ABC News' Brian Ross on War Vets and Drug Addiction

ABC News' Brian Ross talks about a "20/20" investigative report on returning war veterans and drug addiction. Is the problem worse than the Army is willing to admit? Can drug addiction be rightly linked to wartime service? Should the Army do more to help these servicemembers recover beyond discharging or even jailing them?

BREAKING!!! F-15s Grounded Again

We just got this breaking news at Military.com in a few minutes ago and I wanted to get the word out to DT readers...

An informed DT reader told me this afternoon the Air Force had re-grounded its fleet of F-15s after they were returned to flight last week.

Military.com reporter Bryant Jordan got the details...

Barely more than a week after returning the F-15 Eagle fleet to flight the Air Force is once again grounding most of the planes, Military.com has learned.

F-15 models A through D -- a total of 442 planes -- were ordered grounded by Air Combat Command,Langley Air Force Base, Va., late on Nov. 27, ACC spokesman Maj. Thomas Crosson said in an interview.

The latest problem is with cracks in the planes' metal support beams, called longerons, that run the length of the aircraft, and make up the sill on which the canopy sits, Crosson told Military.com.

The entire F-15 fleet was ordered grounded in early November after the break up and crash of a Missouri Air National Guard Eagle. The Air Force began lifting the restrictions on the fleet Nov. 19 - starting with F-15E Strike Eagles - following aggressive inspections of the planes.

ACC called for the new groundings after metallurgical analysis of the planes suggested there could be possible cracking problems with the longerons.

Officials now are working at Warner Robins Air Force Base, Ga., to develop an inspection list that will be sent out to F-15 maintainers across the Air Force.

Crosson said the list should be completed in a day or two, and will include a timeframe for how long the actual inspections should take.

He could not say how long it would before the latest restrictions would be lifted from the entire fleet.

USAREUR Announces '08 Deployments

HEIDELBERG, Germany -- Some 8,000 Europe-based soldiers will be heading to Iraq and Afghanistan next year, according to an announcement Wednesday from U.S. Army Europe.

Officials announced the upcoming deployments of some 4,200 soldiers to be sent between March and November, for an expected 15-month tour. Those units come mostly from the 21st Theater Sustainment Command, headquartered in Kaiserslautern but with units based throughout Germany.

There are currently 13,500 Europe-based troops deployed to Iraq and Afghanistan, officials said.

The newly announced units are in addition to some 3,800 soldiers with the Baumholder-based 2nd Brigade, 1st Armored Division, whose expected 2008 deployment was previously announced by the Department of Defense.

Additionally, a number of units scheduled for deployment next year originally were scheduled to deploy this year. Those units are marked with an asterisk (*).

All but one of the units deploying next year are based in Germany. The exception is the 1st Platoon (Postal), 111th Adjutant General Company, from Vicenza, Italy.

Numerous communities in Germany will be affected by the unit deployments, including Bamberg, Baumholder, Grafenwöhr, Hohenfels, Illesheim, Kaiserslautern, Mannheim, Stuttgart and Wiesbaden.

Larger NATO Force Needed in Afghanistan

NATO-led forces in Afghanistan do not have the means to secure the country in the face of a barrage of insurgent attacks, a senior French general with the force has warned.

"The 41,OOO soldiers in ISAF are largely insufficient to ensure security," said Brigadier General Vincent Lafontaine, the chief of planning for the International Security Assistance Force deployed here under a UN mandate.

"That does not mean we are going to lose this operation, but it is going to take a lot longer for us to finish the job," Lafontaine told visiting journalists this week at ISAF headquarters in the Afghan capital.

The officer -- one of the most senior in France's 1,070-strong contingent here -- also expressed concern about the chronic shortage of transport helicopters used to move soldiers and supplies around the war-ravaged country.

The United States provides most of the helicopters, but is due to start pulling them out in early 2008.

Lafontaine said as a result, top-level NATO officials were now mulling the possibility of outsourcing logistics tasks to private helicopter companies.

NATO has long called for the 38 nations involved in ISAF to contribute more to beat the intensifying conflict.

But the high cost of the operation here -- both financial and personal, with more than 210 international soldiers killed this year alone -- has made it unpopular in several countries.

Lafontaine insisted the NATO-led force had "scored some points and put pressure" on the Taliban-led insurgents, crippling their ability to stage mass attacks involving hundreds of fighters like they did a year ago.

The extremists now were forced to resort to suicide attacks, kidnappings and roadside bombs to target convoys of Afghan and international security forces.

