sensitivity Low High
Stability Low High
*Time-savings Lengthy set-up Minimal set-up
*Sources of Error Many Few
*Accuracy Low High
Ideal Applications High temperature oven profiling, Cryogenic freezing Warehouse monitoring, Stability testing, Chamber qualification, Cooler and Freezer, Monitoring, Lab monitoring, Cold Chain monitoring.


* This comparison looks at a total data logging system, and not just the sensor.

Temperature Range

Thermocouples offer the widest range of measuring capabilities, which admittedly makes them a suitable choice for extreme temperature applications such as oven profiling and cryogenic freezing.

However, in the range of -86 to 150°C (-123°F to 302°F), thermistors become an option, and for most applications they are the better choice. Thermistors are primary sensors, meaning that they operate independently, without the need for a second reference sensor. In fact other systems, including thermocouple systems, often use thermistors as their reference sensor.

It should be noted that the stated temperature range of -80 to 150°C (-123°F to 302°F) is just for the thermistor itself, and not for an enclosed Veriteq data logger. Veriteq data loggers are designed to withstand the range of -86 to 85°C (-123°F to 185°F) meaning that the loggers themselves can be placed in the temperature environment and left there. This makes them an ideal solution for chamber qualifications, stability testing, warehouse, cooler and freezer monitoring.

Veriteq's solution for the higher range of 85°C to 150°C (185°F to 302°F) requires an external thermistor probe that allows the connected data logger to remains outside the high temperature environment.


Sensitivity

The term sensitivity refers to the size of signal received in response to a temperature change, and is an important component of sensor accuracy. Thermistors are highly sensitive; in fact the name thermistor evolved from the phrase "thermally sensitive resistor". Stuart Ball, an electrical engineer and author for embedded.com writes that "of all passive temperature measurement sensors, thermistors have the highest sensitivity."

In comparing thermistors with thermocouples, Stuart goes on to say: "The voltage produced by a thermocouple is very small, typically only a few millivolts. A type K thermocouple changes only about 40 microvolts per 1°C (1.8°F) change in temperature." With such a small voltage to measure, it becomes difficult to distinguish an actual temperature change from noise. Enercorp Instruments Ltd., a provider of thermocouples and thermistors, speaks directly to this issue:

"The voltage produced is very small and amounts to only a few microvolts per degree Celsius. Thermocouples are therefore not generally used within the range of -30 to 50°C (-22 to 122°F)".

The graphs below are a visual representation of the increased sensitivity that a thermistor based system (such as a Veriteq data logger) detects as compared to a thermocouple system.

Low thermocouple sensitivity makes it hard to distinguish real changes from noise

High sensitivity of Veriteq system makes distinguishing real changes easy


Stability

Thermistors are very stable, which makes them ideal for portable applications such as warehouse and chamber qualifications. For example, Veriteq data loggers can be moved frequently without calibration, and still maintain an accuracy of +/- 0.15°C (+/-0.27°F).

To prove the point, Veriteq recently checked the calibration of 106 data loggers after a year of use in the field. Each logger was checked at the following calibration points: -20°C, 25°C, and 70°C. The results were impressive, showing less than 1% of the points to have any excess drift. Still, Veriteq recommends that data loggers are re-calibrated on a yearly basis.

Thermocouples, on the other hand, are known for low stability, which is why a pre-cal / post-cal is required with every use.

Time-savings

A Veriteq data logger is a system in itself, and one that is easy to use. Each data logger, containing a thermistor, is simply set to the desired sampling frequency and then placed in the monitoring location. Following the test period, the data is downloaded via a PC or PDA. The system is very straightforward and doesn't require any stringing of wires - the result is a significant time savings.

In contrast, a thermocouple based set-up can be quite time consuming, especially for high-accuracy applications requiring a pre and post-calibration. For example, qualifying a chamber with a thermocouple system involves first putting all sensor ends (i.e. the hot junctions) inside a calibration unit and going through the pre-calibration process. Following a successful calibration, the thermocouples are strung from the central data logging unit, to the chamber, through a door seal, and then taped into various positions. Care must be taken to keep a good seal on the door while minimizing damage to the thermocouple wire. Only then can the data collection begin. And when that is complete, all thermocouple sensors must still be moved to the calibration unit for post-calibration. Finally, it is not uncommon for thermocouples to fail the post-calibration, meaning that the whole process may need to be repeated.


Sources of Error

Being a self-contained unit means that Veriteq data loggers have less error sources to deal with - there are no wiring errors, no cold junction errors, and no errors associated with in-field calibration (see table below).


Thermocouple System Veriteq Thermistor System
Physical damage to sensor "Cold working" degrades thermocouple wires as they are repeatedly bent, stepped on, or shut in chamber doors. There is minimal risk because the thermistor sensor is protected inside the data logger
Non homogeneity
Consistency of thermocouple wire and the environment it runs through
Always present to some extent N/A
Cold Junction reference error
Temperature deviation between cold junction reference point and the actual cold junction; includes accuracy of cold junction sensor
The single largest source of error N/A
Pre & post calibration errors:
Reference transfer calibration error; traceable temperature standard; environmental stability; movement of sensors
In-field calibration introduces many sources of error Pre & post calibration is not required
Operator Error High level of knowledge required to minimize errors Less risk as the system is relatively simple
Analog to Digital conversion Minor Minor

In contrast, thermocouple systems have numerous sources of error, the most significant being the cold junction reference error. Goran Bringert, of Kaye Instruments, states the following:

"A change in ambient temperature is the most significant source or error in thermocouple measuring systems, particularly multi-channel systems with internal cold junction references"


Accuracy

High accuracy is critical for temperature validations because of the 4:1 rule, which recommends that instruments be at least four times as accurate as the parameter being measured/validated. Therefore, Veriteq data loggers, with their accuracy of +/- 0.15°C (+/-.27°F), can be used to monitor/validate parameters as tight as +/- 0.60°C (+/-1.1°F).

As for thermocouple based systems, a leading provider claims to have a total system accuracy of +/- 0.28°C (+/-0.5°F). While this may be true from a theoretical point of view, it would require having optimal conditions available. Others in the industry believe that +/- 1 to 2°C (+/- 1.8 to 3.6°F) is a more realistic accuracy for such a system, meaning that it could be used to validate parameter specifications of +/- 4 to 8°C (+/-7.2 to 14.4°F), applying the 4:1 rule. In any event, very few people dispute the fact that thermistors are more accurate than thermocouples.

Conclusion

When choosing a system for performing thermal validations, the first question asked should be "what kind of sensor is being used?"

Thermocouple sensors should be avoided because they involve a lengthy set-up, numerous error sources, and marginal accuracy. It would be best to restrict thermocouple systems to applications involving very high or very low temperatures, simply because there are no other choices available at those extremes.

In contrast, thermistor sensors are ideally suited to high accuracy monitoring in the range of -86° to 150°C (-123°F to 302°F). The Veriteq thermistor based system is highly sensitive, stable, accurate and easy to use. In addition, it eliminates the many error sources associated with thermocouple systems, and allows for a much quicker set-up time. In short, you save time, experience less hassle, and obtain high-accuracy results.

