Sunday, 26 August 2007

Panel opposes site-specific data, backs process validation.(Food and Drug Administration's Advisory Committee on Pharmaceutical Science)

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Validation Times , 09/01/1999 1 6

Panel opposes site-specific data, backs process validation.(Food and Drug Administration's Advisory Committee on Pharmaceutical Science)(Brief Article) Reid, Ken *~|~*

COPYRIGHT 1999 Washington Information Source


A special subcommittee of FDA's Advisory Committee on Pharmaceutical Science Sept. 22 sided with industry in recommending against site-specific stability studies for new and generic drugs, but said the three-tiered method FDA proposed in March could be an alternative to process validation. The panel, meeting in Rockville, MD, agreed that process validation could supplant stability testing for each site where a drug is produced.
Charles Ireland, a CMC regulatory affairs manager at Sanofi Pharmaceuticals, attended the meeting and reported the panel's findings to an Institute for International Research (IIR) conference in Bethesda, MD, the same day.
He said that in lieu of site-specific shelf-life testing, companies could:
1. Obtain a certificate of analysis or the equivalent for validation batches.
2. Certify that they have successfully completed validation.
3. Note any changes in regulatory in-process controls.
4. Follow complete ICH stability requirements at the time they file an NDA, BLA or ANDA.
5. In the case of innovator products, present data in their submission three months prior to the user fee "action date," in the first year of the FDA guidance; two months prior in the second year of the guidance and one month prior to the action date in the document's third year and beyond.
Ireland said the requirements would address both the drug substance and drug product. However, FDA is not going to require the submission of a "Validation Report," which is submitted for European Union (EU) clearance.
FDA gave no inkling when a final stability guidance would be issued.
The original guidance was released in June 1998 and the three-tiered site-specific stability compromise the agency offered to industry was issued in March (See May issue, page 1).
At the IIR meeting, Frank Diana, director of analytical technology for DuPont Pharmaceuticals, advised companies to keep copies of the 1998 document, which contain "very helpful tables" describing stability studies needed for a variety of post-approval changes, including packaging.
Diana said the only reason FDA is canning the tables in the final guidance is because they repeat diagrams found in Scale-Up Post-Approval Changes (SUPAC) guidance.
Diana also said the final stability guidance will not allow companies to reduce shelf life on products without stability data.
He also said FDA will require mean kinetic temperatures -- high and low values for the week -- for each site where drugs are stored, not just where they are manufactured.
Diana contended FDA also will want stability data for physician samples and Phase III drugs, though the latter requirement is still being disputed by the industry.
Diana's presentation, including examples of 483 citations for stability problems, is available along with other conference material for a packaged rate of $50 plus retrieval (Doc. 110020R).

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Out-of-spec results cast doubt on API validation.(active pharmaceutical ingredient validation

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Inspection Monitor , 12/01/1998 3 12

Out-of-spec results cast doubt on API validation.(active pharmaceutical ingredient validation, Rhone-Poulenc Rorer Inc.)(Brief Article)

COPYRIGHT 1998 Washington Information Source


Rhone-Poulenc Rorer, Holmes Chapel, UK. Two of FDA's favorite themes B validation and out-of-specification results B elicited a brief 483 to Rhone-Poulenc Rorer>s aerosol and active pharmaceutical ingredient (API) plant in Holmes Chapel, UK.
Investigator Eric Weilage of the Atlanta District Office and microbiologist Ronald Crawford of FDA's Southwest Research Lab considered a series of rejected batches of Tilade (nedocromil sodium 2 mg) inhalers an indication that the system was not validated. The batches were rejected due to Ahigh out-of-specification@ test results, according to the EIR.
The recently released records from the April 1997 audit said the out- of-spec results in-volved medication delivery and dose uniformity.
The company had conducted an Aextensive@ but unsuccessful investigation to identify the cause of the out-of-spec results. Management promised to conduct further investigation, ac-cording to the EIR.
The firm fared better in the other areas covered in the audit. Among these were the API manufacturing equipment and facilities, new equipment and related validation, complaints, cleaning validation and failure investigation reports, plus microbiology lab equipment, procedures and test results. The most recent process validation showed no significant deficiencies, the EIR said.
An investigation into problems with a different product, whose identity was purged from the records, had led to a recall in 1996. But, in that case, FDA termed the company's investigation not only Aextensive@ but Aadequate,@ according to the EIR. A quality improvement program resulted from the firm's findings, the report added.
A new chemical operations building was not covered during the inspection, since it was still under construction and its validation was not complete.
As of deadline, it could not be determined whether the company was able to track down the cause of the Tilade rejects or whether the compa-ny was able to close the issue with FDA.
Rhone-Poulenc Rorer, Holmes Chapel, UK, 4/1-4/97, Doc. 108526M, $4.50 plus retrieval.

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Validation of PLC software. (automation in the pharmaceutical industry)

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Control and Instrumentation , 05/01/1995 v27 n5

Validation of PLC software. (automation in the pharmaceutical industry) Wootton, Paul *~|~*

COPYRIGHT 1995 Centaur Publishing Ltd.


How do you go about validating a PLC system in the pharmaceutical industry? When a pharmaceutical manufacturer realises that validation of either an existing or new computer system is required, and enters into a contract with a supplier, it's important that a working relationship is established. This has to be more than a mere purchase order supply agreement, and has to account for the needs and responsibilities of both parties.
Validation is the documented evidence that a process or system does what it's supposed to do. In the pharmaceutical industry, this means that a process must manufacture the final product within established limits and specifications and that each step of the process be recorded. A computer system which controls the process must operate in a manner that will maintain these product specifications.
This is often thought to extend from the generation of the functional design specification (FDS) through to what is often called a site acceptance test (SAT) of hardware and software (provided by the supplier, based on the functions in the FDS). The requirements to withstand a regulatory body (FDA/MCA) inspection do, however, go much deeper than this.
For pre-qualification, the specification and design criteria for the system must include: a description of the purpose of the system; a list of the functional requirements; normal operating parameters; operational limits; back-up procedures; report formats; security provision; MMI; hardware; PSU specs; and operational environment.
The system description must refer to the final version to be installed (new systems) or to that which is currently being used (existing). All the hardware and peripherals should be listed, together with their equipment numbers and, for software, the data storage requirements and back-up procedures defined. The applicable version of the operating system and application programs must be stated by name and programming language. A schematic of the system should also be included.
An installation qualification verities that hardware, and its installation, meet the specification and design. It should include: hardware installation; power supply; integrity of communications; environmental conditions; security; maintenance; and installation drawings.
Get the evidence
Meanwhile, the operational qualification provides evidence that the system performs as designed. It includes: test equipment; standard operating procedures (SOPs); product application; software identification; software functions; and SOP verification and compliance. There's also: start-up, shut-down and menu selection test; interlocks; testing the computer with normal and abnormal demands and worst-case conditions (at the data handling limits); environmental conditions; and back-up procedures.
The system should be subjected to a series of tests designed to confirm that it will reliably and reproducibly carry out the tasks for which it was designed. These should include: software control routines; data integrity; system capacity (that it's able to operate under worst-case situations); and power failure (effects and action).
Any audit by regulatory bodies, for example the FDA, would begin with a systems overview, a look at environmental factors (physical location, EMC, shielding) before moving on to the major areas of validation. This is where records and documentation are critical to achieve a successful audit.
Many companies use third party consultants for validation. This need not be necessary if a user chooses a systems provider that understands the concepts of validation and has a quality plan (evidenced by ISO9001).
RELATED ARTICLE:
* Silvertech uses two checklists:
* Computer hardware/software validation requirements, based on information from Validation of automated systems in pharmaceutical manufacture, from the PICSVF/ISPE
* A validation programme, taken from the Guide to inspection of computerised systems in drug processing, from the US Food and Drug Administration.
Paul Wootton is with Silvertech.

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Paco hit on OOS testing, process validation errors.(Paco Pharmaceutical)

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Validation Times , 11/01/1999 1 8

Paco hit on OOS testing, process validation errors.(Paco Pharmaceutical)(Brief Article)

COPYRIGHT 1999 Washington Information Source


New Jersey District Office investigator Paul Bellamy's inspection of Paco Pharmaceutical's plant in Lakewood, NJ, unearthed five problems that filled out a one-page 483. However, the firm apparently dodged a warning letter with its response to Bellamy's observations. The inspection, conducted from July to August 1998, revealed several problems with validation of the firm's packing and processing of prescription and OTC drugs. The 483 opened with a citation for failure to validate manufacturing processes for a drug the name of which was redacted. The problem was demonstrated by out-of-specification benzoyl peroxide (BP) content.
The EIR stated that the firm had employed "downscale batch sizes" and company procedures called for one batch to be tested. However, Bellamy insisted that three batches at each strength would need to be evaluated.
In 1998, the firm changed the proportion of BP in two products, but failed to validate the change in formulation. Three of four lots of drugs based on the new formulation were rejected, but apparently went on the market.
Firm agrees to 3-batch validation
The firm's response, dated Sept. 15 and signed by Director of Quality Assurance Abraham More, indicated that the scaled-down batch size would no longer be employed and that, were the procedure to be reintroduced, the firm would draw "three consecutive validation batches for each concentration ...supported by the appropriate stability studies." More also said retained samples of the four lots in circulation were tested and met specifications.
Paco was cited with a three-part observation on the 483 concerning how it documented the handling of OOS results. According to the 483, one lot of an unnamed drug tested OOS twice, which the firm "attributed to laboratory error and the sample was retested and in-specification results were obtained." The 483 stated that the firm lacked validation data supporting the re-work procedure and that documentation was insufficient to invalidate the OOS results of the first two tests.
The EIR noted that the batch in question had been mixed for 90 minutes. Paco's SOPs called for a minimum mix time of one hour, but no maximum was designated. However, there was no data implying whether a mixing time in excess of one hour was detrimental to the mix.
Paco's response indicated a change in procedures to address the documentation deficiencies.
Another lot that tested OOS was passed along as well after a second evaluation. The firm concluded in this case that the problem was with the high-performance liquid chromatography column.
The EIR noted, however, that the difference between the OOS and the in-spec results was only .002%, which Bellamy said was indicative of a column that was "working consistently before and after the re-conditioning."
Paco's response indicated that a new column would be used in "similar future situations." The firm nonetheless insisted that a "split-peak" indicated that the column had been compromised and that the inversion and back-flushing of the column was "a common and acceptable practice."
Another instance of OOS results was attributed to "the age of the standard," which the firm replaced. The fresh standard passed the batch, but the EIR noted that there was no documentation indicating that the old standard was compromised.
FDA cited Paco for a cleaning procedure "that could not be validated." The 483 stated further that "the acceptance criteria for conductivity and residue limit could not be met." The EIR provided no additional detail.
The firm's response stated that the filler "met the acceptance criteria for active drug substance in rinse water samples; however, two of the rinse water samples did not meet the requirement for conductivity after rinsing for 15 minutes and two of the swab samples did not meet the requirement for active drug substance." The letter stated that a "re-clean" brought all results up to acceptance criteria. Paco also promised to revalidate the cleaning "during the next scheduled production."
The second cleaning validation citation was likewise lacking detail in the inspection records. The 483 and the EIR noted only that the firm lacked validation data "to support the adequacy of the cleaning procedures" for a filler, filter housing and transfer lines after a 3% Trypticase Soy Broth media fill run.
Paco said its cleaning procedures allowed filters to stay in place during cleaning. After removing the filters, cleaning efforts met acceptance criteria, but the firm noted that, "since the equipment was cleaned twice before acceptable results were obtained, the process is not considered validated."
Paco indicated that its SOP would be revised to call for "purging of the cleaning agent through air-operated valves during the cleaning cycle," which the letter stated was a validated method. Similarly, the letter promised that "a protocol will be developed to validate the cleaning of media from the filter housings and transfer lines prior to the next scheduled media fill."
Paco Pharmaceuticals, Lakewood, NJ, 7/13-17, 20-23, 27, 30, 31, & 8/3, 4, 10, 12/98, Doc. 108732M, $6.00 plus retrieval.
RELATED ARTICLE: The Checklist - Paco, New Jersey District
* OOS
* Cleaning validation
* Process validation

