QBD- Quality by Design

Quality Systems Approach to Pharmaceutical CGMP- Quality-by-Design (QbD). Part 1

2010-06-15T02:35:00.000-07:00

Dr. Shruti Bhat, is a Leader in Pharmaceutical R&D and QbD specialist presents few salient points regarding the latest quality systems expected by regulators from the life science, more particularly pharmaceutical industry. But first, a brief chronology of evolution of quality systems.

Definitions and scope of quality systems in pharmaceuticals has evolved over a period of time. The “Thalidomide babies tragedy” prompted the concept of continuous or cGMP. With cGMP came into existence the concept of Quality Assurance or “Zero defect”. QA advocated that quality cannot be created at the end of processing, but has to be in-built into a product at every step of manufacturing process.

Further improvements in quality systems throughout the 1990’s and beyond brought about concepts of internal audits, documentation and validations. Y2K improved quality systems further...introduced 21CFR part 11 compliance measures. Year 2010 and beyond promises further refinement in quality systems- Quality-by-Design (QbD).

What is quality by design?

Quality by design means designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process.

Where to implement quality by design?

Quality by design implementation targets the following departments within a pharmaceutical company-
Management, Procurement, R&D, Manufacturing, Testing, Quality control, Quality assurance, Regulatory, Logistics, Sales, Warehouse/ Supply chain including vendors facilities, CRO and CMO.

Principles of quality by design?

QbD scope assume that problems can be anticipated and their occurrence prevented by reviewing data and analyzing risks associated with operational and quality system processes and by keeping abreast of changes in scientific developments and regulatory requirements. The central goal of a quality system is the consistent production of safe and effective products and ensuring that these activities are sustainable. A robust quality system will promote process consistency by integrating effective knowledge-building mechanisms into daily operational decisions. When fully developed and effectively managed, a QbD system will lead to consistent, predictable processes that ensure that pharmaceuticals are safe, effective, and available for the consumer.

Framework of quality by design?

Quality by design integrates quality systems and risk management approaches into its existing programs with the goal of providing the necessary framework for implementing quality by design (building in quality from the development phase and throughout a product’s life cycle), continual improvement and risk management in the drug manufacturing process and also for post development changes and optimization.

Quality risk management (governed by CAPA- corrective actions preventive actions) is a valuable component of an effective quality systems framework. Quality risk management can, for example, help guide the setting of specifications and process parameters for drug manufacturing, assess and mitigate the risk of changing a process or specification, and determine the extent of discrepancy investigations and corrective actions.

CAPA focuses on investigating, understanding, and correcting discrepancies while attempting to prevent their recurrence. QbD system models discuss CAPA as three separate concepts, all of which are used in this guidance:

Remedial corrections of an identified problem.
Root cause analysis with corrective action to help understand the cause of the deviation and potentially prevent recurrence of a similar problem.
Preventive action to avert recurrence of a similar potential problem.

Review outcomes typically include:

• Improvements to the quality system and related quality processes.
• Improvements to manufacturing processes and products.
• Realignment of resources.

The results of a management review would typically be recorded. Planned actions should be implemented using effective CAPA and change control procedures.

To be continued...

Disclaimer- The content of this article is intended to provide a general guide to the subject matter.

A detailed whitepaper on “Introduction of Quality-by-design in Pharmaceutical industry” is available FREE of charge with the author. Interested parties may contact.

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Expert at leading Pharmaceutical R&D.
Translates innovative concepts to PROFITS.
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Shruti has initiated a new blog Http://www.PharmaceuticalCareerDevelopment.blogspot.com which contains articles on motivation, career counselling and coaching, job search strategies, personal branding etc. especially for pharma professionals.

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Diabetes drug may increase fracture risk in women.

2010-03-07T06:52:00.000-08:00

Dr.Shruti Bhat, an Expert in Pharmaceutical industry, brings to you some highlights from current pharma –quality news, views and data.

Diabetes drug may increase fracture risk in women.
According to a study published in the Journal of Clinical Endocrinology & Metabolism, women with type 2 diabetes who take a commonly prescribed drug for the problem are at a higher risk of bone fractures. Researchers found that women taking "a class of medicines called thiazolidinediones, or TZDs," for one year "had a 50% higher chance of developing a bone fracture." Notably, "men were not at increased risk of fractures if they took the diabetes drugs."