The number of such attacks had multiplied in recent months in and around Kabul, which had largely been spared the near-daily violence seen in southern and eastern Afghanistan.

The militants have vowed to spread their campaign of violence to the north. Indeed, the country's worst-ever suicide attack took place in northern Baghlan province on November 6, killing nearly 80 people.

An ISAF spokesman, Portuguese Brigadier General Carlos Branco, said the increased number of suicide bombings were a sign of the Taliban's "weakness".

The Taliban "do not have any real success on the ground," Branco said of the group which ruled Afghanistan from 1996 to 2001, and is now blamed for most of the 130 suicide attacks here this year.

The spokesman said the militants were "unable to take their insurgency to the next level" and so had resorted to "terrorism", the use of propaganda and outright lying about the results of their actions out of desperation.

A General Description of How You Interact with Others

You are clearly a compassionate person; you believe that you should do unto others as you would have them do unto you, and you know that friends help their friends. But with you compassion is just one side of the coin; the other being a side that also expects others to hold up their end of the bargain. So you help others but it is with the expectation that others don't take advantage of you or try to put one over on you. In short, you expect others to treat you as you treat them.

And for those people who do ask for help when they should have taken responsibility for themselves? This is the time when your more hard-edged side comes out. You are skeptical of people when they expect others to bail them out of trouble; if they got themselves into the bind, they should work their way out of the trouble. If it's an emergency, or if it's a friend who has been there for you when you have had hard times, you are there in a quick minute. But you are a discerning person and to you there is a big difference between an emergency and a self-inflicted wound. You just look at the facts: how the situation developed, how serious the situation, and how they can or cannot get through things on their own. The history you have with the person and with similar situations will inform you whether this is or is not a time for you to get involved.

You also have some limits when it comes to being with people. Sure some people need to be with others all the time and seem to get recharged by helping out most anyone else. But that's not you. You know that you do best if you spend a fair amount of time on your own. Not that you are a loner, just that time spent by yourself is not wasted at all with you. You've come to understand that if you don't take good care of yourself, eventually you'll be not good to anyone, including yourself or others.

So your compassion is tempered by realism. Your sympathy for people in trouble is balanced by a critical evaluation of how they got themselves to the place they are. And you've learned to take good care of yourself, so you have something to give to your friends or others truly in need.

Introduction to Agreeableness

This section of your profile describes your interactions with other people. The ways we communicate our feelings, beliefs and ideas to others are influenced by our cultural backgrounds, the way we were raised, and sometimes which side of the bed we got up on this morning. Some of us are very mindful of others making decisions we hope will be in their best interests, even if it means sometimes neglecting our own interests. Others of us believe each person should be responsible for themselves, taking deep pride in our own character and independence with a firm belief that others are best served by doing the same. The following describes how you engage with others; illustrating the dimension of your personality that determines your independence or your desire to reach out and touch others in meaningful ways.

Positive Responses Others May Have Toward You

You are a cherished companion for those friends who can handle emotions well. They will appreciate the candor with which you express even difficult feelings like anger and fear. Your openness will make intimate conversations even more intimate, and make the connections between you as friends deeper and stronger. Some people who have trouble expressing their feelings might find in you a good example of how to be more vulnerable and more open. Your willingness and ability to share your emotions could encourage them to share theirs, and invite them into ways of being friends that will help enrich their lives.

Negative Reactions Others May Have Toward You

Undoubtedly you have met some people who get uncomfortable being around you because your feelings are so close to the surface. They may keep a bit of distance, especially around any subject that might trigger an emotional topic they are uncomfortable with. Over time, they might even stay away from you more and more. You will find you have decisions to make; do you temper your style for their comfort or do you hope they will find ways to become more comfortable with emotional expressions? Given the richness that seems to stem from your emotional life the most meaningful response is probably very apparent to you.

Introduction to Emotional Stability

We're born with the capacity to feel deeply, so it's as natural as breathing to experience a range of emotions. Fear and joy and sadness, anger and shame and disgust lie somewhere within each of us. Ah, but to what extent do we control these emotions, and to what extent do they control us? How you answer this question of how your emotions play out in your life has a great deal to do with your levels of personal satisfaction and with the character of your relationships with others. Do you manage your emotions well, keeping them in check with your thinking and your willpower, or are you someone who lets emotions have their way, giving in to the wild dance of feelings? The following paragraphs describe your emotional range in terms of being a person who is emotionally steady or someone who is responsive to whatever feelings swell up in you.