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Panel opposes site-specific data, backs process validation.(Food and Drug Administration's Advisory Committee on Pharmaceutical Science)

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Validation Times , 09/01/1999 1 6

Panel opposes site-specific data, backs process validation.(Food and Drug Administration's Advisory Committee on Pharmaceutical Science)(Brief Article) Reid, Ken *~|~*

COPYRIGHT 1999 Washington Information Source


A special subcommittee of FDA's Advisory Committee on Pharmaceutical Science Sept. 22 sided with industry in recommending against site-specific stability studies for new and generic drugs, but said the three-tiered method FDA proposed in March could be an alternative to process validation. The panel, meeting in Rockville, MD, agreed that process validation could supplant stability testing for each site where a drug is produced.
Charles Ireland, a CMC regulatory affairs manager at Sanofi Pharmaceuticals, attended the meeting and reported the panel's findings to an Institute for International Research (IIR) conference in Bethesda, MD, the same day.
He said that in lieu of site-specific shelf-life testing, companies could:
1. Obtain a certificate of analysis or the equivalent for validation batches.
2. Certify that they have successfully completed validation.
3. Note any changes in regulatory in-process controls.
4. Follow complete ICH stability requirements at the time they file an NDA, BLA or ANDA.
5. In the case of innovator products, present data in their submission three months prior to the user fee "action date," in the first year of the FDA guidance; two months prior in the second year of the guidance and one month prior to the action date in the document's third year and beyond.
Ireland said the requirements would address both the drug substance and drug product. However, FDA is not going to require the submission of a "Validation Report," which is submitted for European Union (EU) clearance.
FDA gave no inkling when a final stability guidance would be issued.
The original guidance was released in June 1998 and the three-tiered site-specific stability compromise the agency offered to industry was issued in March (See May issue, page 1).
At the IIR meeting, Frank Diana, director of analytical technology for DuPont Pharmaceuticals, advised companies to keep copies of the 1998 document, which contain "very helpful tables" describing stability studies needed for a variety of post-approval changes, including packaging.
Diana said the only reason FDA is canning the tables in the final guidance is because they repeat diagrams found in Scale-Up Post-Approval Changes (SUPAC) guidance.
Diana also said the final stability guidance will not allow companies to reduce shelf life on products without stability data.
He also said FDA will require mean kinetic temperatures -- high and low values for the week -- for each site where drugs are stored, not just where they are manufactured.
Diana contended FDA also will want stability data for physician samples and Phase III drugs, though the latter requirement is still being disputed by the industry.
Diana's presentation, including examples of 483 citations for stability problems, is available along with other conference material for a packaged rate of $50 plus retrieval (Doc. 110020R).

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Validation plans touted for water, but SOPs needed.(water quality standards for pharmaceutical industry)

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Validation Times , 12/01/1999 1 9

Validation plans touted for water, but SOPs needed.(water quality standards for pharmaceutical industry)(Brief Article) Dechnik, Peter *~|~*

COPYRIGHT 1999 Washington Information Source


PHILADELPHIA -- Validation master plans can help pharmaceutical firms deal with water and other utilities problems, and not just to meet FDA or USP requirements, firms were advised here Dec. 7. There is still no sign of FDA's draft guidance on water, which is being overseen by the Center for Biologics (See Guidance Tracker, page 18).
However, at ISPE's winter conference here, manufacturers learned that not only FDA, but non-U.S. regulators, are becoming concerned about water quality.
"FDA sees water as a raw material like sucrose, lactose or any other ingredient in your drug," said Rosty Slabicky, manager of systems validation at Boehringer Ingelheim, Danbury, CT. "The FDA inspector will ask the source of your water. How do you know it's drinking water? Does it comply with established standards?"
Because FDA looks at water primarily from a microbial aspect, Slabicky advised QA personnel to "take a few courses in microbiology. You will have fewer headaches later."
He noted that if USP standards do not apply to a firm's situation, then the firm must create its own standards, as explained in the USP introduction. "FDA will check your water according to your documented standards," Slabicky explained. "If you have knowledgeable people making knowledgeable decisions, the worst the FDA will say is that you made a mistake."
SOPs needed
Validation of the water system must show that SOPs are valid and that the system can consistently produce water meeting the desired specifications. The system must also be able to handle seasonal variations in feed water.
"You should have at least a draft SOP in place before you validate," Slabicky said. "You can't rely on a shelf full of validation texts." He also stressed that validation is distinct from commissioning, saying: "You don't want validation people out in the field inspecting the welds on water pipes."
The water sampling SOP is critical and should include training of the sampling personnel. He decried companies that believe "if the sample is wrong, fire the sampler." He said: "Suppose the sampler must stand on a rickety seven-foot ladder to obtain a sample from a water pipe and you didn't know he's afraid of heights."
Patricia Stewart-Flaherty, validation manager at Bayer, Clayton, NC, emphasized that a validation master plan for an overseas facility may need to comply with not only FDA standards, but also with those of the U.K.'s Medicines Control Agency or other European Union (EU) auditors.
She advised that a master plan be created for a facility that is about halfway through the design stage. "I've often sat down with regulators to review our master plan and identified potential problems," Stewart-Flaherty said.
The master plan should identify the persons responsible, not the entire facility. "Be sure to include the names of individuals to satisfy CFR 211.25 personnel qualifications," she said.
Stewart-Flaherty recommended that the master plan include floor plans of the facility, equipment location, flow diagrams and product flow. "Use plenty of color. Remember, you may need to make a presentation to a regulator."
She said that a master plan for a new facility or system could be created in two or three months, but that prior preparation was essential. "If you begin two or three years ahead of time, you can do a better job of blocking out the time for everyone," the executive added. "You can expect production people to say they're too busy to spare enough time."
The presentations on water are $20 plus retrieval, Doc. 110119R.

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CytoGenix Announces Introduction of Drug Target Validation Services for the Pharmaceutical Industry

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Business Wire , 05/17/2002

CytoGenix Announces Introduction of Drug Target Validation Services for the Pharmaceutical Industry.

COPYRIGHT 2002 Business Wire


Business Editors/Health & Medical Writers HOUSTON--(BUSINESS WIRE)--May 17, 2002
CytoGenix Inc. (OTCBB:CYGX) announces the introduction of a new Drug Target Validation service geared to reducing drug discovery time and money. Using its proprietary single stranded DNA expression technology, CytoGenix offers results in weeks rather than months. The Company operates under GLP quality standards and guarantees customer satisfaction.
"We know that target validation is critical to the continued success of pharmaceutical companies. The market potential for target validations is significant. Our market research indicates that the industry is spending at least $500 million for these services currently," states Malcolm Skolnick, CytoGenix president and CEO. "We have structured our offering very simply as a contract service. There are no licensing fees, no milestone payments and no complex equity deals. We will down regulate genes of interest for a fee. And as with any other business, we expect to attain economies of scale in our labs as customers provide us with multiple projects."
Yin Chen, Ph.D., CytoGenix vice president of research and development, adds "Our expression system is very efficient and we have achieved ranges between 50-95% down-regulation of proteins. We are working towards improving this by optimizing our conditions and expanding applications to different cell lines."
CytoGenix Inc. is a Houston-based biopharmaceutical company that develops and markets innovative products and services based on its proprietary ssDNA expression technology. CytoGenix currently has one issued US patent and 36 international or US pending patent applications claiming methods and materials in connection with this platform technology.
SAFE HARBOR: Except for statements of historical fact, the statements in this press release are forward-looking. Such statements are subject to a number of risks and uncertainties that could cause actual results to differ materially from the statements made. These factors include, but are not limited to, general economic conditions, risks associated with the acceptance of new products, competition, and other factors more fully detailed in the company's filings with the Securities and Exchange Commission. Additional information about CytoGenix and its technology can be found on the Web site at www.cytogenix.com.

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CytoGenix Announces Introduction of Drug Target Validation Services for the Pharmaceutical Industry

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Business Wire , 05/16/2002

CytoGenix Announces Introduction of Drug Target Validation Services for the Pharmaceutical Industry.

COPYRIGHT 2002 Business Wire


Business Editors/Health & Medical Writers HOUSTON--(BUSINESS WIRE)--May 16, 2002
CytoGenix Inc. (OTCBB:CYGX) announces the introduction of a new Drug Target Validation service geared to reducing drug discovery time and money. Using its proprietary single stranded DNA expression technology, CytoGenix offers results in weeks rather than months. The Company operates under GLP quality standards and guarantees customer satisfaction.
"We know that target validation is critical to the continued success of pharmaceutical companies. The market potential for target validations is significant. Our market research indicates that the industry is spending at least $500 million for these services currently," states Malcolm Skolnick, CytoGenix president and CEO. "We have structured our offering very simply as a contract service. There are no licensing fees, no milestone payments and no complex equity deals. We will down regulate genes of interest for a fee. And as with any other business, we expect to attain economies of scale in our labs as customers provide us with multiple projects."
Yin Chen, Ph.D., CytoGenix vice president of research and development, adds "Our expression system is very efficient and we have achieved consistent knockdown in the 50% range. We are working towards improving this by optimizing our conditions and expanding applications to different cell lines."
CytoGenix Inc. is a Houston-based biopharmaceutical company that develops and markets innovative products and services based on its proprietary ssDNA expression technology. CytoGenix currently has one issued US patent and 36 international or US pending patent applications claiming methods and materials in connection with this platform technology.
SAFE HARBOR: Except for statements of historical fact, the statements in this press release are forward-looking. Such statements are subject to a number of risks and uncertainties that could cause actual results to differ materially from the statements made. These factors include, but are not limited to, general economic conditions, risks associated with the acceptance of new products, competition, and other factors more fully detailed in the company's filings with the Securities and Exchange Commission. Additional information about CytoGenix and its technology can be found on the Web site at www.cytogenix.com.

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New Target-Validation Technologies Will Help Pharmaceutical & Biotech Companies Achieve Profitability Goals

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Biomedical Market Newsletter , 05/31/2001 11 5

New Target-Validation Technologies Will Help Pharmaceutical & Biotech Companies Achieve Profitability Goals.