The study showed that "women older than 65 were most vulnerable, with a 70 percent higher risk," The researchers speculated that the increased "risk of osteoporosis and osteoporosis-related fractures" among older women "might explain why they appeared to be the most affected." TZDs "work by lowering resistance to insulin and cutting the amount of glucose made by the liver."

Health Canada says Accutane may cause potentially deadly skin reactions.
The Canadian Press reported that in an advisory from, Health Canada warned consumers that rare but potentially deadly skin reactions have been reported with the use of Accutane [isotretinoin] for the treatment of severe acne. There have been 'very rare' reports of severe skin reactions linked to Accutane that can result in hospitalization, disability, or even death." The agency "said anyone currently taking or recently on Accutane should stop the drug and see their doctor immediately" if they develop a rash with fever, blisters on their face and limbs, mouth or throat sores, and "peeling skin."

Syringes with detachable needles may play role in hepatitis C incidence among drug abusers.
The Los Angeles Times reported, "The high incidence of hepatitis C infections among drug abusers may be due in part to the use of syringes with detachable needles," Yale researchers discovered. In fact, the "virus persisted for nine weeks at most temperatures in so-called tuberculin syringes with detachable needles." Investigators "cautioned that communities operating needle-exchange programs should be aware of the problems with the tuberculin syringes."

FDA unveils risk-management plan for anti-anemia drugs.
The Los Angeles Times reported that Physicians who want to prescribe Amgen Inc.'s anti-anemia drugs for cancer patients will have to register and undergo special training under a risk-management plan unveiled by the FDA. The drug maker "also will require physicians to collect signed statements from patients attesting that they have been informed about the dangers of the drugs." Richard Pazdur, director of the FDA's Office of Oncology Products, said the agency hoped the added burden on physicians would be offset by fewer adverse events.

The plan applies to Amgen's Aranesp [darbepoetin alfa] and Epogen [epoetin alfa] and Johnson & Johnson's Procrit [epoetin alfa]." Studies have linked the class of drugs, called erythropoiesis-stimulating agents, or ESAs, "to faster tumor growth or earlier death in cancer patients, among other risks, and have raised deep concern during the past few years at the FDA.

The drugs "are FDA-approved for people battling cancer, those infected with HIV, people with kidney failure and certain patients undergoing surgery, and all three carry with them an elevated risk of blood clots, stroke, heart failure, tumor promotion and death."

Antibiotics may be overprescribed for ear infections.
The Wall Street Journal reported that many physicians routinely prescribe antibiotics for ear infections in young children, even as current guidelines only recommend the treatment for the youngest and sickest of patients. Meanwhile, mounting research shows that many children recover well without medication. Physicians are debating the issue, according to the Journal, and new guidelines are set to be revealed soon.

Drug counterfeits continue to plague Middle East.
Syria is reportedly aiming to reduce the use of counterfeit drugs as the problem remains widespread in the Middle East. A recent seizure of millions of dollars worth of breast cancer, leukemia and other drugs ended one of the ring's trade of counterfeits to Iraq, Turkey, Lebanon, Iran and Egypt. The Journal adds that one reason why drug counterfeits have thrived in the Middle East is that authorities were unprepared for the scale and sophistication of the counterfeits and had neither the law enforcement framework nor the legislation to deal with them.

Disclaimer- The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

Http://www.drshrutibhat.com
Expert at leading Pharmaceutical R&D.
Translates innovative concepts to PROFITS.
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QA updates on new drug research-

2010-02-13T07:26:00.000-08:00

Glaxo temporarily withdraws application for Avodart to prevent prostate cancer.
British drugmaker GlaxoSmithKline PLC has temporarily withdrawn its application for US approval of a drug to prevent prostate cancer. The drug is currently "sold under the name Avodart [dutasteride], for treating symptoms of an enlarged prostate." The company "said it wants to provide an update to its application to the Food and Drug Administration." The company noted, however, that the update is not due to new safety or efficacy findings. Glaxo said that it will resubmit the application shortly.