A General Description of Your Reactivity

You are an emotional person. In some ways, we are all emotional; we feel joy, anger, sadness and fear; some of us more powerfully than others - and you more powerfully than most. Your emotions are closer to the surface, and your feelings more obvious to you than is the case with most people. You've got your life in a good place, your dominant mood is upbeat, and unless life has been particularly trying for you, you greatly enjoy the richness and intensity of life that being so open with your emotions brings you.

Sure there are times when your feelings come very close to the surface, and life becomes more complicated. At these times you may grow self-conscious, or feel a bit anxious. But all in all, you much prefer being open with your emotions, breathing in all that life offers, than shutting down any part of your emotional experience. Granted, there may be times when these emotions are hard but you realize that is part of life. And more often than not you feel enriched by your emotions, by your ability to be open to all that life brings you. You know that even when you have those times that get you down, there will be even more times when you see life in ways that others just can't.

Millions of children around the world are being sexually abused and molested

Millions of children around the world are being sexually abused and molested. Billions of dollars are changing hands as part of a growing crime wave of child pornography. This is anything but a victimless crime. Children – some as young as infants – are being barbarically assaulted for the sexual gratification of their abusers and those who view their photos.

While inroads have been made in the fight against child pornography, the problem remains severe. We have much more to do.

The Internet has become a child pornography superhighway, turning children into a commodity for sale or trade. Analysts at the National Center for Missing & Exploited Children (NCMEC) have reviewed 9.6 million images and videos of child pornography on the Internet just since 2002. There are millions more such images in cyberspace that we have yet to find.

Tech Talk with Dean Takahashi

"Archive for the 'entertainment' Category Review: Microsoft makes improvements with new Zune portable media player Microsoft is at it again, improving its products one version at a time. The Zune 2 portable media player that debuts today has a better design, a better way to buy songs, and improvements in the way you can share them. Apple doesn’t need to worry about losing its dominance. The newest iPods and the iPhone have better features than the new Zune models. Version 2.0 serves to fill out Microsoft’s product line and give the Zune its own unique identity. But it will still be years before Microsoft can mount a credible challenge to Apple. One step at a time, the Microsoft folks say. This time, Microsoft designed it all in house, a move that is evident in better features such as a wheel that spins like a bicycle wheel, said Jason Reindorp, director of Zune. The company has revamped its music web sites and expanded the social networking uses of the player. And it added FM radio tuners and the ability to sync itself with a computer via Wi-Fi. Read the rest of this entry » Share This Posted on Monday, November 12th, 2007 Under: General, consumer tech news, entertainment, cool stuff, reviews, media | 8 Comments » Al Gore’s Current TV rolls out"

Google reportedly offering online storage - Tech Talk with Dean Takahashi -

Google reportedly offering online storage - Tech Talk with Dean Takahashi -: "Google reportedly offering online storage By Dean Takahashi Tuesday, November 27th, 2007 at 7:55 am in General, Google, storage. Looks like Box.net and others like it are going to have a very big competitor. According to a report in the Wall Street Journal today, Google is working on providing online storage to users. Here’s the top of that story: Google Inc. wants to offer consumers a new way to store their files on its hard drives, in a strategy that could accelerate a shift to Web-based computing and intensify the Internet company’s competition with Microsoft Corp. Google is preparing a service that would let users store on its computers essentially all of the files they might keep on their personal-computer hard drives — such as word-processing documents, digital music, video clips and images, say people familiar with the matter. The service could let users access their files via the Internet from different computers and mobile devices when they sign on with a password, and share them online with friends. It could be released as early as a few months from now, one of the people said. The Mountain View, Calif., company plans to provide some free storage, with additional storage allotments available for a fee, say the people"

Innovation Tour

"Neither is there anything better you can do for short-term results than to focus on recruitment and employer branding. It is increasingly difficult to get the attention of top talent, and firms must carefully craft a powerful message -- whether for a single career opportunity or a comprehensive recruiting campaign. Success demands that HR and marketing pros work hand-in-hand to portray the right image and message: HR must think like marketers, and marketers must understand how employment branding is different from product branding, and that it is just as important to competitive success. Successful organizations pair their most creative HR and Talent Management leaders with marketing professionals to build an employment branding strategy that solves these challenges and complements the organization's overall image."