Trends in pharma validation

Published in Packaging World Magazine,
Written by Brian Pelletier, Contributing Editor

The pharmaceutical industry can barely breathe without mentioning any number of acronyms that govern—and in some cases, ease—the packaging process: 21 CFR Part 11, GAMP, JETT, FAT, PAT and URS are just a few of them, all part of the complicated process called validation.

Simply stated, validation means that the pharmaceutical companies must document each step of the manufacturing process, including packaging, and verify irrefutably that each step, each process, each machine does exactly what it’s supposed to do—each time. This ensures the safety and quality of the medicines that so many people depend on every day.

“Validation ensures that the right product is in right package, that the product has been properly prepared, and that it has the right label. Everything can be traced back for each of the lot numbers,” says Craig Nelson, president, Mission Controls, a machine manufacturer and systems integrator. “We also need to know the containers themselves can be traced back. We have tamper-proof lids to keep someone from putting something into an aspirin bottle on the shelf, but what if someone puts a coating in a bottle?”

“The challenge with validation is that it’s the responsibility of each pharmaceutical company to develop its own program to respond to FDA guidelines,” says Dave Schuh, vice president of sales and marketing at MGS Machine Corp. “But no matter how pharmaceutical companies choose to respond, at the end of the day they’re the ones responsible for compliance.”

“The FDA is looking for proof that the process is in control,” says Jeff Jackson, product manager at the Pharmaceutical Div. of Bosch Packaging. “Every customer has its own way of doing that. We have to meet each customer requirement.”

What makes the process more complicated is the fact that there are no clear guidelines that specify exactly how validation is to be done. So each manufacturer, ultimately responsible for every bit of validation in its processes, interprets the process differently and passes different requirements on to the packaging machinery suppliers. And that’s exactly where pharmaceutical manufacturers need help from packaging solution providers.

cGMPs

The fundamental process for validation has been in place for 10 years: the pharmaceutical company develops qualifications for a packaging machine and passes them off to the supplier, who then designs and manufactures the equipment. The pharmaceutical company then tests it, approves it, and begins operations.

But the FDA made this simultaneously easier and more difficult in September 2004 with the report “Pharmaceutical cGMP’s for the 21st Century—A Risk-Based Approach.” Current good manufacturing practices (cGMPs), sometimes known as good automated manufacturing practices (GAMP), have long been a standard practice in the pharmaceutical industry, but new technologies and approaches to quality assurance required more flexibility—and thus more variability—in the validation process.

The cGMP report discusses the integration of more science into the development and deployment of a new product, and it places the onus on the pharmaceutical companies to demonstrate that they understand what can and cannot affect the quality, stability, and efficacy of the product.

“With the FDA’s risk-based initiative to cGMPs, the FDA is trying to offer an olive branch to the industry,” says. Bikash Chatterjee, COO, of Pharmatech Associates, a consultancy serving the regulated life sciences industry. “Essentially the FDA said, ‘We’re looking for sound science—if you can justify to us that the decisions you have made regarding your critical systems, processes and equipment are scientifically sound, that’s good.’”

The cGMP guidelines, however, make assumptions that make the validation process more difficult. For example, the guidelines assume that each system is custom-designed, which leads to some manufacturers of standard machinery to conclude that the guidelines don’t apply to them. As pharmaceutical manufacturers push the issue, more packaging machine manufacturers find themselves being required to provide validation documentation to their customers.

“The industry kept hammering, so some companies created the documents that would normally be done in the process of designing, even though the product has already been designed,” says Howard Leary, vice president of engineering at Luciano Packaging Technology.

The initial design of the packaging machinery is documented in the Design Qualification, which creates an audit trail from the initial design specifications through the implementation of the new machinery. Savvy manufacturers understand that this upfront documentation can save a lot of trouble further down the road.

“One of the main things the FDA looks for is the upfront documentation, like the design qualification,” says Leary. “To do the spec up front is a more organized way to go.”

Even before the design qualifications, though, are the user requirement specifications, or URSs, which come from the pharmaceutical companies. A well-written URS drives the functional spec, again easing the process on the back end with some effort on the front.

In a perfect world, the pharmaceutical company can simply write the URS, hand it to the machine builder, and then accept delivery of the machine, complete with documentation. The challenge is that many times the pharmaceutical company is investing in a new machine or packaging line but can’t know exactly how the line is going to work, or what they need to do to write a URS.

“Often the back office is writing the specs, and the engineering guys are doing the validation checks and testing it, then they have to go back and rewrite the documents to reflect what they found in the process,” says Dave Whittenton, business development manager at Rockwell Automation. “That’s what’s introducing the inefficiencies.”

“We respect the fact that some end users really struggle with the URS,” says Schuh. “To help them we’ve developed templates that are populated with information to describe the functional specification for the base equipment.”

Also developing templates is the JETT (Joint Equipment Transition Team) Consortium, a special interest group of the International Society for Pharmaceutical Engineering created to help ease the cGMP process. JETT aims to improve communication between users and suppliers of automated production and process equipment to meet validation requirements more effectively. The group offers a number of documents and templates for various validation processes (www.jettconsortium.com).

“JETT is looking at some of the documentation, like design requirements, and developing templates based on cGMP that have a validation checklist, or something very similar,” says Whittenton. “You can just pull down the template for a bottle capper, for example.”

“As a supplier, we invest in keeping abreast of user groups working on validation standards, and working on processes for users and suppliers to interact, like the JETT Group,” says Schuh. “End users and suppliers can together hash through specifics of how to interact and develop a process flow that improves efficiency in improving equipment.”

“We see a lot of user requirement specifications, and the trend now is to re-evaluate how to write a URS and how we can improve the URS documentation,” says Whittenton. “The entire industry needs to get better at writing those.”

But not every supplier is enthusiastic about documentation.

“If someone doesn’t have or is unwilling to provide it, we as an integrator may not select them for a line,” says Leary. “Some companies have a standard machine and that’s what they sell, and other activities are a burden for them.”

Paying extra

In other cases, the customer is willing to pay extra to have those documents created. But the machinery manufacturer might not have qualified people to create the documentation. Only in the past decade or so have packaging companies begun to understand this requirement, according to Leary.

“When manufacturers do their homework, they lay that all out, and the detail of the specification documents becomes the supplier’s responsibility,” says Leary.

The industry responded to the cGMP report with Process Analytical Technology, or PAT, a system to design, analyze, and control manufacturing and packaging processes through timely measurements of critical quality and performance attributes. The goal of PAT is to understand and control the processes with the assumption that quality can’t be tested into products, but rather should be built in by design.

The PAT framework aims to apply the “quality by design” tenet to ensure a predefined quality at the end of the manufacturing process, improving efficiencies while simultaneously reducing risks to quality. In-line measurements and controls will reduce cycle times, prevent rejects and scrap, and improve operator safety and overall efficiency. The FDA has since created several subcommittees to provide recommendations on how PAT could be adopted throughout the industry.

“PAT fundamentally allows you to release your product without any additional release testing,” explains Chatterjee. “Currently you sample it, it goes to lab, you test it, and then you can ship it. PAT says that if you can demonstrate that you’re controlling and monitoring the critical attributes associated with the process—the number of pouches, verification of that number, the proper label, the right country, legible printing, etc.—the packaging machine can guarantee that the product will meet your quality standards. It’s the ultimate quality assurance.”

