After another year of steady decline in inspection and drug GMP warning letter activity at FDA's Center for Drug Evaluation and Research under President George W. Bush, there is a palpable expectation that the Obama administration soon will sharply reverse the downward trend in the amount and intensity of CDER enforcement activity.

In the eight years since Bush took office, field staffing has declined 10 percent and inspection activity has declined 20 percent, according to data from FDA's Enforcement Story, a recent FDA Science Board report and the FY 2008 FDA budget (see chart: " ¹ CDER Inspections and Field Staff Declined Under President Bush ").

The annual drug GMP warning letter rate, which had reached as high as 100 in the 1990s, also fell under Bush, particularly in fiscal year 2003 when CDER and the Office of Chief Counsel began reviewing letters prior to issuance ("The Gold Sheet" April 2004). The rate bottomed out at 20 or less over the past four years, including 18 in the fiscal year that ended Sept. 30, 2008.

As the warning letter rate declined, drug recalls increased, particularly during Bush's second term - a possible sign of lax compliance resulting in quality breakdowns (see chart: " ² The Bush Years: Fewer Drug Warning Letters; More Recalls ").

Early indications are reinforcing widespread expectations of an increase in enforcement activity at FDA. From President Obama down, there is a tougher tone. There are criminal prosecutions, there is a flood of money from Congress and there are signs FDA may open the warning letter floodgates.

However, at least domestically, the agency will have to rely heavily on new hires to get tough with industry as senior personnel retire or transfer to the frontlines of the agency's global enforcement crackdown in places like China and India.

Peanut Crisis Strikes Home - at the White House

In an early indication of where FDA could be headed in terms of enforcement, David Chesney of Parexel noted that as a result of the recent Peanut Corp. of America debacle, one of the first things President Obama did after he took office Jan. 20 was to call for a "full review" of FDA.

Speaking at a March 25-26 Pharma Conference meeting in Bethesda, Md., on U.S. and EU inspections, Chesney noted that "now you have a new president elect who has promised a lot of change and he has two beautiful children and one morning he wakes up and the young one has gone off to school with her peanut butter sandwich in her Hannah Montana lunchbox and he starts reading the newspaper and says, 'hmm, that might be the salmonella-tainted peanut butter sandwich.' How would you feel if you are the new president elected on a platform of change? He went on the Today show on February 2 and said that he was ordering a complete review of FDA for failure to recognize this problem and he said that they are not catching things as quickly as he would like them to."

The contaminated peanut butter crisis has lawmakers looking at giving FDA mandatory recall authority over food so it will not have to wait for industry to act. It also has industry worried about a more prosecutorial bent at the agency.

More Criminal Prosecutions Anticipated

Chesney predicted that FDA will bring more criminal prosecution cases against medical product and food manufacturers, harkening back to a time in the 1970s when such prosecutions were more common. As evidence of this trend, he cited cases FDA has brought against Purdue Frederick and the Peanut Corp. of America.

Chesney said that these cases are "influencing this trend in public outrage and demands for accountability of companies and executives stemming from the economic crisis and related scandals in the financial world."

Chesney said that in the Purdue Frederick case, three executives of the company were subject to "strict liability prosecution" over alleged misbranding of OxyContin (oxycodone) extended-release tablets.

The $634 million settlement was FDA's third largest with a pharmaceutical company in a health care fraud investigation.

It was also the first time in about 30 years that the government had invoked the "responsible officer doctrine" to hold executives accountable for the company's claims that OxyContin was less addictive and less likely to cause withdrawal than other pain medications.

"The use of that doctrine in Purdue was somewhat of a shock to many executives in the pharmaceutical and life sciences industry," said Brien O'Connor, a partner at Ropes & Gray. "People are wondering if it's the beginning of a trend, or if the Purdue case can be explained by the fact that it involved a drug - OxyContin - with obvious, serious and direct potential effects on the public health," he told "The Gold Sheet."

And in the case of PCA, FDA is working with the Department of Justice in an investigation of the company. Salmonella-tainted peanuts from PCA are believed to be linked to eight deaths and the illnesses of more than 500 people in 43 states.

While any criminal charge against the company would come from a DOJ investigation, FDA also is considering other enforcement action, including seizures of PCA products and injunctions against the company's operations. The company has filed for chapter 11 bankruptcy.

A Shot in the Arm from Congress

For FDA to ramp up enforcement activity, particularly overseas, it will need a substantial infusion of resources.