Israeli troops killed three Palestinians

The Statesman: "Monday November 26, 2007 Mashriq Group of Newspapers Editor-in-Chief Syed Ayaz Badshah Israeli army kills three Palestinians TULKAREM: Israeli troops killed three Palestinians on Sunday, one of them in a refugee camp in the occupied West Bank and two in the Hamas-run Gaza Strip, officials on both sides said. In the northern West Bank town of Tulkarem, Israeli troops shot dead Mohammad Qozah, 25, of the Al-Aqsa Martyrs' Brigades, a group loosely linked with president Mahmud Abbas's Fatah party, medics and Palestinian security sources said. An army spokeswoman said that troops had entered the Tulkarem refugee camp in search of two fighters and shot at the men as they tried to flee. One of the men was killed and the other wounded and evacuated to hospital in Israel, she said. In the Gaza Strip, two fighters -- one from Islamic Jihad and another from the Popular Resistance Committees -- were killed early on Sunday. The army said that an Israeli patrol saw the men approaching the border fence that separates the impoverished territory from Israel and killed the militants in a subsequent exchange of fire. - AFP Head Office Islamabad Office Lahore Office Karachi Office Bilal Town, G T Road Peshawar City P.O. Box 1107 "

30 militants killed as army launches grand operation

MINGORA: Eventually Army has launched a grand operation against pro-Taliban Maulana Fazlullah and his armed militants after imposing curfew for an indefinite time in the picturesque highland valley on Sunday.

The security forces have besieged Imam Dehri village, a stronghold of the militants, a day after food and necessary items supply was discontinued to the area.

"Curfew has been imposed in the valley for indefinite time to deny the militants any chance to escape," said Iqbal, in charge of Press Media Centre in Mingora.

He said the army artillery and gunship helicopters have destroyed the ammunition reserve of the militants, main source of their weaponry in a government school in Imam Dehri.

Security forces have secured prominent heights including Najia top and Usmani Sar thus dominating Imam Dehri, Kuza Banda, Bara Banda and Ningualai areas.

Authorities have confirmed the death of 30 militants, one security personnel and four other injured in the operation launched on Saturday midnight.

Till filling of this report, the security forces were shelling the hideouts of militants from Saidu Sharif airport, FC Kanju camp, Golf Course, Fizagut, Rumi rest-house and Kabal areas.

It was learnt that three painters, who were working at a house at Salundai, and two others persons at Bandai village were killed by mistake as mortar shells fired by military hit them.

Telephone lines and mobile connections had been off in the areas still in the control of Maulana Fazlullah's militants. Power supply to the affected areas in Swat had also been suspended.

PHARMACOLOGY OF Cefazolin

Pharmacopoeia description

USP 25: A white to slightly off- white, odorless crystalline powder. Slightly soluble in water, in water, in alcohol, and in methyl alcohol; sparing soluble in acetone; practically insoluble in chloroform, in dichloromethane, in ether, and in benzene; soluble in dimethylformamide and in pyridine; very slightly soluble in ethyl acetate, in isopropyl alcohol, and in methyl isobutyl ketone. Store in airtight Container.


Cefazolin Sodium (44-m)

1.05 g of monograph substance is approximately equivalent to 1 g of Cefazolin. Each g of monograph substance represents about 2.1 mmol of sodium.
Cefazolin sodium has been reported to be incompatible with Aminoglycosides and many other Groups. When the pH of a solution exceeds 8.5 there may be hydrolysis and when it is below 4.5 insoluble Cefazolin may be precipitated.

Pharmacopoeial description

Ph. Eur, A white or almost white, very hygroscopic powder. Freely soluble in water; very slightly soluble in alcohol; practically insoluble in ether. A 10% solution in water has a pH of 4.0 to 6.0. Store at a temperature not exceeding 30º in airtight container. Protect from light.