COPYRIGHT 2001 Biomedical Market Newsletter, Inc.


NEWTON UPPER FALLS MA -- Target validation, experts agree, is pivotal to the survival of pharmaceutical and biotech companies seeking to pump up pipelines and improve efficiency through genomics. To meet this need, a growing range of increasingly productive approaches are being considered.

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Exten Industries Inc. Reports Pharmaceutical Validation, Commercialization, Record Revenues and Moves beyond Development Stage Classification

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Business Wire , 04/14/2003

Exten Industries Inc. Reports Pharmaceutical Validation, Commercialization, Record Revenues and Moves beyond Development Stage Classification.

COPYRIGHT 2003 Business Wire


Business Editors/Health/Medical Writers WARWICK, R.I.--(BUSINESS WIRE)--April 14, 2003
Exten Industries Inc. (Exten) (OTCBB:EXTI) released consolidated financial results for its fiscal year ended Nov. 30, 2002.
Most significant is growth in revenues to over $800,000 for the year, causing the company's independent accountants, J.H. Cohn, LLP to remove its Development Stage Company classification. The company's revenues have been steadily increasing since their one-year R&D agreement with Pfizer Inc. (NYSE:PFE) in 2001 and 2002. As a result, the independent accountants have deleted the cautionary wording in its filings with the SEC.
"We are delighted that the company's proprietary human liver cell lines being delivered to major pharmaceutical companies are meeting their research requirements and expectations. As the drug discovery market develops and gains momentum, we can begin to focus on other applications for the company's cell lines," Jerry Newmin, chairman and chief executive officer stated.
Greg Szabo, president of Exten, added, "We are very pleased to progress to the commercialization phase by providing a vital product to the pharmaceutical industry. We believe that our human liver cells will become the 'gold standard' for testing of new compounds in the drug discovery process. Exten is currently in discussions with several additional pharmaceutical firms that are testing Exten's liver cell lines with positive results. We anticipate new purchase commitments within the next two quarters."
Exten provides pharmaceutical companies with liver cells for drug discovery through its subsidiary, MultiCell Technologies Inc. (MultiCell). The importance of using actual human liver cells for testing is the potential reduction in both cost and time to market: According to the Pharmaceutical Research and Manufacturers of America, an industry trade group, only one in 5,000 compounds tested in the laboratory becomes a new drug, and it takes an average of 12 to 15 years to bring a drug to market, at a cost of over $500 million.
MultiCell intends to develop its own cell based toxicological and drug screening tests. MultiCell is also investigating its highly specialized immortalized liver cell lines for various diagnostic and therapeutic uses, including the production of therapeutic proteins and liver stem cell transplantation. MultiCell's liver cells may also be utilized in applications such as Exten's Sybiol(R) synthetic bio-liver device.
Exten's Xenogenics Corp. subsidiary is still in the R&D phase with the Sybiol(R) synthetic bio-liver. The company believes its Sybiol(R) bio-liver device and other competitive liver assist devices will be optimized by the use of MultiCell's liver cells.
Exten is headquartered in Warwick, Rhode Island. Past news and more information are available on Exten's Web site, http://www.exten.com.

The matters set forth in this press release are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially. These risks are detailed from time to time in the company's periodic reports filed with the Securities and Exchange Commission including the company's Annual Report, Quarterly Reports and other periodic filings. These forward-looking statements speak only as of the date hereof. The company disclaims any intent or obligation to update these forward-looking statements.

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Pharmaceutical Cleaning Validation & Sterilization

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Medical Industry Employment Opportunities , 02/28/2003 9 4

Pharmaceutical Cleaning Validation & Sterilization.

COPYRIGHT 2003 Biomedical Market Newsletter, Inc.


Pharmaceutical Cleaning Validation & Sterilization
<pre>
Job Order #03049 DIA
Pharmaceutical Company
England (Basingstoke)
Provide innovative, fast solutions for cleaning validation
issues in pharm industry &amp; other HC environments.
10 yrs exp in pharm validation as in-house
technical authority. Send resume w/cover letter.
Susan Botfield
Steris
Melon Ground Hatfield Park, Hatfield Herts
Basingstoke
AL9 5NB England
011-44 1707 259333 phone
011-44 1707 271366 fax
rsvp@pharmarecruit.com </pre>

http://www.pharmarecruit.com

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Validation, Bio/Pharmaceutical

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Medical Industry Employment Opportunities , 12/21/2001 7 23

Validation, Bio/Pharmaceutical.

COPYRIGHT 2001 Biomedical Market Newsletter, Inc.


Validation, Bio/Pharmaceutical
<pre>
Engineering, Construction &amp; Validation Co
Knowledge of cGxPs, strong communic, organiz &amp;
problem-solving skills. BS in engr/sciences/knowl
of bio/pharmaceutical operations &amp; uS/anti regulatory
&amp; pharm reqmts. Send resume w/cover letter.
Director of Human Resources
Kvaerner E&amp;C
440 Rte 22 E
Bridgewater NJ 08807-6884
908-429-9010 fax
njohr@kvaerner.com </pre>

http://www.kvaerner.com

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The validation of a rapid sterile transfer port (RsTP) system used in barrier filling lines

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Pharmaceutical Technology , 05/01/2003 27 5

The validation of a rapid sterile transfer port (RsTP) system used in barrier filling lines: an improved strategy for materials handling in the pharmaceutical industry. Tingley, Stephen *~|~*Baloda, Suraj *~|~*Belongia, Brett *~|~*Liepold, Gerhard *~|~*

COPYRIGHT 2003 Advanstar Communications, Inc.