At the rate it was going in 2007 for example, it would take the agency 55 years to inspect all the drug establishments in China that are exporting to the U.S., the General Accounting Office found ("The Gold Sheet," November 2007).

In the wake of contamination problems with heparin from China that was linked last year to 81 deaths and hundreds of allergic reactions in the U.S., the agency came under fire from lawmakers for infrequent inspections of plants abroad.

Now Congress is throwing money at the agency to get a handle on foreign inspections. At a time when federal spending was hard to come by, the agency's budget increased 9 percent in fiscal year 2008, and later received an additional 9 percent in supplemental FY 2008 appropriations.

The agency operated under a continuing resolution for the first half of fiscal year 2009. Then in just two weeks and two days, Congress crafted an omnibus spending bill that gives FDA 19 percent more and rushed it to President Obama, who signed it March 11.

The omnibus bill adds $114 million to FDA's drug, device and biologics centers for medical product safety. This comes atop a $21 million increase and a supplemental $58 million for the prior year budget.

Those funding increases should give FDA the capability to "significantly increase foreign and domestic medical product facility inspections, improve laboratory infrastructure and rapid analysis tools, and conduct many more laboratory analyses and several thousand import exams and samples," said Rep. David Obey, D-Wis., chairman of the House Appropriations Committee, in an explanatory statement he introduced into the Congressional Record Feb. 23.

It should also enable IT upgrades for data sharing and adverse event analysis, a data warehouse that FDA can share with other regulatory agencies, and the integration of risk-based information into the agency's electronic screening of imports, among other things.

Obey also noted a $142 million increase in FY 2009 for food safety, which he expects FDA will use to inspect more domestic and international food production and processing facilities, inspect more high-risk facilities making other products, and further expand its presence overseas, among other things.

How Much More HQ Review of Warning Letters?

To the extent that churning out warning letters instills fear in drug GMP slackers, FDA has in recent years given minor violators little reason to tighten up the quality of their drug manufacturing operations.

Since 2003, warning letters have required the review and concurrence of attorneys in the Office of the Chief Counsel prior to issuance, and those that address GMP issues also have required CDER's approval. Only the most egregious violators have been passing those tests.

The extra review led to a marked decline in the number of warning letters. The party line at FDA was that it made for better, more consistent warning letters that focused attention on the most important issues. But there was an undercurrent of frustration in the field offices, where many suspected a laissez faire ideology lurked behind the restrictions.

Phil Campbell of FDA's Atlanta Regional Office fielded a question March 12 at the 33 International GMP Conference in Athens, Ga., on whether headquarters review of warning letters will continue.

The March 9-12 conference was sponsored by the University of Georgia College of Pharmacy, the Georgia Center for Continuing Education and FDA.

Campbell responded that - at least for the time being - the policy will remain unchanged. "Every CDER GMP warning letter has to be reviewed and approved by [Monica Caphart's] group. I have to convince her that this is a good use of the agency's resources. They have clearly raised the bar as to what it will take to trigger the issuance of a drug GMP warning letter. There's no question about that."

He added that because the field offices know how difficult it is to get headquarters to approve warning letters, they "go to great lengths" to try to convince manufacturers to change voluntarily. He said that headquarters has "clearly raised the bar. The letter comes back to us, why is this significant? Why is this significant? If we do not have a good answer it will not be approved."

Whether the Obama administration will lower that bar remains an open question, but there are signs that it may.

Last November the Prescription Project, a public interest group in Boston, proposed discontinuing the Office of Chief Counsel's review of warning letters as the most urgent of 16 policy changes recommended for the first 60 days of Obama's FDA.

The group referenced a January 2004 letter from Rep. Henry Waxman, D-Calif., then the ranking minority member of the House Government Reform Committee, complaining to the agency that the additional review was reducing and slowing its response to false and misleading advertising.

On Waxman's committee staff at the time was Joshua Sharfstein, who President Obama appointed March 30 as FDA's deputy commissioner.

In one of his first acts at FDA, Sharfstein April 6 expanded a recall of potentially contaminated pistachios, signaling a pre-emptive approach to enforcement that could carry over into warning letters.

Meanwhile, in an interview earlier this year with the American Health Lawyers Association, the outgoing chief counsel, Gerald Masoudi, argued for continued legal review of warning letters.

"A warning letter is a statement by the agency that there is a violation of law and that the recipient should fix it or the agency will take action. It is inherently a conclusion that needs to be reviewed by lawyers," Masoudi said.