Physician-pharmacist teams may help increase hypertension control.
According to a study published in the Archives of Internal Medicine, hypertension "is better controlled by doctor-pharmacist teams working hand-in-hand than by doctors and pharmacists working alone." Researchers from the University of Iowa College of Pharmacy divided "402 people treated for high blood pressure at six clinics...into two groups." Patients at "three clinics were randomly assigned to a control group," while patients at the other three "clinics were randomly assigned to an intervention group in which physicians and pharmacists underwent team-building exercises." Next, using national guidelines, clinical pharmacists made drug therapy recommendations to physicians in the intervention group. The investigators discovered that "in the control group, mean guideline adherence scores increased from 49.4 ± 19.3 at baseline to 53.4 ± 18.1 at six months (8.1% increase), compared with a 55.4% increase in the intervention group (from 40.4 ± 22.6 at baseline to 62.8 ± 13.5 at six months)."

These results suggest that clinics and health systems with clinical pharmacists consider giving them a more direct role in patient management," the authors said. An editorial accompanying the study pointed out that "so far, the medical home model for chronic conditions such as hypertension typically hasn't included a pharmacist," but "before the medical home" concept "takes further root, comprehensive efforts should be made to ensure that pharmacists are included on the team because of the mounting evidence for their contribution to quality of care."

Diet drug linked to heart problems.
Preliminary analysis of data from a placebo-controlled study of sibutramine (Meridia) suggested an excess risk of cardiovascular events including myocardial infarction and cardiac death among patients taking the diet drug, according to the FDA." These "findings come from a trial of 10,000 high-risk patients who were randomized to sibutramine or placebo." The agency "said there was a 1% absolute difference in the rate of heart attack, stroke, resuscitated cardiac arrest, or death, with 11% of the sibutramine patients reaching that endpoint versus 10% of the placebo patients."

Leading UK pharmacist warns many asthmatics may be using medication incorrectly.
The UK's Daily Mail reported, "Millions of asthmatics could be taking their medication incorrectly, according to a leading pharmacist" in the UK. The "level of public confusion came to light as a result of the new Boots Asthma Inhaler Check," part of a free NHS-sponsored program that "is designed to help patients use long-term prescription drugs properly." Boots pharmacist Angela Chalmers has already "found that nine out of ten patients are not using their inhaler properly." They "either breathe in too fast or not strongly enough."

Disclaimer- This information is for knowledge purpose only and should not be considered as legal or medical advise.

http://www.drshrutibhat.com

Drug- Regulatory updates-

2010-01-18T16:19:00.000-08:00

UK's NICE says bevacizumab is not cost-effective, should not be prescribed.
The UK's National Institute for Health and Clinical Excellence reported that Roche Holding AG's Avastin (bevacizumab) should not be prescribed for bowel cancer patients under the National Health Service because it is too costly. NICE added in its preliminary ruling that Avastin in combination with oxaliplatin should not be paid for by NHS because it is not cost-effective. The recommendation follows Roche's offer to subsidize treatment following discussions with the UK Department of Health.

NICE's formula to determine the cost-effectiveness of drugs "looks at quality of life and overall cost effectiveness," but its maximum limit "has not changed in ten years despite inflation." A number of "patient groups and experts voiced their dismay" regarding the decision, and the Daily Mail adds that NICE, "which has been accused of spending more on spin than on evaluating drugs, has often been criticized for banning drugs from NHS use as too expensive."

Judge dismisses Fosamax case.
The Wall Street Journal reported that a federal judge dismissed a case over allegations that Merck & Co.'s osteoporosis drug Fosamax caused osteonecrosis in a 74-year-old woman. Bessie Flemings claimed that she developed the severe jaw condition from taking the drug and that Merck did not adequately warn of the risk of osteonecrosis.

The judge ruled that "experts for Bessie Flemings...can't establish that Fosamax caused her osteonecrosis," and as a result, "her failure-to-warn claim is insufficient as a matter of law," An attorney for Merck noted that "Flemings did not present any reliable evidence supporting her claim," adding that "Flemings had medical problems that cause people to develop jaw problems regardless of whether they were taking Fosamax." The company, "as of Sept. 30, faced about 953 Fosamax cases, including suits with multiple patients." .