PAT is taking off slowly—it requires a high level of collaboration between the customer and the supplier during the equipment design and development process. It also requires “smart” machines and sensors that can communicate not only the state of the process, but the state of the sensor as well. This has led to a new generation of integrated controls.

In the past, equipment simply controlled its own functions; three or four other systems tracked what was being fed to it, or measured downtime, or tracked performance. But now the machine “knows” when it’s a good machine and when it’s not.

This requires a lot more validation, but in the end it makes the process easier and more efficient, especially when it comes to changeovers, which are another huge challenge to validation.

Some estimate that up to 70% of unexpected downtime is due to errors in changeover, which traditionally relies on paper-based standard operating procedures. But a new approach builds those procedures directly into the batch engine on the packaging machine, automating the changeover and retaining all the documentation in electronic form.

“It essentially uses the control platform on the machine to verify that the operator performed the SOP tasks automatically, and keeps an electronic record,” explains Whittenton. “It could also be integrated into a plant-wide recipe through the MES system, or you could do it manually by scanning the bar code on a carton blank, which kicks off the SOP—giving instructions for changing the inserts, calibrating, changing out, retesting. The operator has to go back and validate each task on the controller, and the platform is monitoring the change of the machine.”

The consistency of standards

Another challenge to validation is the consistency of the validation procedures themselves. The equipment manufacturer might believe that because they understand the machine better than anyone else, they should conduct the validation. But the end user—who is ultimately responsible—might not want to have several different manufacturers applying several different validation procedures, each with different courses of action, vocabularies, and document structures.

“The consistency of validation has become increasingly important,” says Whittenton. “OEMs are improving the situation by offering not just a single machine, but rather a whole packaging line.”

Consistency also plays a role in the integration of the machines. For example, a pharmaceutical manufacturer might want all the machines in a line, or in a plant, to conform to common standards in software and operating system.

“One customer decided to pick a standard for the controllers and all equipment across the board, and he told the manufacturers that they needed to have Ethernet on their machines in order for them to be considered,” recalls Nelson.

“The pharmaceutical companies are looking more to the OEM community to provide process sales of packaging lines,” says Whittenton. “They don’t want to buy islands, or a single machine for each process. They believe that will ease the validation process, and companies are stepping up to the plate and integrating.”

“We’re seeing this in 80 percent of packaging across the board, to have the systems unified ahead of time with the same operating system and communication,” says Nelson. “It’s such a simple thing to do. That alone removes so many hurdles to get them up, running, and validated.”

As smart machines become more prevalent, the process of validating the software becomes more complex. But by making the software modular, manufacturers are further easing the validation process.

For instance, a packaging machine might have 20 servo axes, which are all basically the same subroutine. Instead of validating each axis performance individually, could you validate the subroutine once and be done?

“If I can create a modular code or subroutine and validate that block and then manage that block and reuse it within a certain element or platform, would I have to validate it again?” suggests Whittenton. “There’s a lot of philosophy about how to implement this. If you had a positioning cam subroutine, the OEM could provide the software code with a validation packet explaining how to validate that code. But is this a huge benefit, or just huge marketing? It’s not really saving that much in the cost.”

Factory acceptance tests

The final phase of the new machine is the factory acceptance testing, or FAT, where the machine is run through its paces at the factory where it was built to ensure that everything works properly, and to complete the final validation stages.

“It used to take only a couple of hours to make sure things are running the right way during a factory acceptance test, but today it can take eight to ten weeks to put the equipment and software through the necessary challenges to demonstrate that it will meet today’s quality compliance standards,” says Chatterjee.

“We’ve developed user-editable documentation templates so that we can transfer that information to the end user early on in a project, or we can do more of the spec work for them up front,” says Schuh. “Some customers are looking into executing some portions of the commissioning work during the FAT in the supplier’s factory, with the goal of trying to improve the overall efficiency of a given project. It’s getting mixed results, but it’s a great example of people working together to optimize program results.”

This collaboration might well be the key to success in easing the overall validation burden. Packaging suppliers need to better understand quality systems, which in itself is a huge challenge for smaller companies. But pharmaceutical companies can help by working with smaller, specialized suppliers to help them understand what they need to get out of the process.

“Suppliers need to participate at a more intimate level regarding how these subsystems could affect the quality of the product,” says Chatterjee. “The whole process is forcing packaging suppliers to be more involved in infrastructure development and deployment of the equipment.”

“We learned from working with our customers what they’re really looking for,” says Leary. “Once you produce some of these documents, you have a good understanding. Each company has different approaches and different regulatory departments, but with most companies, if they come up with a good design document, it’s accepted.”

“I strongly encourage companies to create a business team, with the heads of each division on both the client and supplier side, along with people with budget, technical, quality, and deployment responsibilities,” says Chatterjee. “They need to set goals and milestones and to track those on a regular basis to see what’s going on and what needs to happen.”

Chatterjee predicts that as machines and processes become more complex, joint teams will become more prevalent. And with that collaboration will come better understanding, and greater success.

“The machinery industry needs to understand validation requirements and how to support them, not just the schematics and parts lists, but the entire document package that comes with the machine and verifies that it’s complete and accurate,” says Leary. “The packaging industry has learned that this is important. Compared to ten years ago, there’s a tremendous difference with suppliers.”


Guideline on General Principles of Process Validation

I. PURPOSE

This guideline outlines general principles that FDA considers to be acceptable elements of process validation for the preparation of human and animal drug products and medical devices.

II. SCOPE

This guideline is issued under Section 10.90 (21 CFR 10.90) and is applicable to the manufacture of pharmaceuticals and medical devices. It states principles and practices of general applicability that are not legal requirements but are acceptable to the FDA. A person may rely upon this guideline with the assurance of its acceptability to FDA, or may follow different procedures. When different procedures are used, a person may, but is not required to, discuss the matter in advance with FDA to prevent the expenditure of money and effort on activities that may later be determined to be unacceptable. In short, this guideline lists principles and practices which are acceptable to the FDA for the process validation of drug products and medical devices; it does not list the principles and practices that must, in all instances, be used to comply with law.

This guideline may be amended from time to time. Interested persons are invited to submit comments on this document and any subsequent revisions. Written comments should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, Room 4-62, 5600 Fishers Lane, Rockville, Maryland 20857. Received comments may be seen in that office between 9 a.m. and 4 p.m., Monday through Friday.

III. INTRODUCTION

Process validation is a requirement of the Current Good Manufacturing Practices Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211, and of the Good Manufacturing Practice Regulations for Medical Devices, 21 CFR Part 820, and therefore, is applicable to the manufacture of pharmaceuticals and medical devices. Several firms have asked FDA for specific guidance on what FDA expects firms to do to assure compliance with the requirements for process validation. This guideline discusses process validation elements and concepts that are considered by FDA as acceptable parts of a validation program.The constituents of validation

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presented in this document are not intended to be all-inclusive. FDA recognizes that, because of the great variety of medical products (drug products and medical devices), processes and manufacturing facilities, it is not possible to state in one document all of the specific validation elements that are applicable. Several broad concepts, however, have general applicability which manufacturers can use successfully as a guide in validating a manufacturing process. Although the particular requirements of process validation will vary according to such factors as the nature of the medical product (e.g., sterile vs non-sterile) and the complexity of the process, the broad concepts stated in this document have general applicability and provide an acceptable framework for building a comprehensive approach to process validation.

Definitions

Installation qualification - Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.