Uses and Administration

Cefazolin is a first –generation cephalosporin Antibiotic used in the treatment of a variety of infection due to susceptible organisms, including billiary-tract infection, Endocarditis (staphylococcal), and peritonitis (associated with continuous ambulatory peritoneal dialysis). It is also used for surgical infection Prophylaxis, including Prophylaxis of these infections, and their treatment, see under Choice of Antibacterial.
Administration and dosage. Corazon is given as the sodium salt by deep intramuscular injection, by slow intravenous injection over 3 to 6 minutes, or by intravenous infusion. Doses are expressed in terms of the equivalent amount of Cefazolin e. The usual adult dose is 0.5 to 1 g every 6 to 12 hours. The usual maximum daily dose is 6 g; although up to 12 g has been used in sever life –threatening infection. Children over 1month may be given 25 to 50 mg per kg body –weight daily in three or four divided doses, increased in severe infection to a maximum of 100 mg per kg daily. For the Prophylaxis of infection during surgery, a 1-g dose is given half to one hour before the operation, followed by 0.5 to 1 g is given every 6 to 8 hours postoperatively for 24 hours, or up to 5 days in creation cases.
Dosage should be reduced in patient with renal impairment and various modification heave been recommend. The manufacturers suggest the following for adults following a loading dose; creatinine clearance 55 mL or more per minute, usual doses; 35 to54 mL per minute, usual doses but at intervals of at least 8 hours; 11 to 34 mL per minute, half the usual dose every 12 hours; 10 mL or less per minute, half the usual dose every 18 to 24 hours.
Other routes of administration used for Cefazolin sodium include intraperitoneal administration in peritoneal dialysis solution and intra –ocular injections. In some countries a modified –release intramuscular formulation of Cefazolin sodium together with the less soluble Dibenzylamine salt of Cefazolin, in the ratio of 1:4 has been used.

Antimicrobial Action

As for Cefalotin Sodium, p.163, although Cefazolin is more sensitive to staphylococcal beta – lactamase. The minimum inhibitory concentrations of Cefazolin for susceptible Gram-positive cocci range from about 0.1 to 1 µg per mL; for the majority of susceptible Gram-negative bacteria concentration of greater then 1µg per mL are required.

Pharmacokinetics

Cefazolin is poorly absorbed from the gastrointestinal tract and is given by intramuscular or intravenous injection. Following a dose of 500 mg given intramuscularly, peak plasma concentration of 30 µg or more per mL are obtained after 1 to 2 hours. About 85% of Cefazolin in the circulation is bound to plasma protein. The plasma half-life of Cefazolin is about 1.8 hours, and is increased in patient with renal impairment. Cefazolin diffuse into ascetic, pleural, and Synovial fluid but not appreciably into the CSF. It cross the placenta into the fetal circulation; only low concentration are detected in breast milk. Cefazolin is excreted unchanged in the urine, mainly by Glomerular filtration with some renal tubular secretion, at least 80% of a dose given intramuscularly being excreted within 24 hours. Peak urine concentration of more then 1 and 4 mg per mL have been reported after intramuscular doses of 0.5 and 1 g respectively. Probenecid delays excretion. Cefazolin is removed to some extent by Haemodialysis.
High billiary concentration has been reported, although the amount execrated by this route is small.

Pharmaceutical ingredients for both human and veterinary preparations.

Sometimes several firms cooperate in the production (including packaging and labelling) of an active pharmaceutical ingredient. It may also happen that a finished, packed, and labelled active pharmaceutical ingredient is repacked and/or relabelled and given a new designation. Since such procedures constitute part of a manufacturing operation, they should be subject to the relevant guidelines set out below.
The practices outlined below are intended to apply to active pharmaceutical ingredients for both human and veterinary preparations.
Personnel
Each firm should employ personnel with the necessary qualifications and competence for the production and quality control of active pharmaceutical ingredients. There should be an adequate number of staff with appropriate education, technical knowledge, and practical experience related to the job they perform.
The firm should have a defined organization represented in a chart. Individual responsibilities should be laid down in written instructions, to ensure that there are no gaps or overlaps. The responsibilities placed on any one individual should not be so extensive as to incur any risk to quality.
Staff at all levels should be adequately trained for the tasks and responsibilities assigned to them.
Measures should be taken to ensure that no person affected by a disease in a communicable form or having open lesions on the exposed surface of the body is engaged in any production step involving direct contact with the active pharmaceutical ingredients.
Premises
Premises, including areas containing open tanks, should be of suitable construction. They should provide a suitable environment for manufacturing operations and should be adequately adapted to and of a sufficient size for their intended use. The premises should not contribute to actual or potential mix-ups or contamination of the active pharmaceutical ingredients. The arrangement should provide for a logical work flow.
For special purposes, such as the production of sterile products and of certain antibiotics, hormones, and cytostatic substances, separate specifically designed enclosed areas with completely separate air-handling systems should be provided.
To maintain hygienic working conditions, the premises should include facilities for changing clothes, washing, and toilet purposes as well as for eating, drinking, and smoking.
Equipment
Manufacturing equipment should be designed, constructed, located, and maintained in such a way as to:
(a) be suitable for its intended use;
(b) facilitate thorough cleaning;
(c) minimize the risk of contamination of products and containers during production; and
(d) facilitate efficient and, if applicable, validated and reliable operation.