"The consequences of a warning letter are too great for there not to be legal input: It can harm the company's reputation, lead to a lawsuit, and be costly for a company to address. So yes, warning letters should be reviewed by the Chief Counsel's Office."

Masoudi argued that the number of warning letters issued is not a good measure of enforcement. "Today, when a company gets a warning letter, it knows that the Chief Counsel's Office would back it up with legal action if the company fails to take corrective action. Review by the Chief Counsel's Office is protective of the agency. If letters went out that didn't have factual or legal support, industry would ignore them, and the letters would become an ineffective tool for ensuring compliance."

New Leadership Will Set New Course

Observers are predicting that the new administration will take a more proactive approach to enforcement than occurred under President George W. Bush, though what direction they take won't become clear until after they take office.

William Hubbard, a former FDA associate commissioner, told "The Gold Sheet" that "I would expect that you would get stronger enforcement with the Democrats. With Bush there was a de-emphasis on enforcement." Under Obama, he said that he expects to see an increase in warning letters and seizures.

Hubbard noted, however, that it is still too early to know the administration's enforcement priorities with any certainty.

The Senate still must confirm the nomination of former New York City Health Commissioner Margaret Hamburg before she can take office as FDA commissioner. Her principle deputy, former Baltimore Health Commissioner Joshua Sharfstein, is acting in her stead, but the one-time Waxman staffer has just started at the agency.

It is expected that Sharfstein, a pediatrician, will press for stricter oversight of the drug industry. He earned national attention for his role as lead author of a citizen petition asking FDA to revise the pediatric cough/cold monograph, which led to labeling changes and the removal of some products from the market.

"A new administration always tends to order a clean sweep. This one is no exception," observed Parexel's Chesney. "The conventional wisdom is that Democrats are stronger on enforcement than Republicans. Maybe. But [former FDA Commissioner] David Kessler was a Republican and was the strongest enforcement-oriented commissioner in recent history."

Observers agree, however, that with key positions still unfilled it may be too early to tell what will happen. These positions include the chief counsel, the associate commissioner for regulatory affairs and the director of the office of enforcement.

Campbell noted at the Georgia GMP conference that "we're anxious to get those positions filled because once they are filled our enforcement challenges will change. The sooner we can get those positions filled, the better. There are key positions now vacant at FDA that, when filled, will set the inspection and enforcement tone going forward."

More Investigators but Less Experience

A huge influx of new investigators at FDA won't necessarily translate to tougher enforcement, at least initially.

Campbell told the Georgia conference that, thanks to a recent spending bill approved by Congress, the agency has hired 400 new investigators and "there is talk of hiring 200 more."

Campbell noted that "we had not hired to any significant degree since 9/11 and we lost over half of those. … This is clearly what we needed for a long period of time. We were not allowed to say this before but we got to the point where we couldn't do more with less."

However, Campbell warned that many of the new investigators are inexperienced and "the learning curve is pretty steep. We're diligently working to get them up to speed. It looks like we will continue to struggle with resources. We are going to have to continue to make difficult decisions. Hopefully we won't have to make as many of those difficult decisions."

It remains to be seen whether the new money and neophytes will enable FDA to increase enforcement before Congress loses patience.

Seasoned Investigators Transferred Overseas

Meanwhile, the new hires are losing mentors fast.

Chesney told the Pharma Conference meeting that "a generational change is taking place; FDA has lost many key leaders to retirement over the past five years and will lose many more over the next five years. This may result in the industry seeing more trainee-level investigators on inspections for the next couple of years or more."

And while there is an influx of new investigators, many of the more seasoned ones are either being transferred overseas to audit foreign facilities or are retiring, said Chesney.

Campbell said that CDER recently identified 20 drug investigators who will spend the next two years conducting foreign inspections. "Last year," he observed, "there were $2 trillion worth of FDA regulated products imported. The Beyond our Borders Initiative and the Strategic Supply Chain initiative shows we're obviously trying to get a grip" on the additional workload (for more on the Strategic Supply Chain Initiative, see story p. 14).

FDA announced its Beyond Our Borders program on Jan. 15 with the opening of its first office in India. Last year FDA set up its first offices in the Chinese cities of Beijing, Shanghai and Guangzhou.

These two programs, said Chesney, "attempt to address this issue of parity in foreign inspections. The bad part of that is that many of our best and brightest will be off doing these foreign inspections."