Process performance qualification - Establishing confidence that the process is effective and reproducible.

Product performance qualification - Establishing confidence through appropriate testing that the finished product produced by a specified process meets all release requirements for functionality and safety.

Prospective validation - Validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics.

Retrospective validation - Validation of a process for a product already in distribution based upon accumulated production, testing and control data.

Validation - Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.

Validation protocol - A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results.

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Worst case - A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.

IV. GENERAL CONCEPTS

Assurance of product quality is derived from careful attention to a number of factors including selection of quality parts and materials, adequate product and process design, control of the process, and in-process and end-product testing. Due to the complexity of today's medical products, routine end-product testing alone often is not sufficient to assure product quality for several reasons. Some end-product tests have limited sensitivity.(1) In some cases, destructive testing would be required to show that the manufacturing process was adequate, and in other situations end-product testing does not reveal all variations that may occur in the product that may impact on safety and effectiveness.(2)

The basic principles of quality assurance have as their goal the production of articles that are fit for their intended use. These principles may be stated as follows:

(1) quality, safety, and effectiveness must be designed and built into the product;

(2) quality cannot be inspected or tested into the finished product; and

(3) each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications.

Process validation is a key element in assuring that these quality assurance goals are met

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It is through careful design and validation of both the process and process controls that a manufacturer can establish a high degree of confidence that all manufactured units from successive lots will be acceptable. Successfully validating a process may reduce the dependence upon intensive in-process and finished product testing. It should be noted that in most all cases, end-product testing plays a major role in assuring that quality assurance goals are met; i.e., validation and end-product testing are not mutually exclusive.

The FDA defines process validation as follows:

Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.

It is important that the manufacturer prepare a written validation protocol which specifies the procedures (and tests) to be conducted and the data to be collected. The purpose for which data are collected must be clear, the data must reflect facts and be collected carefully and accurately. The protocol should specify a sufficient number of replicate process runs to demonstrate reproducibility and provide an accurate measure of variability among successive runs. The test conditions for these runs should encompass upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure compared to ideal conditions; such conditions have become widely known as "worst case" conditions. (They are sometimes called "most appropriate challenge" conditions.) Validation documentation should include evidence of the suitability of materials and the performance and reliability of equipment and systems.

Key process variables should be monitored and documented. Analysis of the data collected from monitoring will establish the variability of process parameters for individual runs and will establish whether or not the equipment and process controls are adequate to assure that product specifications are met.

Finished product and in-process test data can be of value in process validation, particularly in those situations where quality attributes and variabilities can be readily measured. Where finished (or in-process) testing cannot adequately measure certain attributes, process validation should be derived primarily from qualification of each system used in production and from consideration of the interaction of the various systems.

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V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS

Process validation is required, in both general and specific terms, by the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211. Examples of such requirements are listed below for informational purposes, and are not all-inclusive.

A requirement for process validation is set forth in general terms in Section 211.100 -- Written procedures; deviations -- which states, in part:

"There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess."

Several sections of the CGMP regulations state validation requirements in more specific terms. Excerpts from some of these sections are:

Section 211.110, Sampling and testing of in-process materials and drug products.

(a) "....control procedures shall be established to monitor the output and VALIDATE the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product." (emphasis added)

Section 211.113, Control of Microbiological Contamination.

(b) "Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include VALIDATION of any sterilization process." (emphasis added)

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VI. GMP REGULATION FOR MEDICAL DEVICES

Process validation is required by the medical device GMP Regulations, 21 CFR Part 820. Section 820.5 requires every finished device manufacturer to:

"...prepare and implement a quality assurance program that is appropriate to the specific device manufactured..."

Section 820.3(n) defines quality assurance as:

"...all activities necessary to verify confidence in the quality of the process used to manufacture a finished device."

When applicable to a specific process, process validation is an essential element in establishing confidence that a process will consistently produce a product meeting the designed quality characteristics.

A generally stated requirement for process validation is contained in section 820.100:

"Written manufacturing specifications and processing procedures shall be established, implemented, and controlled to assure that the device conforms to its original design or any approved changes in that design."

Validation is an essential element in the establishment and implementation of a process procedure, as well as in determining what process controls are required in order to assure conformance to specifications.

Section 820.100(a) (1) states:

"...control measures shall be established to assure that the design basis for the device, components and packaging is correctly translated into approved specifications."

Validation is an essential control for assuring that the specifications for the device and manufacturing process are adequate to produce a device that will conform to the approved design characteristics

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VII. PRELIMINARY CONSIDERATIONS

A manufacturer should evaluate all factors that affect product quality when designing and undertaking a process validation study. These factors may vary considerably among different products and manufacturing technologies and could include, for example, component specifications, air and water handling systems, environmental controls, equipment functions, and process control operations. No single approach to process validation will be appropriate and complete in all cases; however, the following quality activities should be undertaken in most situations.

During the research and development (R& D) phase, the desired product should be carefully defined in terms of its characteristics, such as physical, chemical, electrical and performance characteristics.(3) It is important to translate the product characteristics into specifications as a basis for description and control of the product.

Documentation of changes made during development provide traceability which can later be used to pinpoint solutions to future problems.

The product's end use should be a determining factor in the development of product (and component) characteristics and specifications. All pertinent aspects of the product which impact on safety and effectiveness should be considered. These aspects include performance, reliability and stability. Acceptable ranges or limits should be established for each characteristic to set up allowable variations.(4) These ranges should be expressed in readily measurable terms.

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The validity of acceptance specifications should be verified through testing and challenge of the product on a sound scientific basis during the initial development and production phase.

Once a specification is demonstrated as acceptable it is important that any changes to the specification be made in accordance with documented change control procedures.

VIII. ELEMENTS OF PROCESS VALIDATION

A. Prospective Validation

Prospective validation includes those considerations that should be made before an entirely new product is introduced by a firm or when there is a change in the manufacturing process which may affect the product's characteristics, such as uniformity and identity. The following are considered as key elements of prospective validation.

1. Equipment and Process

The equipment and process(es) should be designed and/or selected so that product specifications are consistently achieved. This should be done with the participation of all appropriate groups that are concerned with assuring a quality product, e.g., engineering design, production operations, and quality assurance personnel.

a. Equipment : Installation Qualification

Installation qualification studies establish confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. After process equipment is designed or selected, it should be evaluated and tested to verify that it is capable of operating satisfactorily within the operating limits required by the process.(5) This phase of validation includes examination of equipment design; determination of calibration, maintenance, and

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adjustment requirements; and identifying critical equipment features that could affect the process and product. Information obtained from these studies should be used to establish written procedures covering equipment calibration, maintenance, monitoring, and control.

In assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier, or upon experience in producing some other product.(6) Sound theoretical and practical engineering principles and considerations are a first step in the assessment.

It is important that equipment qualification simulate actual production conditions, including those which are "worst case" situations.

Tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results. All acceptance criteria must be met during the test or challenge. If any test or challenge shows that the equipment does not perform within its specifications, an evaluation should be performed to identify the cause of the failure. Corrections should be made and additional test runs performed, as needed, to verify that the equipment performs within specifications. The observed variability of the equipment between and within runs can be used as a basis for determining the total number of trials selected for the subsequent performance qualification studies of the process.(7)

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Once the equipment configuration and performance characteristics are established and qualified, they should be documented. The installation qualification should include a review of pertinent maintenance procedures, repair parts lists, and calibration methods for each piece of equipment. The objective is to assure that all repairs can be performed in such a way that will not affect the characteristics of material processed after the repair. In addition, special post-repair cleaning and calibration requirements should be developed to prevent inadvertent manufacture a of non-conforming product. Planning during the qualification phase can prevent confusion during emergency repairs which could lead to use of the wrong replacement part.

b. Process: Performance Qualification

The purpose of performance qualification is to provide rigorous testing to demonstrate the effectiveness and reproducibility of the process. In entering the performance qualification phase of validation, it is understood that the process specifications have been established and essentially proven acceptable through laboratory or other trial methods and that the equipment has been judged acceptable on the basis of suitable installation studies.

Each process should be defined and described with sufficient specificity so that employees understand what is required. Parts of the process which may vary so as to affect important product quality should be challenged.(8) In challenging a process to assess its adequacy, it is important that challenge conditions simulate those that will be encountered during actual production, including "worst case" conditions. The challenges should be repeated enough times to assure that the results are meaningful and consistent.

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Each specific manufacturing process should be appropriately qualified and validated. There is an inherent danger in relying on what are perceived to be similarities between products, processes, and equipment without appropriate challenge.(9)

c. Product: Performance Qualification

For purposes of this guideline, product performance qualification activities apply only to medical devices. These steps should be viewed as pre-production quality assurance activities.

Before reaching the conclusion that a process has been successfully validated, it is necessary to demonstrate that the specified process has not adversely affected the finished product. Where possible, product performance qualification testing should include performance testing under conditions that simulate actual use. Product performance qualification testing should be conducted using product manufactured from the same type of production equipment, methods and procedures that will be used for routine production. Otherwise, the qualified product may not be representative of production units and cannot be used as evidence that the manufacturing process will produce a product that meets the pre-determined specifications and quality attributes.(10)

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After actual production units have successfully passed product performance qualification, a formal technical review should be conducted and should include:

  • Comparison of the approved product specifications and the actual qualified product.
  • Determination of the validity of test methods used to determine compliance with the approved specifications.
  • Determination of the adequacy of the specification change control program.

    2. System to Assure Timely Revalidation

There should be a quality assurance system in place which requires revalidation whenever there are changes in packaging, formulation, equipment, or processes which could impact on product effectiveness or product characteristics, and whenever there are changes in product characteristics. Furthermore, when a change is made in raw material supplier, the manufacturer should consider subtle, potentially adverse differences in the raw material characteristics. A determination of adverse differences in raw material indicates a need to revalidate the process.

One way of detecting the kind of changes that should initiate revalidation is the use of tests and methods of analysis which are capable of measuring characteristics which may vary. Such tests and methods usually yield specific results which go beyond the mere pass/fail basis, thereby detecting variations within product and process specifications and allowing determination of whether a process is slipping out of control.

The quality assurance procedures should establish the circumstances under which revalidation is required. These may be based upon equipment, process, and product performance observed during the initial validation challenge studies. It is desirable to designate individuals who have the responsibility to review product, process, equipment and personnel changes to determine if and when evalidation is warranted.

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The extent of revalidation will depend upon the nature of the changes and how they impact upon different aspects of production that had previously been validated. It may not be necessary to revalidate a process from scratch merely because a given circumstance has changed. However, it is important to carefully assess the nature of the change to determine potential ripple effects and what needs to be considered as part of revalidation.

3. Documentation

It is essential that the validation program is documented and that the documentation is properly maintained. Approval and release of the process for use in routine manufacturing should be based upon a review of all the validation documentation, including data from the equipment qualification, process performance qualification, and product/package testing to ensure compatibility with the process.

For routine production, it is important to adequately record process details (e.g., time, temperature, equipment used) and to record any changes which have occurred. A maintenance log can be useful in performing failure investigations concerning a specific manufacturing lot. Validation data (along with specific test data) may also determine expected variance in product or equipment characteristics.

B. Retrospective Process Validation

In some cases a product may have been on the market without sufficient premarket process validation. In these cases, it may be possible to validate, in some measure, the adequacy of the process by examination of accumulated test data on the product and records of the manufacturing procedures used.

Retrospective validation can also be useful to augment initial premarket prospective validation for new products or changed processes. In such cases, preliminary prospective validation should have been sufficient to warrant product marketing. As additional data is gathered on production lots, such data can be used to build confidence in the adequacy of the process. Conversely, such data may indicate a declining confidence in the process and a commensurate need for corrective changes.

Test data may be useful only if the methods and results are adequately specific. As with prospective validation, it may be insufficient to assess the process solely on the basis of lot by lot conformance to specifications if test results are merely expressed in terms of pass/fail. Specific results, on the other hand, can be statistically analyzed and a determination can be made of what variance in data can be expected. It is important to maintain records which describe the operating characteristics of the process, e.g., time, temperature, humidity, and equipment settings.(11) Whenever test data are used to demonstrate conformance to specifications, it is important that the test methodology be qualified to assure that test results are objective and accurate.

IX. ACCEPTABILITY OF PRODUCT TESTING

In some cases, a drug product or medical device may be manufactured individually or on a one-time basis. The concept of prospective or retrospective validation as it relates to those situations may have limited applicability, and data obtained during the manufacturing and assembly process may be used in conjunction with product testing to demonstrate that the instant run yielded a finished product meeting all of its specifications and quality characteristics. Such evaluation of data and product testing would be expected to be much more extensive than the usual situation where more reliance would be placed on prospective validation.

(1) For example, USP XXI states: "No sampling plan for applying sterility tests to a specified proportion of discrete units selected from a sterilization load is capable of demonstrating with complete assurance that all of the untested units are in fact sterile."

(2) As an example, in one instance a visual inspection failed to detect a defective structural weld which resulted in the failure of an infant warmer. The defect could only have been detected by using destructive testing or expensive test equipment.

(3) For example, in the case of a compressed tablet, physical characteristics would include size, weight, hardness, and freedom from defects, such as capping and splitting. Chemical characteristics would include quantitative formulation/potency; performance characteristics may include bioavailability (reflected by disintegration and dissolution). In the case of blood tubing, physical attributes would include internal and external diameters, length and color. Chemical characteristics would include raw material formulation. Mechanical properties would include hardness and tensile strength; performance characteristics would include biocompatibility and durability.

(4) For example, in order to assure that an oral, ophthalmic, or parenteral solution has an acceptable pH, a specification may be established by which a lot is released only if it has been shown to have a pH within a narrow established range. For a device, a specification for the electrical resistance of a pacemaker lead would be established so that the lead would be acceptable only if the resistance was within a specified range.

(5) Examples of equipment performance characteristics which may be measured include temperature and pressure of injection molding machines, uniformity of speed for mixers, temperature, speed and pressure for packaging machines, and temperature and pressure of sterilization chambers.