Material transfer into Class A filling environments is one of the most common causes of aseptic processing failure. The authors in this paper review the challenges and options for material transfers, including a new UV light-based technology. **********
Material transfer into Class A filling environments has been identified as one of the most common causes of aseptic processing failure. Traditional filling facility design layout has placed the filling machine in a Class B environment. Process operations require that sterile materials be transferred across the B environment to the Class A filling area. Keeping such a filling line supplied with components requires numerous operator interventions that present a contamination risk.
In recent years, the development of barrier-isolator filling lines has made the challenge of supplying components to filling lines even more difficult. The most recent FDA draft concept paper on aseptic processing recognizes that it is not necessary to place a barrier-isolator inside a Class B environment provided that a validated materials-handling process is used. This article reviews the challenges and options for material transfers, including the validation of a new UV light-based rapid sterile transfer technology that reduces the risk of contamination from multiple material transfers into the Class A environment. By sterilizing the interface between the Class A and Class C environments, this system provides a secure method of material transfer and allows barrier-isolator lines to be placed in the significantly less costly Class C environment. This system, the rapid sterile transfer port system (RsTP), features a 3-min UV sterilization cycle that provides validation at!
the point of transfer. The UV light-based system design is more robust, reliable, and easily validated than previous applications of UV sterilization in the pharmaceutical industry.
The challenges of sterile material transfer
The heart of any liquid parenteral final fill-and-finish operation is the filling machine. The filling machine is a conveyor system responsible for bringing empty sterilized containers, glass vials, and syringes from a sterilization tunnel and delivering sterile filled and sealed parenteral dosage formats to a packaging line.
Certain dosage forms such as naked glass syringe barrels must be assembled before the drug solution is filled. Before the filling step, a sterile hypodermic syringe needle is assembled onto the glass syringe barrel, and the container is sealed closed. Rubber closures, in this case plunger tips, are delivered by a hopper-feed system.
The critical filling operations are identified as those in which sterile liquid, containers, and components are exposed to the environment before sealing. These operations are conducted in highly controlled Class A environments.
A recent Parenteral Drug Association (PDA) survey identified material transfer as a significant contributor to aseptic processing failure (Table I). In an 8-h shift, it is typical to supply 10,000 to 100,000 components to the filling area. The number of components transferred at any one time can range from 2000 to 5000, and a typical filling run of 100,000 containers would require an average of 20-50 transfers. Each time a transfer is made, there is an increased risk of elevated microbial challenge to the filling environment. Obviously, the more transfers that must take place, the greater the practical risk. Operators are the single-largest source of microbiological contamination within the aseptic filling core.
Current practices in managing sterile material transfer
There is a broad range of current practices and product technologies for managing sterile material transfer processes. The material transfer process depends largely on the details of facility design and manufacturing philosophy, which can be illustrated by two extreme examples: filling operations contained within a Class B cleanroom and those contained in a barrier-isolator filling operation.
Filling operations in the Class B cleanroom. In the first example, a Class B cleanroom uses wipe-and-pass methodology as the presterilized components are transferred from a Class C area into the Class B environment (see Figure 1). The primary concern with this transfer is to avoid contamination of the Class B room with particles or microorganisms. Wipe-and-pass transfer techniques using a small chamber between the staging area and the cleanroom are often implemented. An operator in the staging area removes a layer of protective packaging and/or wipes the external surface of the packaging with a cleaning and sanitizing agent. Once completed, the operator places the package in the chamber for passage to the cleanroom. An operator inside the cleanroom removes the transfer container containing the package and places it on a captive trolley.
[FIGURE 1 OMITTED]
The transfer container moves across the cleanroom to the Class A filling area. The challenge associated with this second transfer is double. The Class B environment has contaminated the external packaging of the components, so in transferring the sterile components, the operator again has to remove a layer of packaging and/or wipe down the external surface of the transfer container with a cleaning or sanitizing agent. The next task is to get the sterile components inside the Class A filling environment without compromising the sterility of the components or the environment immediately surrounding them. The component packaging cannot be opened in the Class B area because this would compromise the sterility of the components. Therefore, the operator has to partially enter the Class A environment. In some processes, the operator stops the filling operation, cuts open the container packaging, and replenishes the component feed hopper. By entering the Class A environment, the o!
perator is in close proximity to the sterile components and sterile liquid dispense heads, risking contamination. By bringing the nonsterile transfer container into the Class A environment, the operator also increases the microbiological challenge to the aseptic filling process.
Wipe-down procedures are subjective and, hence, are difficult to validate. Transfers of this type rely on quality operator training and accurate execution of standard operating procedures (SOPs). Risk increases with the number of transfer steps and the complexity of each. Each planned operator intervention must be included in the validation and re-validation of the media fill protocol. Sterility failure can be catastrophic; even failure during a media fill will result in significant extra work and lost production time.
Barrier-isolator filling operations
In the second example, barrier-isolator filling lines that have rapid transfer port (RTP) technology are used for the transfer of sterile materials. RTP technology uses a flexible or solid container to transfer the sterilized components. These containers must still be transferred from the staging area into dose proximity with the isolator. The materials are then transferred from the Class B environment to the isolator.
Alpha-Beta RTP systems are a two-component port system. The Alpha component is a stainless steel port that is set into the wall of the barrier and sealed by a plastic door. The Beta component is a stainless steel flange attached to the transfer container and sealed by a plastic door. Neither door can be opened unless the two components are docked together. The exterior door faces the room environment and is exposed to contaminants. However, the port-docking process seals the two nonsterile door faces together, which minimizes the risk of external contamination (see Figure 2).
[FIGURE 2 OMITTED]
The primary benefits of barrier-isolator systems that use RTP technology include the following:
* Operator manipulations are managed only through an isolator glove port.
* The need to introduce packaging materials into the isolator environment is eliminated.
Because of the primary benefits that RTP technology offers, it is widely considered to be state-of-the-art for a filling environment.
One significant limitation of RTP technology is that the transfer is aseptic rather than sterile. For the port to open, the canister cover must pass through the port opening. This opening action is facilitated by a small mechanical clearance between the outside diameter of the canister cover and the inside diameter of the port. This small exposed ring (termed the ring of concern) could contain contaminants. This risk was illustrated in 1995 by the Barrier User Group Symposium using the "toner test" in which copy machine toner was applied to the docking surfaces of the canister and port. The canister was docked to the port and the door was opened. When the port door was opened, two lines of toner were visible. One line appeared at the interface of the canister and port flanges, and the other line appeared at the interface of the port door and the canister cover (1). It is normal practice for the ring of concern to be sanitized with alcohol before starting a transfer to redu!
ce this risk.
Sterile materials handling, isolators, and future process design
Pharmaceutical manufacturing is increasingly requiring more process security, which includes minimizing or removing operator intervention in the process. This approach has increased regulatory and industry support for barrier-isolator filling line installations. This trend brings new challenges such as how to design component supply processes to feed a barrier filling line that ensures minimal risk and regulatory acceptance. FDA's preliminary concept paper, "Sterile Drug Products Produced by Aseptic Processing Draft" evidences this trend. Relevant conclusions of this concept paper include the following:
* Barrier-isolator filling lines appear to offer an advantage over classical aseptic processes.
* A Class 100,000 (Class C) background is appropriate for most manufacturing situations.
* The ability to maintain integrity and sterility of an isolator is affected by the design and use of the transfer ports.
A reasonable conclusion is that well-designed secure transfer port systems, which are vigorously validated, will facilitate the use of isolator filling lines in Class C environments. One solution for executing such a strategy is the RsTP. The major benefit of such systems over RTP systems is that the transfer is sterile rather than aseptic, and a sterile transfer interface is easily validated.
Overview of RsTP systems
One sterilizable transfer port uses the Alpha-Beta double-door design and addresses the ring of concern by integrating dry-heat sterilization into the Alpha port (see Figure 2). An electric heater is installed in the port flange, which heats this area to >200 [degree]C in 3 min. This temperature is maintained for 30 s followed by a 3-min cool down period. The double door is opened and a shield is moved into place. The purpose of the shield is to prevent damage to the components by the heated edges of the port.
More recently, a new UV light-based RsTP system has been introduced. This system is a double-door system, but does not depend on a mechanical rotating interlock. Operation of this RsTP system is simple. A filled, sterilized container is directly docked to the UV port (see Figure 3).
[FIGURE 3 OMITTED]
A simple molded collar, integrated into the flexible transfer container, is pushed into place and locked by a cam-and-pin system. The operator starts the 3-min UV sterilization cycle by pushing a button. This system uses flexible bags as the sterile transfer container. The components are sterilized inside sealed transfer containers using either gamma or autoclave sterilization.
Although the FDA preliminary concept paper "Sterile Drug Products Produced by Aseptic Processing Draft" leads us to a conclusion that RsTP systems are valuable tools in aseptic processing, it should be noted that in the concept paper, FDA questions the use of UV light as an acceptable sterilizing technology for transfer port technology. The authors of this article believe that a thorough review of UV science, past application, and rigorous validation of this technology is merited. The rest of this article is dedicated to a discussion of UV suitability, repeatability, and validatability as it applies to a UV light-based RSTP system.
Mechanism of ultraviolet sterilization
The biological effects of UV light and the mechanisms of action are well understood (2-5,8-10). The bactericidal effect of a low-pressure mercury UV lamp is a direct result of its emission wavelength intensity and the absorption by the bacterial cell's nucleic acid (4-5). The absorption of germicidal UV light interferes with the replication of DNA and RNA and consequently disrupts the normal cell function necessary for survival. Nucleic acids show maximum LTV absorption at wavelengths between 260 and 265 nm (11) with most nucleic acids showing a rapid decrease in UV absorption in the region of 290-315 nm (2).
UV irradiation has long been used as a fairly selective tool for causing cell damage. Understanding the effect of UV irradiation on the vital cellular processes also led to observation of the recovery of previously "dead" cells. The term photoreactiration describes this recovery of cells rendered nonviable by UV irradiation. It has been observed that the viability of irradiated Streptomyces griseus was increased 10-fold following storage for 1-2 days. Subsequent studies demonstrate that exposure to visible light was in part responsible for the photoreactivation. Experimentation showed that exposure of UV-irradiated suspensions of S. griseus to visible light resulted in an increased recovery of viability from 100,000- to 400,000-fold (3). The following three repair mechanisms may occur, depending on the organism:
Photoreactivation or photoenzymatic repair. DNA photolyase, activated by absorption of light between 300 and 500 nm, found in microorganisms and plants, is capable of binding and splitting dimmers (4). Exposure to light within 2-3 h after UV irradiation is required for recovery (7).
Excision repair. Found in most organisms, this repair mechanism is independent of the presence of light. Repair involves cleaving and excision of damaged DNA by nucleases followed by the synthesis of new DNA strands by means of a DNA polymerase (3,5).
Postreplication repair. Damaged DNA is replaced with a parental DNA sequence from either multiple replicate DNA or complementary DNA strands (3-5).
The cellular capacity for viability recovery may partially explain apparent discrepancies in laboratory results with respect to the use of UV light as a sterilizing source (3). This should be considered during validation study design.
Factors contributing to the success of UV sterilization
UV light has been widely used to control microbiological contamination (6). The most notable limitation has been the ability to develop applications where UV light can be reliably harnessed to provide sterilization that can be validated for use in the pharmaceutical industry.
Germicidal use of UV light has been implemented in the health industry for more than 60 years. In most of these applications the action of the UV light has been termed as sanitization or disinfection and rarely as sterilization. The major reason for this dichotomy rests with the choice of application. In almost every documented use of UV light for microbiological control, the target subject has been large in size or volume or distant and diffuse with respect to the UV source. Shechmeister provides an overview of how UV light has been used to sanitize air, surfaces, and water in the hospital, laboratory, and beverage manufacturer settings (6). In each of these applications the UV source has typically been mounted on walls or encased in quartz glass placed around the transport pipes (12). In these applications the intensity of the UV radiation, hence the killing power delivered to the target, is diminished. The distance between the sterilization target and the UV source, the!
presence of moisture, and particulate contamination combine to reduce the effectiveness and predictability of the UV dosage (13). These factors make sterilization unlikely and validation difficult.
UV sterilization in RsTP technology
The sterilization performance and validation of an RsTP system incorporating a UV sterilization source can be directly attributed to the design of the UV source and RsTP/barrier interface as an integrated system. The critical design characteristics of such a system must provide a consistent delivery of a known intensity of 254 nm of UV light.
The UV RsTP has been designed to meet these criteria. It consists of a sterilization port and a sterile transfer container (see Figure 4). The sterilization port is installed in the barrier--isolator wall and is sealed from the outside environment by an internal door. This door houses the UV sterilization source. The components to be transferred are sterilized in the transfer container bags by gamma, autoclave, or ethelene oxide sterilization.
[FIGURE 4 OMITTED]
In isolator applications, the port is sterilized by opening the UV door and inserting a plug in the open port. All internally exposed areas and the UV door are decontaminated during the vapor-phase hydrogen peroxide sterilization cycle of the isolator. The control systems of the port and isolator are linked, ensuring a full decontamination cycle has been completed. Once all the hardware is sterilized, the transfer system is ready for use.
A number of safety features, including a series of interlocks and alarms, prevent the inside of the isolator from being exposed to the outside environment by the premature opening of the door. Similarly, the UV sterilization cycle is closely monitored and alarmed and is stopped should an alarm condition occur. In such an event, the door cannot be opened. The sterile transfer container is removed from the port, and the alarm condition is corrected. Only at this stage can a new transfer cycle be initiated.
Designing a UV light sterilization interface for validation
Validation of the sterilizing capability of UV light was conducted by a direct microbiological challenge. To meet the validation requirement, the design of the RsTP system needed to ensure:
* a consistent level of energy output from the UV light source
* a consistent level of UV radiation at the sterilization site
* a consistently low bioburden level at the sterilization site.
Ensure a consistent level of energy output from the UV light source. The effectiveness of the mercury vapor lamp decreases as the temperature of the lamp increases. The temperature of the low-pressure mercury lamp rises because infrared (IR) light is produced along with the UV light. As a result, the longer the lamp runs, the more IR is produced, resulting in greater heat output. This lowers the intensity of the 254 nm UV and converts some of the UV light to wavelengths outside the effective range for sterilization. To address this, critical design features have been enhanced, thereby enabling the UV source to run at 40-45[degrees]C, its optimum temperature for maximizing the UV output.
Consistent UV intensity is key to the reproducibility and validation of the UV sterilization process. Consistency can only be achieved if the UV lamps are functioning correctly. A lamp-monitoring circuit integrated into the starter design monitors the amount of current drawn by each lamp, which ensures functionality of the UV source. Any change would equate to a reduction in UV intensity and generate a system alarm.
Ensure a consistent level of UV radiation is present at the sterilization site. UV light intensity decreases with distance from the source. The Inverse Square Law is often used to compute the intensity of light at any distance from a lamp but is inaccurate in the near field where most of the germicidal effect occurs. Other models such as the radiation view factor equation provide a more accurate prediction of LTV intensity at short distances (15). This is one of the key reasons why the use of UV in this application is significantly different than in other disinfection applications. In other applications performance was compromised because the UV source was far away from the sterilization target. In the sterile transfer application, however, the UV source is placed very close to the transfer collar interface to be sterilized (0.185 in./4.699 cm). By tightly controlling the dimensions of the transfer container collar and its position in the port and only allowing the sterili!
zation cycle to begin once the collar is locked into place, a consistent distance is maintained between the interface and the sterilization source.
Shadowing can also reduce the effectiveness of a UV sterilization system and make validation more difficult. Shadowing occurs when the UV rays are blocked or obstructed by foreign objects such as particulates or crevices. The profile of the transfer container collar of the RsTP is designed to minimize the effects of shadowing. In addition, a removable collar cap protects the collar face from scratches or particles that may collect on the collar face. Manufacturing the transfer collars in a Class 1000 environment further minimizes particulate contamination.
Ensure a consistently low bioburden level at the sterilization site
A low bioburden at the site of sterilization is ensured in the following four ways:
* Design of the collar interface: A tightly fitting protective cap that permits gamma or autoclave sterilization covers the entire transfer collar interface surface.
* Manufacturing practice: A Class 1000 molding environment minimizes bioburden contamination before sterilization.
* Presterilization of the transfer interface collar: The transfer interface collar is autoclave or gamma-sterilized along with the components.
* On-site SOPs: The protective cap is only removed inside a Class C/B environment, seconds before it is docked into the UV RsTP. Risk assessment studies have concluded that a 5-min exposure in a Class C room would result in a maximum contamination rate of 92 cfu on an exposed 100 mm (79 cm2) interface collar (16).
Validating UV light sterilization in the RsTP system
For any sterile transfer system to be of value to the pharmaceutical industry, its functionality must be validated in terms readily understood by the industry and acceptable to regulators. In determining an acceptable validation standard for sterile transfer, the starting point has to be the application. The purpose of the RsTP system is to create a sterile transfer interface between a Class A environment (barrier-isolator) and the surrounding Class B or C environment. In looking for an acceptable standard of sterility, the obvious candidate is the sterility assurance associated with autoclave sterilization. The expectation is that an autoclave cycle is capable of sterilizing a microbiological challenge of 1 x [10.sup.6] cfu, giving a theoretical assurance of a sterility level of 1 in 1,000,000.
Scientific data suggests that Tobacco Mosaic Virus (TMV) has a high resistance to UV, requiring a dose of 440 mWatts/[cm.sup.2] to achieve a 100% kill, although Bacillus anthracis spores require a dose of only 46 mWatts/[cm.sup.2] to achieve sterility. In the validation process, the total dose delivered by the UV sterilization source of the RsTP during a 90-s cycle was at least 1000 mWatts/[cm.sup.2], which is more than twice the minimum required dosage for TMV. The cycle requiring validation had a duration of 180 s, ensuring a larger dosage than is required for sterilization.
The sterilizing capability of the UV cycle was validated by a direct microbial challenge. This bacterial challenge was inoculated directly onto samples of low-density polyethylene (LDPE) material used to manufacture the transfer interface collars. An approximate concentration of [10.sup.6]-[10.sup.7] spores of Bacillus pumilus (ATCC 27142) was used. Complete sterility of the LDPE collar interface was shown after a minimum UV exposure of 45 s (see Table II).
Photoreactivation is considered an essential component of the sterilization validation protocol. To assess the sustained lethality of the UV irradiation dose associated with the RsTP sterilization cycle, a validation protocol was developed that would assess the ability of UV-irradiated organisms to repair themselves through photoenzymatic and dark repair mechanisms. The possibility of photoenzymatic repair (photoreactivation) was excluded by exposing irradiated organisms to monochromatic and broadband light. Similarly, the possibility of excision (dark) repair mechanisms was excluded by incubating irradiated organisms in the dark. Photo protection with preceding illumination was not investigated as it was considered that the inoculation organisms were already exposed to light before irradiation, and any recognized benefit would have been included in the original sterilization validation (2).
The study using B. pumilis was conducted three times on separate days and 36 gamma-irradiated 2 in. x 2 in. LDPE slides were tested with an inoculum size approximately ranging from 1.2 x [10.sup.6] to 1.6 x [10.sup.6] spores in 40% alcohol. Each slide was exposed to UV light for 180 s. For enumeration of the recovered bacteria following the UV exposure, four exposed slides were incubated in 100 mL of trypticase soy broth (TSB) at 30-35 [degrees]C for 14 days. Furthermore, two procedures were used to test for photoreactivation. In the first procedure, 16 slides were placed in glass petri dishes and stored under fluorescent light (light intensity: 500 [+ or -] 40 lux) for 7 days at 2-8, 20 [+ or -] 1, 24 [+ or -] 1, and 35 [+ or -] [degrees]C. In the second procedure, another set of 16 slides were incubated for 7 days in the dark followed by 7 days of exposure to fluorescent light (light intensity: 500 [+ or -] 40 lux) at the following temperatures: 2-8, 20 [+ or -] 1, 24 [+!
or -] 1, and 35 [+ or -] [degrees]C. The results showed that all 36 slides exposed to UV light for 180 s were sterile, indicating that B. pumilus spores did not undergo photoreactivation after exposure to UV light.
Conclusion
RsTP systems offer potentially significant benefits to the pharmaceutical manufacturer over existing aseptic RPT systems. The most notable benefit is a decreased risk associated with component transfer to a high-speed filling line. With the older aseptic transfer port systems, operator intervention is required several times each hour to feed more components to the filling line. With each successive transfer, there is a small but real risk of an increased microbiological challenge to the filling area, either from the operator or from the transfer process.
Until recently, the only available sterile transfer system was based on old mechanical Alpha-Beta RTP technology and dry-heat sterilization. Now, UV light has been successfully developed, validated, and used as a sterilizing source for a new rapid sterile transfer process. To make UV sterilization practical, the design of the transfer port interface has been optimized from a complex Alpha-Beta flange system to a simple docking collar and door assembly. The simple design of the one-piece molded collar facilitates using UV sterilization. Logistical problems associated with the cleaning, repair, tracking, and replacement of the beta flanges and their gaskets have been eliminated by the implementation of a single-use one-piece molded collar interface.
Thus, by addressing one of the most common causes of aseptic processing failure--material transfer into the Class A filling environment--RsTPs facilitate the development of more-secure materials handling processes. In addition, these improved processes permit the placement of isolators in less costly, less environmentally controlled areas, thus reducing capital investment and running costs.
<pre>
Table I: Top causes for aseptic processing
failure (PDA Industry Aseptic
Processing Survey 2001)