Chesney concurred that FDA's new offices in China and soon-to-be opened office in India will be staffed by seasoned inspectors. For example, he noted that Michael Kravchuk, who will oversee operations in China, is the former head of FDA's New England District Office and a 36-plus year veteran of FDA's inspection force.

Chesney noted also that "the influence of international GMP inspectorates within the U.S. will increase, just as FDA increases its presence and influence abroad. Look for more and closer close cooperation between FDA and its international counterpart agencies."

Warning Letter Focus Shifting Overseas

There was one notable shift in last year's warning letters: The number sent to foreign firms doubled. Six of the 18 FY 2008 warning letters went to foreign sites, compared to three in FY 2007 (see "The Gold Sheet," June 2008, p, 1).

The heparin tragedy last year and the ongoing quest to prevent contaminated active ingredients from entering the U.S. supply chain were reflected in this shift.

Three of the foreign warning letters went to API manufacturers in China and Japan for manufacturing adulterated ingredients.

FDA issued one on April 21, 2008, to Changzhou SPL, the Chinese facility that supplied Baxter with contaminated heparin API linked to numerous severe and fatal allergic reactions ("The Gold Sheet," May 2008, p. 6).

The warning letter offered insight into the agency's interpretation of regulatory and compendial guidelines for ensuring the purity of active ingredients and the adequacy of API manufacturers' suppliers.

FDA said that Changzhou SPL failed to provide assurance that the processing steps it used to manufacture heparin API were capable of removing the impurities.

An Oct. 31, 2007, warning letter sent to Northeast General Pharmaceutical Factory graphically illustrates GMP problems at an API manufacturing facility in Shenyang, China (see "The Gold Sheet," November 2007, p. 21).

The letter describes a production area, which was not operational during the inspection, where there was "rust and flaking paint on the inside of [redacted]. Above these ports was an unclean and damaged ceiling. Inside the [redacted] of another vessel were numerous dried white paint drips running down the inside of the vessel. In the bottom of this vessel were white flakes that appear to be chipping paint…These conditions pose a potential for product contamination."

Decline in Foreign Inspections Resumed

Anthony Charity of CDER's Division of Manufacturing and Product Quality told the March 26 Pharma Conference meeting that the number of CDER domestic inspections dropped from 2,058 in FY 2006 to 1,812 in FY 2007 and 1,770 in FY 2008.

The number of foreign inspections similarly dropped after experiencing a slight gain in FY 2007. The number of foreign inspections was 342 in FY 2006, 501 in FY 2007, and 451 in FY 2008.

Campbell noted that out of the total number of domestic inspections in FY 2008, FDA issued Form 483s to 42 percent of all the domestic firms inspected, and to 60 percent of all foreign firms inspected.

Campbell said that these numbers were fairly consistent with the year before. In FY 2007, FDA issued Form 483s to 45 percent of all domestic firms inspected and 54 percent of all foreign firms inspected.

Nature of GMP Problems Unchanged

The nature of last year's drug GMP problems had not changed from the year before, Campbell told the Georgia GMP meeting.

"What really struck me as I put this [presentation] together was how little things had changed. Things that dominated our time and attention in 2007 pretty much dominated our time in 2008. Things like food safety, counterfeits and unapproved new drugs, drug safety, post market surveillance safety, supplier issues, certainly those are not new issues but they still demand a lot of our time and attention."

Campbell noted that in terms of warning letter trends "there is nothing really earth shattering here. There has been a kind of leveling out. … A warning letter is the most common advisory action taken by the agency and is our attempt to notify management, and is our attempt to work things out with top management on a voluntary basis. And it has been proven to be effective."

The number of GMP warning letters has nearly leveled in the past few years after falling sharply earlier in the decade. There were 20 in FY 2006, 19 in FY 2007 and 18 in FY 2008 (see chart: " ³ The Bush Years: Fewer Drug Warning Letters; More Recalls ").

The most oft-cited GMP provision in warning letters that FDA issued in FY 2008 was Section 211.192, production record review. This citation was observed in 11 of the 18 letters issued by FDA that year. The year before, it was tied for first place with Section 211.165, testing and release, and in FY 2006, it was in a three-way tie for second place.

The next most commonly cited provision last fiscal year was 211.100, inadequate written procedures and failure to follow up on deviations. It was cited in eight warning letters. In FY 2007, it was one of the fifth most-cited provisions, and in FY 2006, one of the fourth (see chart: " ⁴ FY 2008 Drug GMP Warning Letter Cites ").