(6) The importance of assessing equipment suitability based upon how it will be used to attain desired product attributes is illustrated in the case of deionizers used to produce Purified Water, USP. In one case, a firm used such water to make a topical drug product solution which, in view of its intended use, should have been free from objectionable microorganisms. However, the product was found to be contaminated with a pathogenic microorganism. The apparent cause of the problem was failure to assess the performance of the deionizer from a microbiological standpoint. It is fairly well recognized that the deionizers are prone to build-up of microorganisms -- especially if the flow rates are low and the deionizers are not recharged and sanitized at suitable intervals. Therefore, these factors should have been considered. In this case, however, the firm relied upon the representations of the equipment itself, namely the "recharge" (i.e., conductivity) indicator, to signal the time for regeneration and cleaning. Considering the desired product characteristics, the firm should have determined the need for such procedures based upon pre-use testing, taking into account such factors as the length of time the equipment could produce deionized water of acceptable quality, flow rate, temperature, raw water quality, frequency of use, and surface area of deionizing resins.

(7) For example, the AAMI Guideline for Industrial Ethylene Oxide Sterilization of Medical Devices approved 2 December 1981, states: "The performance qualification should include a minimum of 3 successful, planned qualification runs, in which all of the acceptance criteria are met.....(5.3.1.2.)

(8) For example, in electroplating the metal case of an implantable pacemaker, the significant process steps to define, describe, and challenge include establishment and control of current density and temperature values for assuring adequate composition of electrolyte and for assuring cleanliness of the metal to be plated. In the production of parenteral solutions by aseptic filling, the significant aseptic filling process steps to define and challenge should include the sterilization and depyrogenation of containers/closures, sterilization of solutions, filling equipment and product contact surfaces, and the filling and closing of containers.

(9) For example, in the production of a compressed tablet, a firm may switch from one type of granulation blender to another with the erroneous assumption that both types have similar performance characteristics, and, therefore, granulation mixing times and procedures need not be altered. However, if the blenders are substantially different, use of the new blender with procedures used for the previous blender may result in a granulation with poor content uniformity. This, in turn, may lead to tablets having significantly differing potencies. This situation may be averted if the quality assurance system detects the equipment change' in the first place, challenges the blender performance, precipitates a revalidation of the process, and initiates appropriate changes. In this example, revalidation comprises installation qualification of the new equipment and performance qualification of the process intended for use in the new blender.

(10) For example, a manufacturer of heart valves received complaints that the valve-support structure was fracturing under use. Investigation by the manufacturer revealed that all material and dimensional specifications had been met but the production machining process created microscopic scratches on the valve supporting wireform. These scratches caused metal fatigue and subsequent fracture. Comprehensive fatigue testing of production units under simulated use conditions could have detected the process deficiency.

In another example, a manufacturer recalled insulin syringes because of complaints that the needles were clogged. Investigation revealed that the needles were clogged by silicone oil which was employed as a lubricant during manufacturing. Investigation further revealed that the method used to extract the silicone oil was only partially effective. Although visual inspection of the syringes seemed to support that the cleaning method was effective, actual use proved otherwise.

(11) For example, sterilizer time and temperature data collected on recording equipment found to be accurate and precise could establish that process parameters had been reliably delivered to previously processed loads. A retrospective qualification of the equipment could be performed to demonstrate that the recorded data represented conditions that were uniform throughout the chamber and that product load configurations, personnel practices, initial temperature, and other variables had been adequately controlled during the earlier runs.

http://www.fda.gov/CDER/GUIDANCE/pv.htm

Sunday, November 16, 2008

Qualification, Validation, and Verification

This article considers the distinction among the terms qualification, validation, and verification in the context of pharmacopeial usage.A recommendation for a standardized usage of the terms validation and verification is provided,and general requirements for validation and verification activities are given.The article also emphasizes the importance of knowing when validation or verification is necessary relative to the use of a method to satisfy pharmacopeial article requirements (for which a monograph..
The terms qualification, validation, and verification occur numerous times in US Pharmacopeia 29 (1). Qualification is found in Chapters ‹1035› "Biological Indicators for Sterilization," ‹1043› "Ancillary Materials Cell, Gene, and Tissue-Engineered Products," ‹1046› "Cell and Gene Therapy Products," and ‹1119› "Near-Infrared Spectrophotometry," among others. Validation appears in ‹1225› "Validation of Compendial Procedures," ‹1223› "Validation of Alternative Microbiological Methods," ‹1010› "Analytical Data—Interpretation and Treatment," ‹1043› "Ancillary Materials for Cell-, Gene-, and Tissue-Engineered Products," ‹1117› "Microbiological Best Laboratory Practices," ‹1120› "Raman Spectrophotometry," and many others. Verification appears in ‹1010› "Analytical Data—Interpretation and Treatment," ‹1035› "Biological Indicators for Sterilization," ‹1035› "Biological Indicators for Sterilization," ‹85› "Bacterial Endotoxins Test," and others. The terms also are present in documents from the US Food and Drug Administration, the Environmental Protection Agency (EPA), and the International Conference on Harmonization (ICH). Given the numerous definitions for the three terms, this article in part is intended to provide an approach to fostering more consistency in the usage of the terms.

A recent issue of the Pharmacopeial Forum (2) had a diagram from a proposed General Chapter ‹1058› "Analytical Instrument Qualification" that was intended to show "...four critical components involved in the generation of reliable and consistent data (quality data)." From most to least critical, the components were quality-control check samples, system suitability tests, analytical methods validation, and analytical instrument qualification. In this article, consider system-suitability tests to be the same as verification. Why this usage should be acceptable will be explained. This article will consider validation and verification in detail. Reference to analytical instrument qualification is made. For further discussion of the top tier, "Quality Control Check Samples," refer to Chapter ‹1058› "Analytical Instrument Qualification" (1).

Qualification

Qualification of analytical instrumentation is essential for accurate and precise measurement of analytical data. If the instrumentation is not qualified, ensuring that the results indicated are trustworthy, all other work based upon the use of that instrumentation is suspect. For the purposes of this article, the assumption will be made that the foundation of validation and verification work to follow is based solidly upon well-qualified instrumentation.

Validation

Definitions. Numerous documents provide definitions of validation. A dictionary definition (3) of validation includes "...the process of determining the degree of validity of a measuring device," and for validate: "to make legally valid," with synonyms "verify, substantiate." Clearly, the synonyms do not distinguish between validation and verification, so let us now turn to definitions provided by other sources. USP chapter ‹1225› "Validation of Compendial Procedures" provides the following:

"Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications."

From the ICH document Validation of Analytical Procedures: Text and Methodology:

However, it is important to remember that the main objective of validation of an analytical procedure is to demonstrate that the procedure is suitable for its intended purpose (4).


FDA provides a definition of validation in numerous documents. One such document, Guidance for Industry: Analytical Procedures and Methods Validation Chemistry, Manufacturing, and Controls Documentation says "methods validation is the process of demonstrating that analytical procedures are suitable for their intended use" (5). There also are numerous documents defining validation within the context of processes. From FDA's Guideline on General Principles of Process Validation:

"Validation—Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (6)."

The same definition is provided in other FDA documents, such as Guideline on Sterile Drug Products Produced by Aseptic Processing. FDA document Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations provides this definition:

"With proper design (see section IV.C.1), and reliable mechanisms to transfer process knowledge from development to commercial production, a manufacturer should be able to validate the manufacturing process. In a quality system, process validation provides initial proof, through commercial batch manufacture, that the design of the process produces the intended product quality (7). "

The remainder of the discussion about validation in this article will be restricted to a discussion of method validation.