application of cGMP

Since there are fundamental distinctions between the production of bulk active pharmaceutical ingredients and the formulation of finished pharmaceutical products, the strict application of GMP as set forth in the main part of this guide is not always practical or necessary. The present supplementary guidelines outline procedures and practices that manufacturers should employ to ensure that the methods, facilities, and controls used for the production of active pharmaceutical ingredients are operated or managed so that such products have the quality and purity appropriate for their use in finished pharmaceutical products.
General considerations
In the manufacture of active pharmaceutical ingredients, overall control is essential to ensure high quality. Haphazard operations cannot be permitted in the manufacture of substances that may be used to save life or to restore or promote health.
Recommended practices for the manufacture of active pharmaceutical ingredients are set out below. Adherence to these practices, complementing the various control tests carried out from the beginning to the end of the production cycle, will contribute substantially to the production of consistently uniform batches of high-quality active pharmaceutical ingredients.
The manufacturer must assume responsibility for the quality of the active pharmaceutical ingredients produced. The manufacturer alone can avoid mis-takes and prevent mishaps by exercising adequate care in both production and control procedures. Full evidence of compliance with GMP should be given from the step from which the processes or the starting materials used have a critical influence on the quality of the active pharmaceutical ingredient. This step should be determined in each individual case by agreement between the competent authority and the manufacturer.
The good practices outlined below should be considered general guides; whenever necessary, they may be adapted to meet individual needs provided the established standards of quality of the active pharmaceutical ingredients are still achieved. The good practices are intended to apply to the manufacturing processes (including packaging and labelling) used in the production of active pharmaceutical ingredients.

REGULATORY APPROACH

One goal of this guidance is to tailor the Agency's usual regulatory scrutiny to meet the needs of PAT-based innovations that (1) improve the scientific basis for establishing regulatory specifications, (2) promote continuous improvement, and (3) improve manufacturing while maintaining or improving the current level of product quality assurance. To be able to do this, manufacturers should communicate important scientific knowledge to the Agency and resolve related technical issues in a timely manner. Our goal is to facilitate a flexible regulatory assessment involving multiple Agency offices with varied responsibilities.

This guidance provides a broad perspective on our proposed PAT regulatory approach. Close communication between the manufacturer and the Agency’s PAT review and inspection staff will be a key component in this approach. We anticipate that communication between manufacturers and the Agency will continue over the life cycle of a product and that communication will be in the form of meetings, telephone conferences, and written correspondence. Any written correspondence should be identified clearly as Process Analytical Technology or PAT. All marketing applications, amendments, or supplements to an application should be submitted to the appropriate CDER or CVM division in the usual manner.

We recommend general correspondence related to PAT be directed to our new FDA PAT Team. Manufacturers can also contact the PAT Team regarding any PAT questions or issues related to nonapplication drug products or not pertaining to a specific submission or application at the address below.

FDA Process Analytical Technology Team
Office of Pharmaceutical Science, HFD-003
Center for Drug Evaluation and Research
5600 Fishers Lane
Rockville, MD 20857

For currently approved products, during their planning phase, manufacturers should consider the effects of PAT on the current process, in-process controls, and specifications. When consulting with the Agency, manufacturers may want to discuss not only specific PAT plans, but also thoughts on a possible regulatory path.

This guidance is also intended to encourage research to explore suitability and validation strategies for new technologies prior to planning and implementing PAT-based manufacturing. If research is conducted in a production facility, it should be under the facility's own quality system. Information generated from this research along with other information that provides process understanding can be used to formulate and communicate implementation plans to Agency staff. Plans for implementing and regulatory assessment of PAT can be agreed to with the Agency through a variety of communication channels.

Section 116 of the 1997 Food and Drug Administration Modernization Act amended the Food, Drug, and Cosmetic Act by adding section 506A (21 U.S.C. 356a), which provides requirements for making and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes. We recommend that manufacturers continue to consider all relevant FDA guidance documents for recommendations on the information that should be submitted to support a given change.