Section 211.22, quality control unit responsibilities, came next. This one always ranks highly and topped the list in FY 2006. Last year it was in a tie with Section 211.160, laboratory controls, which has gained prominence in recent years as FDA has focused more on data integrity concerns.

Production Record Review Problems at Ranbaxy

A pair of warning letters issued last September to India-based Ranbaxy Laboratories regarding its facilities in Dewas and Paonta Sahib, India, highlights FDA's ongoing concerns with production record review and deviation under 21 CFR 211.192. Following the warning letters, the agency also announced import restrictions on 26 finished drug products and seven APIs manufactured at those plants.

Ranbaxy's problems deepened in February 2009 when FDA issued an application integrity letter to the firm for fabricating data at its Paonta Sahbi facility (see "The Gold Sheet," March 2009, p. 11).

Last year's Paonta Sahib warning letter noted that "the firm's procedures for review and approval of drug product production and control records by the quality unit, including those for packaging and labeling, are inadequate to determine compliance with all established, approved written procedures before a batch is released or distributed. Also, investigations into any unexplained discrepancy or the failure of a batch of any of its components to meet any of its specifications are not extended to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy whether or not the batch has already been distributed."

And FDA's warning letter for the Dewas site addressed the same GMP problems as seen at the Paonta Sahib site. The letter notes that "your procedures do not provide for a thorough review of unexplained discrepancies or failure of a batch or any of its components to meet its specifications whether or not the batch has been already distributed."

Types of Form 483 Violations Unchanged

Campbell noted that the types of violations listed in Form 483 reports have remained essentially unchanged over the years.

Citing information from FDA's Turbo Establishment Inspection Report software system, which the agency started using in 2002, Campbell said that the 10 drug cGMP observations with the most 483 citations recorded for calendar year 2008 were:

· Inadequate QCU responsibilities at 211.22(d) at 887 citations;

· Lack of adherence to production procedures at 211.100(b) at 709 citations;

· Inadequate production procedures and validation at 211.110(a) at 618 citations;

· Insufficient laboratory controls at 211.160(b) at 553 citations;

· Inadequate written procedures for production at 211.100(a) at 518 citations;

· Inadequate investigations at 211.192 at 506 citations;

· Inadequate testing and release at 211.165(a) at 478 citations;

· Inadequate personnel qualifications and training at 211.25(a) at 456 citations;

· Inadequate batch record preparation and review at 211.188 at 449 citations; and

· Inadequate equipment cleaning and maintenance under 211.67 (b) at 397 citations.

Campbell said that "the number one drug cite showing up on 483s were deficient QC units. It has been number one over the last five years and is not in danger of losing its number one status. What happens is if FDA goes out and they find a significant number of deviations, and they see that there are many things wrong there must be a deficient QC unit."

The one new citation appearing on the turbo top 10 list is inadequate cleaning and maintenance of equipment at adequate intervals, said Campbell. "Gone are the incomplete batch production and control records. You're doing a better job with control of production records but you are not cleaning your equipment properly."

Data Integrity Concerns Persist

Campbell said that data integrity continues to be one of the more damaging 483 observations, followed by responses to OOS results, evaluating new suppliers, and launching new products.

"Just to make sure I have covered all my bases I went to our drug investigators and I asked whether there were things they were concerned about. First thing that came back was data integrity issues. It just will not go away. It is very surprising to me because it is the most damaging finding that we can make against your firm."

He added that "the supplier issue we can discuss to death. It is obviously a big deal. The next issue for new products is kind of related to new suppliers in that firms are bringing on new products and not doing due diligence. We expect more of this to occur as firms downsize and products evolve slowly. If you're bringing new products into a facility take a very close look at the initial validation. When you start manufacturing for the first time in your facility make sure that you are aware of any unexpected out of trend or out of spec results. Is it really responding or is it performing as it is supposed to? We're very sensitive to those changes that are unexpected so make sure you do an adequate investigation for out of trend or out of specification products."

Fewer Injunctions Seen Last Year

Campbell said that the number of FDA injunctions at all centers dropped from 17 in FY 2006 to 12 in FY 2007 to five in FY 2008. CDER only had one injunction in FY 2008.

"There was a precipitous decline in the number of injunctions. I don't know why the drop, it is surprising. You would expect to have a dozen a year. I'm sure this number will be looked at closely by the various offices of compliance," he noted.

Campbell said that of the five injunctions this year three involved the adulteration of products and the distribution of unapproved new drugs.