Pfizer ordered to pay $103 million in punitive damages in hormone drug cases.
On the front page of its Business Day section, the New York Times reported that, "Pfizer has been ordered to pay a total of $103 million in punitive damages to two women who were found to have breast cancer after they used" the hormone drugs Premarin and Prempro. Pfizer units Pharmacia and Wyeth "marketed the drugs as a standard, long-term hormone treatment for menopausal women, until medical evidence emerged indicating that such therapy raised women's risk of breast cancer." Now, a jury has "reached a $28 million judgment" in a case Monday, "while a judge unsealed a month-old $75 million judgment in the other case."

Lawyers for the plaintiff Monday noted, "This is just the tip of the iceberg as Wyeth faces lawsuits from more than 10,000 additional women who also claim that Wyeth's drugs gave them breast cancer," But, a Pfizer spokesman said that "of the 34 trial-set cases to date, there have been only four plaintiffs' verdicts that have not been set aside."

Disclaimer : The information presented here is for information purpose only and should not be interpreted as medical advise.

Pharma regulatory updates-

2010-01-09T06:07:00.000-08:00

Human Genome Sciences seeks FDA approval for hepatitis C drug.
Human Genome Sciences, Inc. reported that it has filed for marketing approval of its hepatitis C drug Zalbin [albinterferon alfa-2b]." Human Genome "did not say when it expected a response to its biologics license application," but did say that "its partner Novartis AG will file for European Union approval before the end of 2009." The company plans "to market the drug under the name Joulferon" outside of the US.

FDA delays decision on drug to treat hospital-acquired pneumonia.
Theravance, Inc. said that the Food and Drug Administration delayed a decision on whether to approve its infection drug Vitabiv [telavancin] as treatment for hospital-acquired pneumonia." The FDA "asked for more data and analysis on patients who participated in clinical trials of Vitabiv," according to the company. The agency also "wants more information about deaths in Theravance's clinical trials, comparing patients on Vitabiv to those on other treatments, as well as details on why Theravance combined data for two trials.

NHS decides not to make sorafenib, bevacizumab available.
In the United Kingdom, the National Health Service (NHS) has decided not to make two more cancer drugs available because of cost." According to the National Institute for Health and Clinical Excellence, the use of "sorafenib (Nexavar) for liver cancer and...bevacizumab (Avastin) for metastatic colorectal cancer" is "not cost-effective." But, the decision on bevacizumab "is preliminary, and the manufacturer, Roche, has said that it will continue to work with NICE on making the drug available." The moves "have sparked headlines about cancer patients being denied life-prolonging drugs" as well as criticism from some oncologists. Karol Sikora, MD, medical director of Cancer Patterns UK, noted that "the British decision about sorafenib puts it 'hopelessly out of step with the rest of Europe,' because every other country within the European Union makes the drug available."

FDA delays decision on Exalgo.
The Boston Business Journal reported that the FDA "has advised Cambridge-based CombinatoRx Inc. and Canada-based Neuromed Pharmaceuticals Inc. that it will put off making a decision on whether to approve the companies' pain drug target," called Exalgo (hydromorphone HCl), "for three months." The agency said the companies "may need to submit additional data," and that "it will now complete its review by Feb. 22, 2010."

Disclaimer : This information is for knowledge purpose only and should not be interpreted as medical advise.

Pharma QA updates-

2010-01-05T08:11:00.000-08:00

WHO recommends earlier treatments for HIV patients.
World Health Organization "issued new guidance" advising doctors to start giving patients AIDS drugs a year or two earlier than usual." According to the agency, "the advice could double the number of people worldwide who qualify for treatment, adding an extra 3 to 5 million patients to the 5 million already awaiting AIDS drugs." The new recommendations "also advise pregnant women with HIV to take the drugs earlier and while breast-feeding," and urged countries to discontinue the usage of "the commonly used AIDS drug stavudine because of its toxic side effects."

Chemotherapy may be linked to neurological side effects in some testicular cancer survivors.
Neurological side effects are among the potential problems faced by long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy," according to research published online Nov. 25 2009, in the Journal of the National Cancer Institute. In a study of "1,409 men treated for unilateral testicular cancer," researchers "found that between four and 21 years after the start of treatment, men who'd received any chemotherapy had a statistically significantly higher risk for more severe side effects, including sensory neuropathy, tinnitus, hearing impairment and a discoloration of the hands or feet when exposed to the cold...than those who didn't have chemotherapy."