* Personnel contamination

* Nonroutine activity

* Aseptic assembly

* Human error

* Mechanical failure

* Airborne contaminants

* Improper sanitization:
surface contaminants

* Material transfers:
failure of 0.2-[micro]m filter
failure of HEPA

* Improper sterilization.

Table II: Microbial Challenge Data

Exposure CFU
Inoculum (HDPE) Ave. Conc. time (s) Per Slide % Recovery

Bacillus subtilus 5.6 x [10.sup.6] 60 0 0.0%

Bacillus pumilus 6.3 x [10.sup.6] 180 0 0.0%

Bacillus 6.8 x [10.sup.6] 60 0 0.0%
stearothermophilus

Deinococcus 4.5 x [10.sup.6] 60 0 0.0%
radiothurans

Pseudomonas 7.5 x [10.sup.6] 60 0 0.0%
aeroginosa

Staphylococcus 7.7 x [10.sup.6] 60 0 0.0%
epidermidis </pre>

References
(1.) Sterilizable Rapid Transfer Port for Pharmaceutical Isolators Joint PDA/ISPE Conference on Advanced Barrier Technology, 1995.
(2.) Harm, Walter, "Biological Effects of Ultraviolet Radiation," Cambridge University Press, 1980.
(3.) Kelner, Albert, "Effect of visible light on the recovery of Sterptomyces griseus condia from ultraviolet irradiation injury," Proceedings of the National Academy of Sciences, 35 (2), Feb, 1949, pp. 73-79.
(4.) Wang, Shih Yi, "Photochemistry and Photobiology of Nucleic Acids," Volumes I and II, Academic Press, 1976.
(5.) Hader and Tevini, "General Photobiology," Pergamon Press, 1987.
(6.) Shechmeister, I.L., "Sterilization by Ultraviolet Irradiation," Disinfection, Sterilization, and Preservation, 4th Edition, Seymour S. Block, 1991, pp. 553-565.
(7.) Wright, H.B., and Cairns, W.L., "Ultraviolet Light," Trojan Technologies Inc Technical Bulletin #52, 1998.
(8.) Lehninger, A.L., Nelson, D.L., and Cox, M.M., The Principles of Biochemistry, 2nd edition, Worth Publishers, NY, NY, 1993, pp. 330-345.
(9.) Groocock, N.H., "Disinfection of drinking water by ultraviolet light," J. of the Institute of Water Engineers and Scientists, 38 (20), 1984, pp. 163-172.
(10.) Schenck, G.O., "Ultraviolet Sterilization," Handbook of Water Purification, Chichester: Ellis Horwood Ltd.; 1981, pp. 530-595.
(11.) Cohn, A., "The UV-Tube as an Appropriate Water Disinfection Technology: An Assessment of Technical Performance and Potential for Dissemination," Master's Project for The Energy and Resources Group, 24 May 2002, pp. 12-17.
(12.) Srikanth, B., "The application of UV technology to pharmaceutical water treatment," European Journal of Parenteral Sciences, 3 (4), 1998, pp. 97-102.
(13.) Melgaard, N.L. and Haas, P.J., "Continuous Production UV Sterilization Transport Applications," Journal of Pharmaceutical Processing, November 1997, pp. 3-8.
(14.) Stockdale, D. and Nase, R.S., "Ready to Use Stoppers: A Novel Outsourcing Alternative," Pharmaceutical Engineering, March/April, 2002, pp. 52-54.
(15.) Kowlaski, W.J. and Bohnfleth, W.P., "Effective UVGI System Design through Improved Modeling," ASHRAE Transactions, 106(2), 2000, pp. 4-13.
(16.) Bergin, Brian, Eurostar Technology Limited, Bredbury UK, "SafePass UV Transfer Process Risk Assessment."
Stephen Tingley is the director of biopharmaceutical marketing in the BioPharmaceuticai Division of Millipore Corporation, Bedford, MA, tel. 781.533. 2559, steve_tingley@millipore. com. Suraj Baloda, PhD, is the group manager for process microbiology and sterile applications, and Brett Beiongia, PhD, is the applications engineer consultant for disposable product technology applications R&amp;D in the BioPharmaceutical Division, both at Millipore. Gerhard Liepoid is the managing director at GL Tool, Livingston, NJ.
Stephen Tingley, to whom all correspondence should be addressed.

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Pharmaceutical validation package

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Packaging Digest , 05/01/2003 40 5

Pharmaceutical validation package. (Product News).

