GUIDELINE TO CLEANING VALIDATION

By – Mr. R.M. Gupta ; Mr. Vishnu P. Choudhari ;

(Perfect Pharmaceutical Consultants Pvt. Ltd. Pune)

(Maharashtra Institute of Pharmacy, Pune)

Contact www.perfect-consultants.com for ready to use Validation Protocols at an affordable price.

Validation of cleaning procedures has generated considerable interest to avoid adulteration or cross contamination in Bulk drugs, Pharmaceutical formulations, Biotechnology product and in Microbiological processes etc.

Benefits associated with validation

1	Identification and correction of potential problem previously unidentified, which could compromise safety, efficacy or quality of subsequent batches of drug product processed with the Equipments.
2	Prevention of serious problems arising from cross contamination

GENERAL CLEANING METHODS AND CONCEPTS

Methods used for cleaning may be classified as

· Manual cleaning procedure,

· Semiautomated procedure,

· Fully Automated procedure (CIP system).

Steps Involved in Manual cleaning procedures: -

1	Equipment disassembly (If required)
2	Pre-washing inspection
3	Washing
4	Initial rinse
5	Final rinse.
6	Reassembly (If required)

Steps Involved in Semiautomated cleaning process (cabinet type stationary machines with plumbed utilities)

1	Loading of cleaning agents in the machine
2	Automatic cleaning of the vessels
3	Unloading of excess cleaning agent from the machine

Steps involved in Fully Automated cleaning procedures:-

Used mostly for cleaning of large stationary piece of equipment’s.

1	DQ,IQ,OQ , PQ of CIP system.
2	PQ for cleaning Process Sampling consideration i.e. Addition of sampling port maybe required for ease of sampling of wash or rinse fluid. Pause capabilities may have to be changed or added to the cleaning program to allow inspection and / or sampling.
3	Material supply:- Fully automated system require hard plumbed supply lines and tank for water, cleaning agents, acids or bases etc
4	Actual automated cleaning

General cleaning procedure and systems (Pre-validation Verification)

Before switching to actual cleaning validation one should insure that the cleaning procedures, controls & documentation systems are logical, controlled & properly documented. Therefore cleaning procedure must consistently meet the limits set. The steps taken for these are,

A) Documentation & Tractability :-

This includes -

1	Identification of equipment
4	Cleaning Equipment’s should be suitably calibrated wherever required, cleaned and maintained and SOPs made available for the same.

B) Utilities Used: -

Utilities like WFI, D.M. Water, Compressed air should be qualified and operated as specified.

C) Control of cleaning material: -

Production or Purchase, testing & use of cleaning material should be effectively

Controlled to ensure reproducibility in the cleaning, these materials include

Solvent, cleaning agents, ancillary utilities like steam compressed air, potable

Water, scrubbing agents, etc.

1

Solvent : Water is a primary solvent required & quantity of water in cleaning use will depend on purpose. Minimum water quantity required for the given steps have to be clearly specified. The water system itself should be qualified and operated as per established (validated) procedures. Source & quality of non-aqueous solvent where used should be controlled & should be used only if absolutely necessary due to their safety, cost & environmental considerations.

2	Cleaning Agents: - Use of these agents introduce another potential contaminant that must be removed by the cleaning procedure. Control of composition of cleaning agent is difficult as commercial preparations are proprietary and compositions are changed without user’s knowledge. Now a days trend is to manufacture the cleaning agent in house for in house use.
3	Ancillary utilities: - Steam under pressure, compressed air is used to aid in or facilitate cleaning & should be free from particulate matter, oil, microbes & other potential contaminants.
4	Scrubbing Agents: - Removal of residual actives from the encapsulation machines is better achieved by running placebo formulation. Placebo formulation to be used should be clearly identified & quality or Raw material used should be adequately controlled.

D) Control of ancillary tools & equipments for cleaning:-

1	Cleaning Tools:- Brushes, rags , sponges and other cleaning tools should be selected to avoid contamination. Appropriate cleaning method for these tools should be evaluated & followed to avoid contaminant being introduced due to use of these materials.
2	Cleaning Equipment:- Equipment should be maintained, calibrated & controlled as like processing equipment & should be subject to routine maintenance & calibration.

E) Frequency of Cleaning :-

1	Cleaning between batches of same product & strength or ascending strength (provided color is same):- This is also called type ‘A’ cleaning provided non-aqueous solvents not used for cleaning or for product is not non-aqueous. When the cleaning process is used only between batches of same product the firm need only meet criteria of “visibly clean” for the equipment. Such between batch cleaning do not require validation
2	Cleaning during change over of product with different actives, color, descending potency, and after not more than ‘6 ‘ times “A” type of cleanings,
3	Cleaning after maintenance
4	Cleaning after accidental contamination
5	General criteria can be summarized as – “ Minor cleaning for same product “or “Major cleaning for different product”. Also the manufacturer may have one process for removing water-soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios.

Validation Protocol: - This shall include

1	Scope and objectives
2	Introductory information of background
3	Actual procedure
4	Results
5	Normal and Statistical Analysis of results
6	Acceptance criteria
7	Validation Report

Equipment cleaning validation may be performed either after normal use of

equipment for desired product or by chanllenging the cleaning procedure by

deliberately contaminating the equipment.

Cleaning limits :

Limits for the following contaminants may be set:

· Active Ingredient

· Excipients used in the formulation

· Residues of the cleaning agent

Analytical Method:- Method developed:

* Should be able to detect the substance/ingredient selected for cleaning

evaluation and its some of major degradation products.

* The same shall be fully validated.

Acceptance Criteria:- There are many basis for establishing limits for

cleaning processes. Some of them are:-

1	Based on medical dose
2	Based on toxicity
3	Based on analytical delectability
4	Based on process capability of the cleaning process
5	Microbial Load on the cleaned container
6	No of particles recovered from the cleaned equipment

Evaluation:- Following methods can be used

1	Swab sampling
2	Rinse sampling
3	Placebo samples
4	Visual Evaluations

Microbiological contamination:-

This type of contamination has concern in sterile as well nonsterile formulation. Poor cleaning process lead to increased bioburden and pyro-burden, which have serious concern with use of such equipments.

Unlike residual actives and cleaning agent’s, microbes have capacity to proliferate on the poorly cleaned surface therefore matter of prevention is of more concern.

Time limits allowable between process end and start of cleaning must be specified. Cleaned equipment should be protected from subsequent microbial contamination.

Particulate matter contamination:- Smaller visible particles and microscopic particle are of concern for parentral and ophthalmic preparations. To avoid presence of such particles with the cleaned equipments final rinse solvent should be appropriately filtered.

For evaluation of particulate matter load with cleaned container, standard procedures should be used e.g. microscopic evaluation, electronic particular counters (Coulter Counter), etc.

Revalidation:- Revalidation need for these cleaning validation arises due to various reasons. One reason is to perform routine validation based on time period elapsed after validation. But more pragmatic and practical approach is to revalidate for cause. And this links revalidation to change control in an important way. These incidences where revalidation required are:

1	Change in processing equipment
2	Significant changes in cleaning equipment used to clean the processing equipment
3	Change in cleaning agent(s) used
4	Change in cleaning procedure
5	Change in location of the equipment

__________________________________________________________________

This Article is brought to you by Perfect Consultants (India), for more detailed information please visit our site at:

1) www.perfect-consultants.com

2) www.perfect-consultants.com/services.html

3) www.perfect-consultants.com/products.html ( For ready to use protocols)

Or email us at

info@perfect-consultants.com , gupta1@vsnl.com

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

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.

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.”