WHO investigates Tamiflu-resistant swine flu cases in US, Britain.
World Health Organization spokesman Thomas Abraham said the agency is investigating reports of Tamiflu-resistant cases of H1N1 in both the United States and Britain. The Health Protection Agency (HPA) in Britain confirmed five cases in Wales, each with severely compromised immune systems. "We'll see if we need to put any additional measures in place to protect this vulnerable group of patients. It might mean that they are at more serious risk than others," Abraham said.

Glaxo urges Canadian doctors to halt usage of one vaccine batch.
GlaxoSmithKline, the sole provider of the H1N1 vaccine in Canada, has told Canadian doctors to "hold off" on using one vaccine batch as the company "probes reports of higher-than-expected occurrences of a side effect known as anaphylaxis." The batch, which contained 172,000 doses of Arepanrix, "was linked to more cases of acute allergic reactions, including swollen tongues, throats and respiratory distress, than is expected, spokeswoman Gwenan White said in a telephone interview." She said the findings would not "have any impact at all on the other vaccine they have received and can continue to administer."

Three drug classes linked to increased risk for elderly falls.
The use of antidepressants, benzodiazepines, sedatives and hypnotics significantly increased the risk of falling among the elderly, a new meta-analysis has found." John C. Woolcott, MA, of the University of British Columbia, and colleagues reported in the Nov. 23 Archives of Internal Medicine that antidepressants "had the strongest association with falls, while the weakest association was for narcotics." The researchers concluded, "The results of our meta-analysis reiterate the need for caution when prescribing these medications to seniors."

Disclaimer : This information is for knowledge purpose only and should not be interpreted as medical advise.

Drug regulatory- QA updates-

2010-01-04T07:12:00.000-08:00

Amgen, Roche settle anemia drug patent dispute.
Swiss drug maker Roche will not be allowed to sell its anemia drug Mircera in the US until July 2014 under terms of a settlement with Amgen Inc., the companies reported. According to Amgen, "a US District Court in Boston ruled that Mircera infringes on five patents supporting Amgen's anemia drugs Aranesp and Epogen." Roche had acknowledged that the disputed patents are valid and enforceable. But, the settlement does not cover any payments between the companies. The disputed "patents cover critical steps in the production of" a "genetically engineered protein" called erythropoietin.

UK drug regulators back Yondelis after Zeltia agrees to cover some of the cost.
Zeltia SA's Yondelis [trabectedin] will be offered by the UK's National Health Service as a treatment for soft- tissue sarcoma after the company agreed to pay for any patient who needs more than five cycles of the drug." The UK's National Institute for Health and Clinical Excellence "reversed an earlier recommendation rejecting the drug as too expensive. NICE has recommended its use where other treatments have failed or cannot be tolerated because of side effect."

Austria makes morning-after pill available without prescription.
Austria's health ministry says the contraceptive morning-after pill is now available in pharmacies without a prescription." The health ministry "said that women of all ages can now buy the pill...over the counter."

FDA begins hearings on Internet marketing of medical products.
The Food and Drug Administration "is hearing from dozens of drug and advertising executives at a two-day meeting on Internet marketing of medical products." After complaints from both web companies and the pharmaceutical industry that marketing guidelines were too restrictive for the medium, "the agency has agreed to consider developing rules for online ads." Yahoo "is testing a new type of ad that would contain an extra link to detailed drug information, including risks," while Google "is proposing a similar design that would list a short summary of drugs risks, followed by a link to full prescribing information."

Cephalon, Barr settle patent infringement suit.
Cephalon Inc. will give Barr Pharmaceuticals Inc. a license to sell a generic version of the pain drug Fentora in 2018 as part of a patent lawsuit settlement, according to a Securities and Exchange Commission filing. Under the deal, Cephalon "will give Barr a non-exclusive, royalty-free right to sell a generic version of Fentora in October of 2018," even though "the patent is not set to expire until 2019." But, "if another generic version of Fentora reaches the US market before October 2018, Barr is allowed to launch its version.