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The co.'s validation package includes information such as design and functional specifications, as well as standard operating procedures required to ensure consistent operation. Package also outlines product performance tests that can be conducted by customers to verify that design and performance meet the established specifications. This package of tests gives pharmaceutical customers a vendor-approved base from which to begin creating their internal testing procedures, saving them development costs and allowing them to create the FDA's required documentation. A tailored reliability engineering plan consisting of a preventive maintenance plan, an installation plan and an employee-training plan are also available. Current devices covered under the package include the SmartDate [R] family of thermal-transfer coders and the SmartLase [TM] laser coder. Markem Corp., 866/263-4644.
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Validation requirements for building automation systems in pharmaceutical and bio-medical manufacturing facilities

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Building Design &amp; Construction , 05/01/2003 44 5

Validation requirements for building automation systems in pharmaceutical and bio-medical manufacturing facilities. Renna, Agostino *~|~*Weddle, Gregory *~|~*

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Most information Technology (IT) professionals can recall the nervous anxiety they experienced at 11:59 pm on December 31, 1999 in anticipation of what some thought would be the implosion of the computerized world. The great news is that Y2K came and went without incident, and IT professionals now reminisce about the good old Y2K days when computer system budgets were large and IT was king. We are among the many people who believe that the reason Y2K came and went with no major consequence was not because it was a hoax, or that the risks identified with regards to computer systems were not real, but rather because most organizations took a systematic global approach to solving the problem.
Title 21 CFR Part 11, more commonly known as Electronic Records/Electronic Signatures, or just "Part 11," became law in August of 1997. Part 11 defines the criteria under which the FDA will consider electronic records and signatures to be equivalent to hand-written records and signatures in highly regulated environments that must comply with FDA requirements. In June of 2000 the application of Part 11 was furthered when then President Clinton signed into law the "Electronic Signatures in Global and National Commerce Act," which gave electronic signatures equivalent weight to hand written signatures.
Although Part 11 had been a law for more than two years when Y2K came around, it was lower down on the list of priorities for most pharmaceutical organizations. Though not publicly stated, perhaps the FDA clearly understood that asking pharmaceutical organizations to pull their IT intellectual capital off of Y2K resolution to have them focus on Part 11 compliance could be detrimental to the industry.
After the Y2K challenge had passed, the agency became very proactive about Part 11. In the FDA's fiscal year 2000, the agency recruited and hired a significant number of new investigators who were neither biochemists, molecular biologists nor genetic engineers but IT professionals whose mandate it would be to audit regulated pharmaceutical facilities for Part 11 compliance. Ten Part 11 related 483s (warning letters) were issued by the FDA in 2000 and the number is steadily increasing; simply stated, Title 21 CFR Part 11 became real.
Industry experts estimate that Part 11 resolution will cost pharmaceutical organizations three to five times what it cost them to resolve Y2K related issues. Part 11 differs from Y2K in key ways due to the fact that as technology advances and the interpretation of the Code matures, the compliance target mines. However, there are also many similarities between the two initiatives.
For example, getting there quickly and cost effectively is critical. No computer system is exempt, whether legacy or new. Also, like Y2K, computer systems need to be prioritized with regard to criticality, gaps identified and assessed, remedy plans created, funds secured and finally solutions implemented. Validation, defined by the Food and Drug Administration (FDA) means establishing documented evidence providing a high degree of assurance that a specific system, process, or facility will consistently produce a product meeting its predetermined specifications and quality, attributes. FDA Title 21, CFR 11/58 / 210 / 211 / 820 defines the manufacturing and laboratory testing requirements for Pharmaceutical and Bio Medical manufacturers. These industries are bound to the FDA and must prove compliance to these regulations through solid testing and documentation practices.
Manufacturing processes for drugs and medical devices must be validated to ensure compliance to FDA regulations in order to make sure products are safe for sale to the public. Computer systems controlling these processes--and the HVAC systems that provide the tempered environment around these processes--must be validated in order to comply with these regulations.
One of the most difficult challenges facing our customers is determining what portions of their Building Automation Systems (BAS) require validation. Our experiences with dozens of pharmaceutical and medical device manufactures has shown that it is a combination of three conditions that create the validation target for systems--those are a company's interpretation of the FDA codes; the environmental impact to product / employees, and a company's internal policies.
Interpretation of FDA Code can be found in a company's Master Validation plan and will discuss application to diverse activities like research, pilot production, production, stability warehousing and distribution. It should provide direction and response to the codes identified earlier in this document. One industry common reference to interpretation of FDA codes comes from a consortium of pharmaceutical manufacturers called ISPE (International Society of Pharmaceutical Engineers). ISPE, along with other organizations, has issued guidance to interpreting the codes through the GAMP or Good Automated Manufacturing Practices guidelines. GAMP recently released a baseline guide on commissioning and qualification that has been a tremendous help to companies struggling with these issue.
Environmental impact to product/employees can be broken down into two aspects, product quality and employee safety. First is the impact the space environmental conditions have on product consistency or quality. The GAMP (Good Automated Manufacturing Practice) Guide on Commissioning and Validation provides guidance and reasoning to determine environmental conditions with "direct," "indirect" or "non-impact" on the product.
In essence, this is a process that evaluates the Basis of Design conditions for product or research against the building and control components and deliverables that are controlled. It culminates in a series of boundaries drawn around control components and mechanical/electrical systems. The GAMP guide indicates "direct" and "indirect" systems should be validated, "non-impact" systems should be commissioned. Safety issues may deal with contamination or exposure. Where risks are identified, those systems that operate to protect employees should be validated.
Internal Company Policies must also be considered when determining what systems require validation or other higher level testing and commissioning. These policies can touch many aspects of system application, so care must be taken to obtain a clear understanding of these requirements. Typically we find policies around these business issues to most greatly impact BAS validation, security access to the facilities or special areas, information technology (IT) requirements, maintenance procedures, and quality reporting.
For example, if your IT department has a written policy which indicates all computer systems will require computer system validation, then every computer, whether cGMP or not, must be validated unless a rationale indicating otherwise can be written and approved by IT and QA.
We recommend working together to create a rationale statement that defines direct, indirect and non impact systems and what validation or commissioning steps will be applied to each. It is important to define in detail tire procedures for both validation and commissioning efforts to standardize on both efforts and understand the delivery use and approval requirements of both.
The diagram below helps to identify the difference between commissioning and validation.
The horizontal dotted line represents a transition from non-critical above, to critical or cGMP systems below. In the upper left quadrant a process is indicated involving Good Engineering Practices for the design, build and commissioning of your facility. Facilities systems that fall in this quadrant will be built to specifications and requirements defined by general building practices and building codes.
[ILLUSTRATION OMITTED]
BAS systems that apply here might be administrative spaces, cafeteria and some central plant utility equipment. The process below the dotted line in the lower right quadrant represents the plan, design, build and qualification steps required for cGMP or critical systems. This process is known in the life sciences industry as the validation "V" and is the foundation of the FDA's expectations of manufacturers for how they build and operate facilities and systems where product quality impact exists. The primary difference between the two processes are the addition of procedures and formal approval/testing/signoff (qualification) required on the cGMP systems.
Activities in the lower right quadrant will involve your quality department and key technical experts in the area of approval and signoff for each step. All actions performed in the quadrant must be documented, organized, trained and maintained throughout your Facility life cycle. This documentation is what defends your operation in event of an audit by the FDA.
BAS network considerations: Many of our customers combine validated and non-validated systems on the same BAS network and separate operator access via logical security. Other customers place validated systems on dedicated Network Controllers that connect to a common BAS network. Still others provide physically separated networks for validated and non-validated BAS net works. The direction taken here leads to how your networks will need to be maintained.
Common networks allow a single BAS operations staff to manage and maintain both validated and non-validated systems, but require that special attention (Change Control) be given to non-validated systems added or deleted from that network. Segregated networks force dual operating staffs or a single staff managing dual graphical user interfaces and managing the question of which network that system is on. However, segregated networks divorce changes on non critical systems from the validated network, simplifying validation maintenance. Each approach should be weighed against your operating staff capabilities, legacy system installations, and the complexity of validation efforts for your sites.
Proper project planning is essential to the success of a project and ensuring compliance to FDA regulations. Detailed project planning, system design and development and system testing to ensure that the design functions as intended are key components to successful validation efforts. Proper operation and monitoring of the systems by trained personnel and an ongoing preventative maintenance program incorporating Standard Operating Procedures (SOPs) ensure that systems continue to function consistently and reliably. The goals of all manufacturers are to increase product quality and decrease downtime while at the same time minimize the risk potential to the public and to themselves. The techniques used to comply with FDA regulation aid to these goals.
Compliance to FDA regulations often produces several by-products that can benefit these regulated industries. The means to compliance, if properly planned and executed, result in company and vendor standards, consistent practices, and procedures that produce a quails, product, decrease process downtime, and ultimately reduce the costs of producing a product. Recently, computer chip manufacturers and other high tech industries, not necessarily under the jurisdiction of the FDA, have incorporated standard testing and documentation practices because they understand and appreciate the value and benefits that such practices offer.
Conclusion: It is our experience that the scope of a validation effort on a BAS installation must reflect three key issues:
* Your company's current interpretation of the FDA codes for the building type and activity.
* Your company's policies regarding IT, security and safety. There must be clearly identified rationale and approval for any deviation from these policies.
* You must be focused on direct and indirect product quality, impact of the controlled variables managed and recorded by the BAS.
Each of our current pharmaceutical and medical device customers are in some way validating their BAS installations and operations today. The application by the FDA of Title 21, CFR Part 11 (electronic records/electronics signatures) has heightened the need for compliant and validated systems. It has also forced BAS vendors to provide a more complete and usable environmental package for its customers. A win/win for both parties.
Appendix: Johnson Controls focus in the Life Sciences Market
Johnson Controls Inc. has been validating HVAC systems for over fourteen years, primarily in the pharmaceutical and medical device markets. Johnson Controls expanded its capabilities in the validation market by forming a team that focuses on assisting our offices and global customers in designing, installing, testing, and operating facility environmental systems to cGMP requirements. This team, called Validation Support Services (VSS), reviews and interprets cGMP regulations and applies these regulations to the HVAC controls business and in particular, systems applied to cGMP facilities. VSS has developed and processes and procedures that have been refined and tested over time and can be adapted to existing customer standards or can be the basis for new applications in the pharmaceutical, medical device, and food processing industries. These processes integrate seamlessly into new and retrospective validation opportunities and have application to non-regulated industries a!
s well.
The validation process developed by VSS stresses that the success of a project stems from early involvement, especially during the planning and design phases of a project. Johnson Controls stresses the importance of being part of the design team to ensure that product is accurately selected and correctly applied to mechanical systems, and that the product selected will function within the design criteria forth by the customer.
Detailed processes for planning, designing and testing systems and facilities have been developed to minimize a customer's time to production, to reduce errors and rework and to build in reliability. Standard acceptance test documentation, such as installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) produces are available for use on nay system. Software development guidelines and tools have been developed to gain efficiencies and ensure standardization and consistency in the design and development of such documentation. Yet the guidelines offer flexibility so that they can be easily modified to meet specific customer requirements and standards.
The cGMP guidelines for the pharmaceutical and medical device industries define the minimum requirements for compliance to the regulations. These regulations define what must be done, not how to do it. The process established by Validation Support Services of Johnson Controls is designed to assist customers in defining the "how to" aspect of validation for the pharmaceutical and medical device industries. The standard methodology ensures that systems are properly designed, completely commissioned, validated, and fully operational. The completed project documentation provides a good defense for FDA audits. Customers that must rely on historical information can rely on documentation that is well prepared and properly executed. Regardless of the level of regulations that various industries are bound to the processes and procedures designed and developed by Johnson Controls can be efficiently adapted to any industry and any regulation.
--Agostino Renna is Director, Life Sciences for Johnson Controls in Milwaukee, Wis. and Gregory Weddle is Manager of Validation Support Services for Johnson Controls in Indianapolis, Ind.

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Using a Delphi survey to assess the value of pharmaceutical process validation

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Pharmaceutical Technology Europe , 08/01/2003 15 8

Using a Delphi survey to assess the value of pharmaceutical process validation part II: expert opinions.(Survey results) Helle, Marjo-Riitta *~|~*Heinamaki, Jyrki *~|~*Mannermaa, Jukka-Pekka *~|~*

COPYRIGHT 2003 Advanstar Communications, Inc.