Does it suit its purpose? The foregoing is clearly not an exhaustive list of the manners in which validation has been defined. It does appear that a recurring theme among the various definitions pertains to demonstrating that the method or process is suitable for its intended use. In this article, consider validation to be the demonstration that a method or process is suitable for its intended purpose. Accepting that, it is imperative that the intended purpose of a method or process is clearly stated at the outset of the validation. An example of the importance of such a statement can be found in Chapter ‹71› "Sterility Tests" (1). It states that "the following procedures are applicable for determining whether a Pharmacopeial article purporting to be sterile complies with the requirements set forth in the individual monograph with respect to the test for sterility." The next paragraph states

"These Pharmacopeial procedures are not by themselves designed to ensure that a batch of product is sterile or has been sterilized. This is accomplished primarily by validation of the sterilization process or of the aseptic processing procedures."

During the years there has been concern that the tests for sterility as provided in Chapter ‹71› are not adequate to prove that a batch of product is sterile. As stated previously, the tests in Chapter ‹71› were intended only to show that a Pharmacopeial article is sterile. Such a demonstration constitutes a necessary but not sufficient condition for sterile pharmacopeial articles. If one were to validate an alternative procedure for that in Chapter ‹71›, it would not be necessary to develop one that is intended to demonstrate sterility of an entire lot of product.

In addition, it is appropriate that the conditions are provided under which the validation was performed. Given that there are essentially countless variations on experimental conditions, product matrix effects, and so forth, a validation cannot reasonably expect to address all such permutations. For example, Method 3 in the section of Chapter ‹1047› "Biotechnology-Derived Articles—Tests", which addresses assays for total protein, indicates in a note:

"[Do not use quartz (silica) spectrophotometer cells: the dye binds to this material. Because different protein species may give different color response intensities, the standard protein and test protein should be the same.] There are relatively few interfering substances, but detergents and ampholytes in the test specimen should be avoided. Highly alkaline specimens may interfere with the acidic reagent (1)."

Therefore, given the following from FDA's Guide to Inspections of Pharmaceutical Quality Control Laboratories: "Methods appearing in the USP are considered validated and they are considered validated if part of an approved ANDA" (8), the use of Method 3 would be valid if the conditions stated are met in testing the material of interest. The same FDA document states "For compendial methods, firms must demonstrate that the method works under the actual conditions of use," which, for the sake of this article, will be considered verification. Chapter ‹1047› provides several other procedures, all also validated, that could be considered given test material that does not satisfy the conditions for Method 3.

Remember the purpose. It is important to bear in mind the purpose of the method to be validated. If the method is intended to serve as an alternative to a pharmacopeial method, then one must establish its equivalence to the pharmacopeial method in terms of the end result. Remember that the purpose of a method in the pharmacopeia is to determine whether the pharmacopeial article (for which a monograph exists in the pharmacopeia) satisfies the requirements in the monograph. If instead the purpose behind the use of a pharmacopeial method is for a purpose other than demonstrating that the article complies with monograph requirements (for example, imagine that total organic carbon is to be determined using Chapter ‹643› "Total Organic Carbon"), it is not necessary to perform the validation relative to the pharmacopeial results. This means that the validation should be conducted relative to the specific purpose for which it is intended. Also implicit in this is the use of a nonpharmacopeial method to determine something for which a pharmacopeial method exists, but again for purposes unrelated to satisfying a monograph requirement. In such a case, it is unnecessary to consider validating the method relative to that in the pharmacopeia.

Verification

If the use of the term validation is restricted to mean the demonstration of suitability of a method or process for its intended purpose, and the term verification for the demonstration that the previously validated method is suitable for use given specific experimental conditions that may or may not be appropriate given the conditions present during the validation, the terminological situation may be clarified.

Figure 1
These actual conditions include specific ingredients or products, specific laboratory personnel, equipment, and reagents. There are, however, instances in the literature where this distinction is not maintained. Consider the dictionary definition given previously for validation and its use of verification as a synonym for validation. Further muddying of the waters occurs when phrases such as "system suitability tests" (see Figure 1 and the system-suitability section in Chapter ‹621› "Chromatography"). The phrase also appears in the "Suitability of the Counting Method in the Presence of Product" section of Chapter ‹61› "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests", the "Suitability of the Test Method" section of Chapter ‹62› "Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms", and the "Validation Test" section of Chapter ‹71› "Sterility Tests." (1). In all cases, the intention is to ensure that the validated method will work under the specific conditions the analyst plans to use.

This means that a chromatographic system can deliver resolution and reproducibility on par with the system used during validation. For the two microbiology test chapters for nonsterile products, one must show that microbial growth in the presence of the article to be tested is not hindered. This is because the method depends on unencumbered microbial growth for it to work. In other words, a condition established in validating the method initially was unhindered microbial growth. The use of "validation test" in Chapter ‹71› is unfortunate because the intention was again to demonstrate that microbial growth is not hindered, as indicated in the following text:

"If clearly visible growth of microorganisms is obtained after the incubation, visually comparable to that in the control vessel without product, either the product possesses no antimicrobial activity under the conditions of the test or such activity has been satisfactorily eliminated. The test for sterility may then be carried out without further modification."

It may be advantageous, and more consistent, for the text in Chapter ‹71› to be changed to "Suitability of the Test Method," if not to "Verification of the Test Method." The latter change also may be appropriate for Chapters ‹61› and ‹62›, given that what is being assessed is the verification that the actual test conditions relative to those established during the validation permits the proper functioning of the method. Given the harmonized status of these three chapters, such changes, although possible, would certainly take longer to become official.

The same cautions provided at the end of the section on validation are applicable here. If a method in use previously was derived from a pharmacopeial method but used for a purpose other than satisfying monograph requirements, it is not necessary to adopt a revised method in the pharmacopeia when it becomes official. It is therefore not necessary to reverify the suitability of your test article to the revised method. Likewise, the use of a nonpharmacopeial method for purposes other than satisfying a monograph requirement when a pharmacopeial method exists of potential relevance does not necessitate reverification.

General requirements for validation

There are numerous documents that describe the general approach to a validation process. They describe several characteristics (data elements in Chapter ‹1225›) that may be examined during validation, with specific sets selected based upon the nature of the test method. A brief description of these characteristics is provided herein using the characteristics as outlined in the IC Harmonization Harmonized Tripartite Guideline, Validation of Analytical Procedures: Text and Methodology.

Accuracy is a determination of how close the measured value is (in the case of an analytical method) to the true value. As such, one might define accuracy of method as equal to true value plus error. Error may contain both the systematic error (bias) and imprecision of measurement. With the potential error possible, it is important to include a means of reflecting the "true value" as closely as possible. For many compendial tests, this involves the use of a reference standard. Because a method is expected to be useful over a range of true values, the accuracy should be assessed over the expected range of values to which the method is to be applied. As stated previously, the validation should also state the conditions under which the accuracy was determined. Because it is not possible to determine all possible sets of conditions for which a compendial assay might be applicable, accuracy may need to be verified before use of a validated method. The concept of accuracy is more problematic for microbiological assays.

The precision of a method determined during validation should be representative of the repeatability (reproducibility) of the method. As was the case for the determination of accuracy, it should be determined over the expected range of articles to be measured, and the conditions used during the validation should be clearly stated. As for accuracy, the use of reference standards is common because the goal of the assessment of precision is to determe method repeatability without introducing unknown variance as a result of different test articles or test articles drawn from a heterogeneous source. The latter point also complicates the validation of microbiological assays.