"What really struck me when I looked at these was the compliance history. All of them involved a series of violative inspections on the part of the agency. One of them had six questionable inspections since 2005. Also, there was a history of repeated warnings from the agency to try to work this out on a voluntary basis. It involved 483s, meetings with the agency, it involved warning letters and in one case multiple warning letters. There was a very clear pattern but in the end FDA had to resort to the injunction."

First 2009 Injunction Went to KV Pharmaceuticals

So far this year, FDA has already filed one injunction. It was against KV Pharmaceuticals for manufacturing problems that had persisted despite a series of warning letters and Form 483 reports dating back to May 2000 (see "The Gold Sheet," March 2009, p. 8).

The company has since entered into a consent decree with FDA that specifies measures the company must take to get back on the market.

Under the decree, the defendants cannot resume manufacturing and distributing drugs until both an independent expert in cGMPs and FDA officials review their facilities and certify they are in compliance with the Food, Drug and Cosmetic Act and the decree. The defendants must destroy all drugs recalled since May 2008 and all in-process drugs, drug components and finished drugs on hand.

The complaint for permanent injunction notes that an FDA inspection in February revealed that certain drugs manufactured by the defendants lack approved new drug applications or abbreviated new drug applications. FDA also found certain drugs were misbranded because they are unapproved new drugs and lack scientific evidence to demonstrate that they are safe and effective in their directions for use. The complaint includes a list of 55 unapproved drug products.

Process Validation Problems Seen

An ongoing problem noted by Parexel's Ronald Tetzlaff at the Georgia GMP meeting was that in calendar year 2008, process validation continued to be "among the more common FDA 483 observations."

Tetzlaff noted that "at least 55 companies" were cited for manufacturing adulterated drugs and devices due to non-conformance with process validation requirements under GMPs at 21 CFR Part 211 and QSR 21 CFR Part 820 in calendar year 2008. This included 20 drug manufacturers and 35 device manufacturers.

Tetzlaff said that process validation issues generally fell into one of the following categories in 2008 and 2009 in descending order of occurrence.

· Failure to validate processes and software

· Product and process specifications

· Process deviations

· Process changes

· Validation procedures

· Validation reports and documentation

· Corrective and preventive actions

· Other

One FY 2008 warning letter focused on process validation issues. The Aug. 12, 2008, warning letter faulted Sandoz's Wilson, N.C., facility for relying on end-product testing to release lots of metoprolol succinate tablets despite process validation failures that showed the manufacturer had not identified or controlled factors causing process variability (The Gold Sheet," September 2008, p. 17).

By Science or by Law, FDA Aims for Control

At the Georgia GMP meeting, Joe Famulare, deputy director of the CDER Office of Compliance, discussed the "ultimate consequence" of not following process validation principles as espoused in FDA guidance.

Non-adherence to these principles "can result in consent decrees, seizures and other types of legal actions that have as its central core a lack of process validation," he said.

"I call this truth or consequences. What happens when process validation is not robust and it doesn't work? We have a document here called a consent decree for a permanent injunction and what happens when we enter into such an agreement if you go back and look at these there are public comments. This is one that was just filed two weeks ago, so you can imagine the U.S. as a plaintiff and your company's name here and the list of responsible individuals which will include the CEOs. As bad as a consent decree is, the good part is that it does at least represent some agreement going forward as to what a company will do to correct the issues that it has found."

Famulare further noted that the revised process validation guidance, issued in November 2008, represents the agency's interest in trying to "modernize our approach to process validation. …We started by changing our CPG and we're trying to get away from enslaving ourselves to this three-batch approach, and we wanted to align our activities with the product lifecycle and the pharmaceutical quality systems initiatives and really build on our guideline that is out there from 1987. We really wanted to answer the question on what scientific evidence assures me that the process is capable of consistently delivering a quality product. How can I demonstrate that my process works as intended and remain in control?"

He went on to explain that, "Whether you are talking about process analytical technology or real-time release mechanisms, you can't look at these things in vacuums when you can have capabilities now to really test more deeply batch-to-batch. We should be able to take advantage of that; these are consistent with the ideas we're promoting in ICH."

- Joanne S. Eglovitch (j.eglovitch@elsevier.com) and Bowman Cox (b.cox@elsevier.com)

(see chart: " ⁵ Drug GMP Warning Letters By Category ")

Drug GMP Warning Letters, Enforcement Could Rebound in Obama's FDA

More from Archive

More from Pink Sheet