European expert opinions regarding pharmaceutical process validation were collected and studied by performing an Internet Delphi survey. In total, 36 experts from 10 countries representing the pharmaceutical fields of industry, regulation and academia participated in the survey. The overall attitude to process validation appeared to be positive; however, a number of concerns were raised. More education, better use of prioritizing tools and increased evidence of cost-effectiveness is needed to further develop and facilitate process validation. **********
Many doubts regarding the value of process validation (PV) have been raised during the past 30 years. For many, validation is still associated with bureaucracy and excessive paperwork, which only serves to hinder progress. However, a systematic evaluation of its real value has long been overdue.
The value of PV is difficult to estimate because it cannot be evaluated using solid empirical measurements. Therefore, a method capable of both evaluating the subject by in formed judgement and structuring the information for which there is some evidence, but not quantitatively measurable knowledge, was needed. Therefore, the synthesis method of technology assessment (TA) was applied. (1)
For the first part of the assessment, a literature search was performed, (2) but a lack of European opinion was evident. To address this, an Internet Delphi survey was performed in autumn 2001 involving 36 experts from the pharmaceutical fields of industry, regulation and academia.
Objectives
The objectives of the survey were
* to explore the value of pharmaceutical PV and to ascertain the best tools to perform it
* to explore the advantages and disadvantages of PV using the experiences of the pharmaceutical industry and regulators
* to investigate academic attitudes to PV
* to search for differences in approach between the three parties or between countries.
Once collected, the information and knowledge was used to provide support for the further development of pharmaceutical PV.
Methods
The Delphi method. The survey was performed using the Delphi technique--a series of questionnaires based on a structured process with controlled feedback. The results of one round of questions were summarized and used to construct the next questionnaire. The method attempts to mimic discussion through controlled feedback allowing respondents to change their minds on the basis of the opinions from the previous round. This reiterative process is continued until the participants reach consensus or clear disagreement. To accelerate the process, the Internet and e-mail were used. Furthermore, the Internet offered additional tools during the survey. (3)
Questionnaires and analysis. Only two rounds of questionnaires were required for adequate consensus. Both questionnaires mostly consisted of multiple-choice questions under the following subheadings
* How do you feel about PV?
* What are the benefits of PV?
* What are the negative issues of PV?
* How can we get the most out of PV and how can we make it easier and more effective?
* What are the main barriers to positive thinking of PV?
* What is the cost of validation?
For quantitative measurement regarding PV, the multiple-choice answers were categorized using a 1-5 Likert scale, which was used to summarize the results. (4) A "no opinion" option was added and these were omitted from the mean calculation.
Attitudes were also tested by asking the participants how far they agreed/disagreed with a number of statements concerning PV in general and its usefulness in specific areas. The overall attitude was also estimated through one control question, which was the first question in the first round (Q1) and repeated as the last question in the second round (Q2). The estimation of the application possibilities of PV was based on the responses to statements presenting applications of PV and statements under the heading of "Benefits of Process Validation."
The sections of the questionnaire trying to ascertain the reasons for the overall attitude were evaluated question by question, calculating percentages for different choices. To determine whether there had been any evolution of the opinions between Q1 and Q2, the quantitative values of Q1 for certain questions were compared with the Q2 values for the same questions. The decision to continue the survey with further rounds rested on this comparison. Because the size of the expert group was relatively small, no further statistical analysis could be performed on the results.
Results
In total, 36 experts from the three pharmaceutical parties participated in Q1, 28 of whom continued to Q2. There were participants from 10 European countries--Belgium, Denmark, Finland, France, Germany, Iceland, Norway, Sweden, Switzerland and the UK. (3)
Overall attitude and application possibilities. The overall attitude to PV appeared to be very positive, but some stated that its applications were not practicable and others believed that PV should be reserved for its original purpose: to ensure patient security. Therefore, the mean value for application possibilities was less than that for overall attitude (Figure 1).
[FIGURE 1 OMITTED]
No one had the opinion that PV was just a regulatory requirement without real benefits for the manufacturer. There were no differences in this opinion between the three parties and the opinion was not dependent on the participants' age, gender, education, primary business or function. Q1 answers did not differ statistically from the Q2 results and results for the overall attitude are presented in Figure 2.
[FIGURE 2 OMITTED]
The proposed application areas of PV were
* as an opportunity to learn about the process
* as a quality management tool
* as a marketing tool
* as a cost saving tool
* as a general good business practice.
The lowest reported value related to the usefulness of PV as a marketing tool. The participants agreed that PV increases patient security, and provides cost savings through better performing manufacturing processes and less rejectable material, reprocessing and retesting. Further benefits of PV included cost savings through the early detection of failures and less troubleshooting. However, half of the participants had doubts concerning whether PV could provide cost savings by reducing control requirements for the final product. It was also unclear whether PV would ensure better conformance with regulatory requirements and thus shorten delays in obtaining marketing authorization. No clear differences regarding these attitudes were apparent between Q1 and Q2--all application areas received positive mean values (Figure 3).
[FIGURE 3 OMITTED]
Two questions in Q1 highlighted major differences in opinion. Little agreement could be found on whether PV simply constitutes a bureaucratic exercise or whether validation provides an enormous opportunity for consulting companies to earn money at the cost of the pharmaceutical manufacturers.
Some differences between the attitudes of the pharmaceutical parties could be seen regarding the application possibilities of PV. The regulators were most critical of PV as a useful marketing tool (Figure 4); however, they found the application possibilities quite extensive. Of the three pharmaceutical parties surveyed, academia most strongly agreed with the survey statement that PV is a hindrance to flexible product development and a destroyer of innovation (Figure 5); however, they had the least positive attitude to the application possibilities of PV, unlike the industry participants who found merit in all suggested applications.
[FIGURE 4-5 OMITTED]
Cost of validation. In Q1 there were seven questions regarding validation costs. The results showed that the costs are difficult to estimate.
Half of the participants, particularly the regulators, considered that validation costs are not one of the main reasons for the high prices of medicinal products. Most were of the opinion that negative attitudes regarding PV could be blamed on the general assumption that validation is expensive. In Q2, a new question was added, asking participants whether they had ever seen reports clearly showing that validation had increased total quality costs--92% had not.
The participants were also asked to estimate the cost-effectiveness level of PV if the minimum effort to meet the requirements of the European regulators was made. Sixty eight per cent of Q1 participants found that that level would represent the optimum economic level of PV; this attitude was further strengthened in Q2 (81%).
In Q2, participants had to choose between two suggested models for pharmaceutical quality costs--the traditional quality cost model (Figure 6) and the continuous improvement model (Figure 7). Eighty five per cent favoured the continuous improvement model.
[FIGURE 6-7 OMITTED]
Optimizing process validation work. The best organizational model. In Q1, the participants were asked to choose the best organizational model for PV. The most popular (86%) was a validation group composed of production, quality assurance (QA) and product development personnel because they felt that as a cross-functional discipline, PV would benefit from experience from all of these departments. Some people even added engineering experts to the group.
Those who opted for a separate validation department did so because they believed that this provided a company with separate resources with validation knowledge. Having a validation group as part of the product development department was supported by some people because they believed it would offer the perfect combination for process improvements. Other participants felt that having a validation group as part of QA department would offer The most benefits.
In Q2, the question was modified, asking participants to name the model that is currently employed by their company or was used by previous employers. Again, the most popular model (55%) was a validation group composed of production, QA and product development staff. It was discovered that in some companies, validation activities had been divided between several departments, each performing different parts of the PV, but this model never worked perfectly, because communication between the departments was ineffective. Other named models are listed in the sidebar "Other named models for optimizing PV."
Prioritizing process validation. Results showed that the most popular (63%) method for choosing which processes to validate was the use of common sense. Failure Mode Effect Analysis (FMEA), (5-7) was unknown by 43% of the experts and the process capability method,S was only slightly better known.
Making process validation easier. Seventy seven per cent of participants were against outsourcing PV and only 3% supported it. In Q1, 69% believed that PV should be started at the earliest stage of product development, but 23% did not find this profitable. In Q2, however, there was less resistance to this idea. Participants who were against this idea interpreted the question differently to those who found it to be a good idea. Apparently, process optimization and PV were mixed here.
Half of the participants based PV on the ongoing follow-up of process parameters rather than on the evaluation of three consecutive production batches, because as one expert stated: "Statistics on many batches gives higher assurance of performance than statistics on three batches."
Barriers to positive thinking. Although this article has already mentioned some of the barriers to positive thinking on PV, further obstructions were identified.
Eighty three per cent of participants thought the lack of PV education was to blame. Furthermore, 45% of industry experts reported that senior management rarely understands quality attributes, which in turn breeds negativity throughout the company. Finally, 89% of the participants (excluding the authorities) found that the unconditional attitude of the regulators regarding PV and their inability to evaluate the need for it on an individual basis, hindered positive thinking.
Discussion
Applications of process validation. The overall positive attitude regarding PV corresponded well to the results of the former literature review. (2) Therefore, despite the criticism concerning PV, experts have not only found clear advantages to it, they have also learnt to use it for many other purposes. One possible reason for the former criticism regarding PV is that it was originally viewed as a regulatory burden. (9) At that time, people working in the pharmaceutical industry were not trained in PV and, consequently, resented its inherent bureaucracy and expensive scientific work. (10)
If PV was more business oriented and was introduced, for example, as part of total quality management, a lot of unnecessary work would have been avoided. (9,10) One participant stated: "It is of great importance to involve the entire company in a general quality progress strategy" and it is also important to give sufficient education regarding the meaning of different quality tools to the whole company. When the benefits of PV have been recognized and taught to the younger generation, attitudes have become more positive. From the survey, it was evident that 'traditional' opinions still exist because some academic participants view PV as a "hindrance for creative product development" and those from regulation see it as "nothing to do with marketing." It was also the participants' experience that PV still does not mean less quality control regarding the final product, and that the regulations have partly been applied too schematically by the authors. The new annex to the Eur!
opean Guide to Good Manufacturing Practice (GMP) concerning parametric release (11) and the decision of the US Food and Drug Administration (FDA) to re-evaluate its pharmaceutical manufacturing regulations to focus on the highest risks to public health, and to ensure that enforcement of standards does not impede innovation, (12) are thus welcome.