In general, PAT implementation plans should be risk based. We are proposing the following possible implementation options:

• PAT can be implemented under the facility's quality system; CGMP inspections by the Agency follow.
• PAT can be implemented following CGMP inspection by the PAT Team.
The PAT Team can assist manufacturers with pre-operational review of the PAT manufacturing facility and process (ORA Field Management Directive NO. 135). The recommendations in the inspection report will serve as a summary basis of final approval of the process and be filed in the relevant application, where needed, and facility databases within the Agency.
• A supplement (CBE, CBE-30 or PAS) can be submitted to the Agency prior to implementation, and, if necessary, an inspection can be performed by a PAT Team or PAT certified investigator before implementation.
• A comparability protocol can be submitted to the Agency outlining PAT research, validation and implementation strategies and time lines. Following approval of this comparability protocol by the Agency, one or a combination of the above regulatory pathways can be adopted for implementation.
It should be noted that when certain PAT implementation plans neither affect the current process nor require a change in specifications, several options can be considered. manufactures should evaluate and discuss with the Agency the most appropriate option for their situation.

Regulatory Strategies

The Agency understands that to enable successful implementation of PAT, flexibility, coordination, and communication with manufacturers is critical. The Agency believes that current regulations are sufficiently broad to accommodate these new strategies. Regulations can effectively support innovation (e.g., new drugs and drug delivery systems) as long as clear communication mechanisms exist between the Agency and industry, for example, in the form of meetings or informal communications between the Agency and manufacturers during drug development.

The first component of the PAT framework described above addresses many of the uncertainties with respect to new technologies and outlines broad principles for addressing anticipated scientific and technical issues. This information should assist a manufacturer who is proposing to the Agency innovative technologies that may call for a new regulatory path. The Agency encourages such proposals and has developed new regulatory strategies to consider such proposals. The Agency's new regulatory strategy includes (1) a PAT team approach for CMC review and CGMP inspections; (2) joint training and certification of PAT review, inspection and compliance staff; (3) scientific and technical support for the PAT review, inspection and compliance staff; and (4) the recommendations provided in this guidance.

The recommendations provided in this guidance are intended to alleviate the fear of delay in approval as a result of introducing new manufacturing technologies. Ideally PAT principles and tools should be introduced during the development phase. The advantage of using these principles and tools during development is to create opportunities to improve the mechanistic basis for establishing regulatory specifications. Manufacturers are encouraged to use the PAT framework to develop and discuss approaches for establishing mechanistic-based regulatory specifications for their products.

We also encourage the use of PAT strategies for the manufacture of currently approved products. Manufacturers may want to evaluate the suitability of a PAT tool on experimental and/or production equipment and processes. For example, when evaluating experimental on- or in-line process analyzers during production, it is recommended that risk analysis of the impact on product quality be conducted before installation. This can be accomplished within the facility's quality system without prior notification to the Agency. Data collected using an experimental tool should be considered research data.

When using new measurement tools, such as on/in-line process analyzers, certain data trends that may be intrinsic to the current acceptable process may be observed. Manufactures should scientifically evaluate these data to determine how or if such trends affect quality and implementation of PAT tools. FDA does not intend to inspect research data collected on an existing product for the purpose of evaluating the suitability of an experimental process analyzer or other PAT tools. FDA's routine inspection of a firm's manufacturing process that incorporates a PAT tool for research purposes will be based on current regulatory standards (e.g., test results from currently approved or acceptable regulatory methods). Any FDA decision to inspect research data would be based on exceptional situations similar to those outlined in Compliance Policy Guide Sec. 130.300. Those data used to support validation or regulatory submissions will be subject to inspection in the usual manner.

Integrated Systems Approach

The fast pace of innovation in today's information age necessitates integrated systems thinking for evaluating and timely application of efficient tools and systems that satisfy the needs of patients and the industry. Many of the advances that have occurred, and are anticipated to occur, are bringing the development, manufacturing, quality assurance, and information/knowledge management functions so closely together that these four areas should be coordinated in an integrated manner. Therefore, upper management support for these initiatives is critical for successful implementation.

Drug formulations and manufacturing processes

Design and optimization of drug formulations and manufacturing processes within the PAT framework can include the following steps (the sequence of steps can vary):

• Identify and measure critical material and process attributes relating to product quality
• Design a process measurement system to allow real time or near-real time (e.g., on-, in-, or at-line) monitoring of all critical attributes
• Design process controls that provide adjustments to ensure control of all critical attributes
• Develop mathematical relationships between product quality attributes and measurements of critical material and process attributes
Therefore, it is important to emphasize that a strong link between product design and process development is essential to ensure effective control of all critical quality attributes. Process monitoring and control strategies are intended to monitor the state of a process and actively manipulate it to maintain a desired state. Strategies should accommodate the attributes of input materials, the ability and reliability of process analyzers to measure critical attributes, and the achievement of pre-established process endpoints to ensure consistent quality of the output materials and the final product.