Cancer prevention drugs said to be widely ignored.
Some researchers state that "the few medicines proved to deter cancer are widely ignored," because "people are not enthusiastic about taking anticancer pills, or are worried about side effects or not really convinced the drugs work." As a result, drug makers say that "it makes little economic sense to spend decades developing drugs to prevent cancer," and instead, "the better business plan seems to be looking for drugs to treat cancer." Meanwhile, researchers say that many "measures that are often assumed -- and marketed -- as ways to prevent cancer may not make much difference." In fact, studies linking cancer to such measures typically "cannot assess cause and effect," while studies that do come up with these associations "are likely to be published, even though often the associations turn out to be spurious."

Canadian officials nix recommendation for second flu shot in children.
Federal health officials in Canada have determined that "all but the youngest children need only a single half-dose of H1N1 vaccine." The new recommendation will "free up vaccine and make more shots available to the general public sooner," and also "means many parents of healthy children who have already endured waits hours long to have them vaccinated will not have to line up again for a second shot."

Disclaimer : This information is for knowledge purpose only and should not be interpreted as medical advise.

Pharma regulatory- QA updates :

2010-01-03T03:56:00.000-08:00

Report says information technology may improve medication adherence among older adults.
Information technology is key to improving medication-related errors and improving medication adherence among older adults, according to a recent report from the Center for Technology and Aging in Oakland, CA. According to the report, "'widespread use' of technology aimed at this population could save thousands of lives and billions of dollars."

Column offers advice on treatment with bone-enhancing drugs.
Who should be treated with bone-enhancing drugs? Until recently, many doctors and drug companies that make these medications were saying almost everyone -- especially older white women, who are at highest risk of one day suffering an osteoporotic fracture." However, "the drugs currently available to enhance bone density" are "expensive...can have side effects, and they are only about 50 percent effective at preventing fractures." Brody suggests that patients with osteopenia should rely instead upon their FRAX risk assessment score, a "bone mineral density test," and their physician's guidance to weigh "possible risks...against known benefits" before starting treatment with such medicines.

Arena seeks FDA approval of weight loss drug.
The first of a new class of obesity drugs moved one step closer to the market as Arena Pharmaceuticals Inc. said it filed for approval of its drug candidate lorcaserin." If approved, the drug is likely to "compete against Vivus Inc.'s Qnexa and Orexigen Therapeutics Inc.'s Contrave32, both of which are still in development." According to Arena, two late-stage trials showed that obese and overweight patients with type 2 diabetes taking lorcaserin experienced significant weight loss, and that the drug was safe and tolerable.

The results appear to meet one of two FDA-recommended goals for obesity drugs: that at least 35 percent of patients taking its drug lose at least five percent of their body weight, and that the group is approximately double the percentage of patients with similar weight loss on the placebo.

Shire seeks full FDA approval of Replagal.
British drugmaker Shire allegedly filed for US marketing approval of its Fabry's disease treatment Replagal [agalsidase alfa]." The drug is currently "available under Food and Drug Administration restrictions.Shire established an early access program in the midst of a shortage in treatments marketed in the US for Fabry disease. The shortages have been caused by the temporary shutdown last summer of Genzyme's Allston Landing manufacturing plant, where the company discovered a virus in a bioreactor in June. If approved, the drug "would compete against" Genzyme's Fabrazyme [algasidase beta].

Disclaimer : This information is for knowledge purpose only and should not be interpreted as medical advise.

Regulatory Affairs updates-

2010-01-01T12:02:00.000-08:00

Safety review board recommends Vical continue trial of cancer drug candidate.
A safety review board recommended" that Vical Inc. "continue a late-stage clinical trial of its cancer drug candidate Allovectin-7 and is expecting a full complement of 375 patients to be enrolled in the Phase III trial" of the melanoma vaccine "in the next few weeks “ according to the company.

Artemisinin-resistant malaria found near Thai-Cambodian border.
The American Press mentions that there is a "spot on the Thai-Cambodian border [that] is home to a form of malaria that keeps rendering one powerful drug after another useless." Now, "scientists have confirmed the first signs of resistance to the only affordable treatment left in the global medicine cabinet for malaria: Artemisinin." In addition to this emergence, "after decades of the overuse and misuse of antibiotics, diseases like malaria, tuberculosis, and staph have started to mutate. The result: The drugs are slowly dying."