Application possibilities should be looked upon with an open mind and new ideas be created, as expressed by one participant: "Validation, although a key GMP requirement, can contribute to the marketing of a product because well developed and validated processes should produce a product that not only meets specifications but is consistent from one batch to another. Dependent upon the medication in question, this could be very important."
Process validation tools
It cannot be denied that PV is a serious issue requiring patience. To survive its challenges and avoid meaningless work, PV has to be supported by a good organizational model, document management systems and other tools for simplifying and prioritizing the procedures,t3't4 The organizational model widely a favoured is a group consisting of QA, product development and production personnel. (15-17) The majority of experts appear to support a team approach that uses experience from different departments. Which departments to include can vary depending on the process to be validated. (10,17) To avoid communication problems between the different departments involved, a project leader is required. Furthermore, using this type of teamwork enables the most effective use of the knowledge and documentation available. (10,18)
Because it is expensive to examine every combination of variables in every process, only the most critical ones should be chosen. (19) The favourite prioritizing method for choosing the most critical steps--common sense--can lead to a wrong order of importance, and thus, the most critical processes may not be validated. This approach is a clear indication that PV has become more of a rote activity rather than one based on scientific principles. (9) Risk evaluation methods such as FMEA and process capability could be very useful if the experts could be trained to use these methods.
One item discussed at length among the experts was whether to base PV on the ongoing follow-up of process variables or on the validation of three consecutive production batches. Clearly, these two approaches are not alternatives to PV, but they are essential parts of the process life cycle. Manufacturing processes for products that have already been on the market for some time can be validated retrospectively, whereas new products should be validated at the beginning. (13,20)
Outsourcing different activities of pharmaceutical manufacturing, including PV, has become a trend in recent years. However, the participants did not warm to that idea because they believe that PV includes such essential knowledge regarding the process that it cannot be left to outsiders. The results of PV are also useful in everyday processing and so it is important that these results are created by those closest to it. (21) The best way to obtain good control of the processes is to start defining the critical process variables from the beginning of the product development and to progress through stepwise process optimization to the final PV. To be able to get the maximum knowledge of the process permanently, in-house staff should be involved. (22-25) Outsourcing could, however, be useful in conjunction with equipment qualifications. (26)
Process validation cost. It is a common assumption that validation and other quality procedures are expensive, but only limited empirical evidence regarding the behaviour of quality costs exists. (27) Few, if any, companies use experimentation to identify their quality cost curves. Even then, most underestimate the non-conformance costs, which can be surprisingly high, particularly in pharmaceutical manufacturing; for example, one multinational pharmaceutical company was fined $500 million because of GMP violations. (28)
To manage quality costs and to avoid misleading assumptions, every company should have a continuous reporting system for quality costs. (29) But for many quality procedures the problem is that the costs are spread among different departments and that the biggest non-conformance costs, such as loss of good reputation, can never be precisely estimated. Many participants found PV expensive although, at the same time, they agreed with the statement that PV could be used to save costs.
Quality control (QC) procedures included in the GMP of pharmaceutical production aim to conform to specifications, but QA procedures such as PV aim to meet the specific requirements of the product. Previously, Taguchi argued that losses occur whenever output deviates from the product specifications and, therefore, investments regarding improving and optimizing processes decrease failure costs more effectively than just the conformance testing. (30) Although Taguchi's calculations have not been verified empirically, his suggestion correlates well with the continuous improvement model of quality cost behaviour (Figure 7) that was chosen in the survey as the best model for pharmaceutical quality costs. (31) This model indicates that once an effective quality programme is established, ongoing non-conformance cost reductions can be achieved with little or no subsequent increase in conformance expenditures, even with a decrease in conformance investments. Aiming al the target va!
lue means investing in the total quality management. These types of investments typically pay back with some delay, but can then further reduce the total quality costs, even if investment in conformance quality decreases.
[FIGURE 7 OMITTED]
PV can be used as a tool to reduce total quality costs in the long-term, but to achieve this, a quality culture has to first be created within the company. If PV is performed only to satisfy the regulators, the most probable result is that total quality costs continue to increase. But, if a company fully realizes the meaning of validation and carefully investigates the critical points, then the validation can be performed cost-effectively. resulting in reductions in total quality costs.
Summary and conclusion
The main finding of this survey is the overall positive attitude to PV. However, closer investigation of the results showed that uncertainty and negativity concerning the value of PV, either through a lack of education or because of experiences of the regulators' unconditional attitude, still exists. Furthermore, economic evidence of the advantages of PV in quality costs is difficult to verify, which feeds many old negative assumptions.
To obtain support from the company management and to strengthen the trust of the operating personnel in the value of PV, investment should be made in better quality cost reporting. All this evidence and better communication with people practising PV in their work would also help the representatives of the pharmaceutical academia to understand the positive value of process validations, and thus they would be able to transmit the attitude to future pharmaceutical students.
Results also indicated that many experts were not familiar with the tools for prioritizing the work--these principles should be included in basic education. Regulators should also invest in their own thinking and ability to evaluate the need for validations from case to case.
The statistics regarding the results of the survey, as well as the possibilities of comparison between different groups, were limited because of the low quantity of participants. But, as the group consisted of many European nationalities, different ages and functions, the group can be regarded as representative of pharmaceutical European experts. However, it has to be noted that approximately half of the participants were from Finland.
The survey was successful in providing a general impression of the attitudes to pharmaceutical PV. This type of survey offers a suitable environment for the experts to anonymously discuss and express themselves. From the significant number of extra comments in Q2, it could be concluded that most of the participants found the subject important. Some of these comments have been cited in the text and some others are presented in the sidebar "Individual comments regarding process validation."
Other named models for optimizing PV
* A validation group composed of production, quality assurance (QA) and product development
* A validation group as part of product development
* A separate validation department for all validations
* A separate technical support group for each dosage form
* For concurrent validations--production and QA
* For prospective validations--product development and QA
Individual comments regarding process validation
* "Process validation is as vital for a company as, for example, product development."
* "The need to validate improves product development. It forces product development and also makes one think through any change request more carefully before implementation."
* "If you look at the intent of the requirements of validation and relate them logically to your own process, then there is a huge potential to learn about the process and to ensure that you have a robust process that will serve you well for a long time."
* "Both production and development are extremely important departments in process validation. Data regarding different scales may be necessary although production scale is most important."
* "The regulators' primary responsibility, like ours, is to protect the patient."
* "You need to be scientifically based to understand the value of, for example, process validation."
* "Reliable, reproducible process equals a constant market supply with a consistent product."
* "One of the many challenges is to minimize the paperwork by focussing on what is important--not equating volume with quality."
* "Validation does not make the process any more effective or improve the quality of a product--it only improves the quality assurance."
References
(1.) J.M Morgall, Developing Technology Assessment--A Critical Feminist Approach (Lund, Sweden, 1991) pp 21-66.
(2.) M-R. Helle, J. Yliruusi and J-P. Mannermaa, "A Literature Review of Pharmaceutical Process Validation," Pharm. Technol. Eur. 15(3), 52 57 (2002).
(3.) M-R. Helle, M. Reijonen and J-P. Mannermaa, "Using a Delphi Survey to Assess the Value of Pharmaceutical Process Validation Part 1: Survey Methodology," Pharm. Technol. Eur. 15(4), 43-48 (2002).
(4.) F.J. Fowler Jr, Survey Research Methods (Sage Publications Ltd, London, UK, 1988).
(5.) R.G. Kieffer, S. Bureau and A. Borgmann, "Applications of Failure Mode Effect Analysis in the Pharmaceutical Industry," Pharm. Technol. Eur 9(8), 36-49 (1997).
(6.) A. Sahni, "Using Failure Mode and Effect Analysis to Improve Manufacturing Processes," Med. Dev. Diag. Ind. 15(7), 47-51 (1993),
(7.) R.G. Kieffer, "Validation and the Human Element," PDA J. Pharm. Sci. Technol. 52(2), 52-54 (1998).
(8.) R.G. Kieffer, "Validation, Risk-Benefit Analysis," PDA J. Pharm. Sci. Technol. 49(5), 249-252 (1995).
(9.) J. Agalloco, "Validation: An Unconventional Review and Reinvention," PDA Z Pharm. Sci. Technol. 49(4), 175-179 (1995).
(10.) P. James, "Integrated Validation: A Way of Streamlining Projects to Reduce Project Validation Time and Cost." Pharm, Eng. 8(1), 72-82 (Jan-Feb 1998).
(11.) "Annex 17 to the EU Guide to Good Manufacturing Practice--Parametric Release" (European Commission, Rue de la Loi, Wetstraat 200, B-1049 Brussels, Belgium, 2001).
(12.) FDA Reassessing GMP Inspection," Scrip No. 2776 (28 August 2002) p 16.
(13.) J. Lignau, "Optimization and Validation of Manufacturing Processes." Drug Dev. Ind. Pharm. 15(6&amp;7), 1029-1046 (1989).
(14.) A. Chao, "'Validation of Oral Dosage Forms: An Industry Viewpoint." paper presented at the Academy of Pharmaceutical Sciences' Midwest Regional Meeting (21 May 1979, Chicago. Illinois, USA).
(15.) A. Laicher, "Validierung in der Galenischen Entwicklung," Pharm. Ind. 51(10), 1145-1149 (1989).
(16.) R.A. Nash. "Process Validation: Solid Dosage Forms." Drug Cosm. Ind. (Septemher 1981) pp 38-39, 104 106.
(17.) T. Byers. "Validation ... Burden or Benefit?" Drug Cosm. Ind. (June 1982) pp 43-44, 82, 86.
(18.) J.E. Gillett, "The Six-Stage Hazard Study Procedure and Process Validation." Pharm. Technol. Eur. 6(9), 58-66 (1994).
(19.) I.R. Berry, "Process Validation of Raw Materials," Pharm. Technol. 5(2), 38-39 (1981).
(20.) K.G. Chapman, "The PAR Approach to Process Validation," Pharm. Technol. 8(12), 22-36 (1984).
(21.) P.H. Derrien and J. Deutch, "Deroulement d'une Validation: Approche Concrete." S.T.P. Pharma Pratiq. 7(5), 340-344 (1997).
(22.) R.F. Tetzlaff, "Project Plans for New Drug Development Activities," Pharm. Technol. 22(1), 46-60 (1998).
(23.) C. DeSain et al., "Process Development That Supports Process Validation." Pharm. Technol. 19(10), 130-136 (1995).
(24.) V.I. Zimmermann, "Up Scaling Pharmazeutischer Herstellverfahren," Pharm. Ind. 53(4), 377-383 (1991).
(25.) R.A. Nash, "Process Validation: A 17-Year Retrospective of Solid-Dosage Forms," Drug Dev. Ind. Pharm. 22(1). 25-34 (1996).
(26.) C. Chemtob. "Principes Generaux de la Qualification des Installations," S.T.P. Pharma Pratiq. 7(6). 431-434 (1997).
(27.) C.I. Ittner, "Exploratory Evidence on the Behavior of Quality Costs," Operations Research 44(1), 114-130 (1996).
(28.) "Cautious Progress for S-Plough," Scrip, No. 2740 (24 April 2002) p 10.
(29.) O. Lecklin, "Laatu Yrityksen Menestystekijana, (Talentum Media Oy, Kauppakaari, Jyvaskyla, Finland, 2002) pp 171-182.
(30.) G.Taguchi and D. Clausing, "Robust Quality," Harvard Bus. Rev. (Jan/Feb 1990) pp 65-75.
(31.) H.J. Harrington, Poor-Quality Cost (Marcel Dekker, New York, New York, USA, 1987).
Marjo-Riitta Helle * is the quality manager at the University Pharmacy, Valimotie 7, FIN-00380 Helsinki, Finland. Tel. +358 9 5420 4433 Fax 1358 9 5420 4499 maiju.helle@yliopistonapteekki.fi
Jyrki Heinamaki is a senior lecturer and Jukka-Pekka Mannermaa is professor of industrial pharmacy, both at the Department of Pharmacy, University of Helsinki.
* To whom all correspondence should be addressed.

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