Within the PAT framework, a process endpoint need not be a fixed time, but can be the achievement of the desired material attribute. This, however, does not mean that process time is not considered. A range of acceptable process times (process window) is likely to be achieved during the manufacturing phase and should be evaluated, and considerations for addressing significant deviations from acceptable process times should be developed. Process end points intended for use in real time release should be considered more critical than those that are only used for in-process control.

Where PAT spans the entire manufacturing process, the fraction of in-process materials and final product evaluated during production could be substantially greater than what is currently achieved using laboratory testing. Thus, an opportunity to use more rigorous statistical principles for a quality decision is provided. Multivariate Statistical Process Control can be feasible and valuable to realizing the full benefit of real time measurements. Similarly, rigorous statistical principles should be used for defining acceptance criteria for end product attributes (e.g., content uniformity) that take into consideration differences in the nature of the test (e.g., continuous monitoring) and sample size between an on-line test and a current laboratory test.

Real time or near real time measurement tools typically generate large volumes of data. Certain data are likely to be relevant for routine quality assurance and regulatory decisions. In a PAT environment, batch records should include scientific and procedural information indicative of high product and process quality. For example, batch records could include a series of charts depicting acceptance ranges, confidence intervals, and distribution plots (inter- and intrabatch) showing measurement results. Ease of secure access to these data is important for real time manufacturing control and quality assurance. Installed information technology systems should accommodate such functions.

Technologies that incorporate greater product and process understanding can provide a high assurance of quality on every batch and provide alternative, effective mechanisms to achieve validation. In a PAT framework, process validation can be enhanced and possibly consist of continuous quality assurance where a process is continually monitored, evaluated, and adjusted using validated in-process measurements, tests, controls, and process endpoints.
Installation of process analyzers on existing process equipment in production should be done after risk-analysis to ensure this installation does not adversely affect the process or product quality (i.e. qualified equipment and validated process). Based on this assessment, it should be decided if the existing process should be revalidated or not.

Risk-based approaches are suggested for validation of PAT software systems. The recommendations provided by other FDA guidances such as General Principles of Software Validation should be considered. Other useful information can be obtained from consensus standards, such as ASTM and Good Automated Manufacturing Practices (GAMP) listed in the bibliography section.

Pharmaceutical manufacturing processes

Pharmaceutical manufacturing processes often consist of a series of unit operations, each intended to modulate certain properties of the materials being processed. To ensure acceptable and reproducible modulation, consideration must be given to the quality attributes of incoming materials and their process-ability for each unit operation. During the last 3 decades, significant progress has been made in developing analytical methods for chemical attributes (e.g., identity and purity). However, certain physical and mechanical attributes (e.g., particle shape, size distribution, inter- and intra-particulate bonding) of pharmaceutical ingredients are relatively difficult to characterize, and adverse effects due to inherent quality variability are often not recognized until after manufacture. Establishing effective standards or specifications for physical attributes of raw (e.g., excipients) and in-process materials poses a significant challenge because of the complexities of such attributes (e.g., particle shape and shape variations within a sample) and because of difficulties related to collecting representative powder samples for testing. It is well known that powder sampling procedures can be prone to sampling errors.

Formulation design strategies exist that provide robust processes that are not adversely affected by minor differences in physical attributes of raw materials. Because these strategies are not generalized and are often based on the experience of a particular formulator, the quality of these formulations can only be evaluated by testing samples of in-process materials and end products. Currently, these tests are performed off line after preparing collected samples for analysis. Different tests, each for a particular quality attribute (e.g., content uniformity, moisture content, dissolution rate), are needed because such tests only address one attribute of the active ingredient following sample preparation (e.g., chemical separation to isolate it from other components). During sample preparation, other valuable information pertaining to the formulation matrix is often lost. Several new technologies are now available that can acquire information on multiple attributes with minimal or no sample preparation. These technologies provide an opportunity to assess multiple attributes, often nondestructively.

Currently most pharmaceutical processes are based on time defined end points (e.g., blend for 10 minutes). However, in some cases, these time defined end points do not completely take into consideration physical differences in raw materials (e.g., excipients). Processing difficulties can arise that result in failure of the product to meet specifications, even if certain raw materials conform to established specifications.

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