Specificity refers to the ratio of false positives to false negatives. A highly specific method would have a very low ratio, given that it should be able to detect the article of interest present in very low quantities in the presence of much higher quantities of similar but not identical articles. As stated previously, specificity should be determined over the expected range of usage for the method, and conditions used during the validation should be clearly stated.

Linearity, in essence, refers to the existence of a direct relationship between the quantity of article contained in the sample being analyzed and the measured value resulting from the analysis. It is not the purpose of this article to delve into statistical intricacies pertaining to data transformation, the use of linear or nonlinear regression techniques, residual analysis, and so forth. Currently, it is sufficient that an assay purporting to be quantitative in nature must have a demonstrable quantitative relationship between the quantity of material of interest contained in the sample and the measured response.

Range is directly related to linearity, and ties in accuracy and precision as well. It represents the lowest and highest quantities of material of interest contained within the samples under analysis that provide data with acceptable accuracy, precision, and linearity.

Detection limit represents the least amount of material of interest contained within the sample under analysis that produces a signal exceeding the underlying noise. No assertions pertaining to accuracy, precision, and linearity are necessary at this level of material of interest. For example, if a method is validated to have a detection limit of 3 ng of total protein using Method 3 (1), then a sample containing 3 ng would elicit a signal discernible from underlying noise. It would not be possible to state from such data alone whether there was in fact an exact quantity ng of protein in the sample, only that there were at least 3 ng.

Quantitation-limit determination is more demanding in that currently it is necessary to establish the minimum quantity of material of interest contained within the sample that produces a signal that lies within the linear range of data. That is to say, the quantitation limit represents the lowest end of the range.

Intermediate precision (ruggedness in USP Chapter ‹1225› [1]) pertains to the establishment of "...the effects of random events on the precision of the analytical procedure" (4). Referring to the previous discussion under accuracy pertaining to error components, intermediate precision considers random error introduced by such factors as specific equipment, analysts, laboratories, days, and so forth. It is not meant to include systematic error (bias).

Robustness is probably most directly related to the consideration of conditions under which a validated method is shown to be suitable. This text is very useful in considering robustness:

"If measurements are susceptible to variations in analytical conditions, the analytical conditions should be suitably controlled or a precautionary statement should be included in the procedure. One consequence of the evaluation of robustness should be that a series of system suitability parameters (e.g., resolution test) is established to ensure that the validity of the analytical procedure is maintained whenever used (4)."

General requirements for verification

One question that may be asked of the compendia is whether a method provided as official (in the compendia or supplements) requires validation. USP Chapter ‹1225› states:

"...users of analytical methods described in the USP-NF are not required to validate accuracy and reliability of these methods, but merely verify their suitability under actual conditions of use (1)."

This text is consistent with the proposal in this article that the term validation be reserved for the process whereby one determines if a given method is suitable for its intended purpose (which must be clearly defined), and that the term verification be reserved for the demonstration that the conditions under which the method is to be performed will be appropriate for the method.

Another question may be given that verification involves demonstrating that the conditions to be evaluated are suitable for use with the validated method, how does one go about assessing that? It should be evident that a subset of the determinations performed during the validation would be appropriate. Important conditions to consider include equipment, possible matrix effects (components included in the article to be tested that were not evaluated during the validation), and other conditions for which there is no clear indication provided in the method as to their suitability. A proposed new General Chapter ‹1226› "Verification of Compendial Procedures" (see reference 9 for a discussion of this chapter) provides some guidance as to how the verification process may be executed, but ultimately the user is responsible for selecting which of the characteristics (data elements) evaluated during the validation should be examined as part of the verification. The user should establish which of those validation characteristics are critical to the successful use of the validated method.

Summary

There has been some confusion about when an analytical method should be validated and when it should be verified. In fact, there have been occasions when the terms have been used interchangeably. It is suggested that the term validation be reserved for the process necessary to demonstrate that a method is suitable for its intended purpose. Effective validation begins with a proper statement of the purpose of the method. This statement should accompany the method validation report, and in some circumstances, such as with Chapter ‹71› "Sterility Tests" (1), the statement should appear in the text accompanying the method. Depending upon the degree to which robustness is assessed during the validation process, there may be a set of conditions determined that may be suitable for the use of the method, and conditions that are contraindicated. If such conditions have been established, it is helpful for them to accompany the text describing the method (for example, Method 3 in [9]).

The term verification should be reserved for the process whereby it is established that the conditions under which an article is to be tested by a validated method are indeed suitable for that method. The verification process might be considered to include a subset of the validation process, as suggested by Figure 1. The characteristics (data elements) of a validation process are contained in several documents, and which of these are incorporated in the validation should be appropriate to the method's intended purpose (and spelled out in the validation protocol.) The characteristics from the validation that are assessed during the verification should be representative of the critical aspects of the method. An example of the verification of the range for Method 3 was provided. Given that verification, as described in this article, is intended to address the suitability of a particular set of conditions for use with a validated method, robustness is not likely to be important for the verification process.

For both validation and verification, one must remember the underlying purpose of the method. If the method is from the pharmacopeia and is intended to be used in demonstrating that a pharmacopeial article meets requirements (for which there is a monograph), the method is considered to be validated, and it would be necessary to verify that the test article is suitable for use with the method. If the method is from the pharmacopeia but is not intended for use in satisfying monograph requirements, it may need to be validated relative to the specific nonpharmacopeial purpose. If instead the method is not from the pharmacopeia but is intended to satisfy monograph requirements, it must be validated as providing equivalent results to the pharmacopeial method. Finally, if the nonpharmacopeial method is not intended to satisfy monograph requirements, it must be validated according to its specific purpose, and this would not require comparison to any pharmacopeial method.

David A. Porter is a pharmaceutical consultant with Vectech Pharmaceutical Consultants, Inc. (Farmington, MI),

Submitted: Oct. 26, 2006. Accepted: Dec. 11, 2006.

Keywords: qualification, USP, validation, verification

References

1. United States Pharmacopeia 29—National Formulary 24, United States Pharmacopeial Convention, (2006).

1. Pharmacopeial Forum 32 (2), 595–604 (Mar.–Apr. 2006).

3. Webster's Seventh New Collegiate Dictionary. (G. & C. Merriam Co., Springfield, MA, 1965).

4. International Conference on Harmonization Harmonized Tripartite Guideline, Validation of Analytical Procedures: Text and Methodology, (ICH, Geneva, Switzerland, 2005).

5. FDA, Center for Drug Evaluation and Research, Guidance for Industry: Analytical Procedures and Methods Validation Chemistry, Manufacturing, and Controls Documentation, (Rockville, MD, Aug. 2000).

6. FDA, Center for Drug Evaluation and Research, Guideline on General Principles of Process Validation, (Rockville, MD, May 1987).

7. FDA, Center for Biologics Evaluation and Research, Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, (Rockville, MD, Sept. 2006).

8. FDA, Office of Regulatory Affairs, Guide to Inspections of Pharmaceutical Quality Control Laboratories, (Rockville, MD, July 1993).

9. Pappa et al., "Development of a New USP General Information Chapter: Verification of Compendial Procedures." Pharm. Technol. 30 (3), 164–169 (2006).

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