More XXDR-TB cases may be unaccounted for, experts suspect.
A case of extremely drug-resistant tuberculosis -- being referred to as XXDR-TB -- in Florida is one of only a handful reported worldwide," and "there may be many more, according to Dean Schraufnagel, MD, a TB expert at the University of Illinois in Chicago and president-elect of the American Thoracic Society." The surge could be attributed to the fact that "first-line medications are not used properly." But, "what is 'worrisome' about the Florida case, Schraufnagel said, is that" the patient "had reportedly not been previously treated for TB, which might mean he contracted the strain from someone else."

Emergence of drug-resistant E. coli strain causes concern.
"First-line use of carbapenem antibiotics for urinary tract infections may become necessary if the spread of drug-resistant E. coli continues, a prominent infectious disease expert warned." According to Johann Pitout, MMed, of the University of Calgary, "an E. coli strain expressing a beta-lactamase enzyme known as CTX-M-15 has suddenly emerged in community-acquired infections worldwide." Pitout pointed out in his paper in Faculty of 1000 Medicine that "this strain is among the most worrisome of a series of recently emerging, community-acquired E. coli clones," because the "so-called extended spectrum beta-lactamases" may "break down cephalosporin and monobactam antibiotics which have been first-line treatments for" UTIs.

Disclaimer : This information is for knowledge purpose only and should not be interpreted as medical advise.

Drug Quality Highlights :

2009-11-14T05:33:00.000-08:00

Adverse drug events jumped in 2008, according to USFDA data statistics -

USFDA received 25 percent more reports of adverse drug events in 2008 compared with 2007, according to a new QuarterWatch report from the Institute for Safe Medication Practices.

In 2008, the FDA received reports of nearly 100,800 cases of serious injury related to drug use...compared with 80,600 in 2007, the largest over a one-year period since the FDA began collecting data in 1998.

Drug Quality updates :

2009-09-14T06:50:00.000-07:00

Read few interesting articles on Drug Quality. Here are some excerpts from my reading for your review-

Glaxo looks to assure safety of Alli following FDA investigation:

"GlaxoSmithKline is scrambling to shore up the safety image of its weight loss pill alli, after watching sales dive on news that federal regulators are investigating the drug." Alli "received a high-profile marketing push as the first over-the-counter weight loss medication," but "Glaxo has spent the last two weeks on damage control after the Food and Drug Administration said it was probing more than 30 reports of liver damage in patients taking Alli and Xenical [orlistat], the prescription version of the drug." The FDA "has not set a deadline for concluding its investigation, but has advised patients to continue taking the drugs as directed."

Suspected adverse reactions to cervical cancer vaccine in UK patients noted :

The UK's Daily Telegraph (9/12, Donnelly) reported, "Doctors' reports show that girls of 12 and 13 have experienced convulsions, fever and paralysis after being given" a cervical cancer vaccine, "which is now administered in schools as part of efforts to prevent women developing cancer." A report prepared by the drug safety watchdog Medicines and Healthcare products Regulatory Agency "earlier this month" noted that most "of the more than 2,000 suspected reactions" were "mild, with dozens of girls recording rashes, pain in the arm, and allergies." The Telegraph noted, "Ministers say that ultimately the scheme will save 700 lives a year, while drug safety experts insist the number of suspected reactions are outweighed by the benefits from the jab."

Gelatin - Mineral interactions - discussion on film studies and liquid phase interactions :

2009-05-07T13:37:00.000-07:00

by Dr.Shruti Bhat

(ii) Film studies-

Cooper et al (1972) reported that an interaction between gelatin and dyes in the gelatin films could be studied by examining the shifts in λ max in the visible range and for changes in the amide I (1625 cm –1) and amide II (1520 cm –1 ) bands of the protein in the IR spectrum.

IR spectra of gelatin films containing RO (at all the concentrations attempted) , copper sulphate and potassium iodide showed disappearance of both these peaks indicating gelatin – mineral interaction. The dissolution data of the above stored films also indicated protracted disintegration. The IR spectra of the films containing manganese sulphate, magnesium oxide, dicalcium phosphate and zinc sulphate did not indicate interaction. The dissolution data (except in case of manganese sulphate) also supports this observation. It was observed that the rate of interaction accelerated due to (1) increased humidity and (ii) presence of RO/ FF (except in case of manganese sulphate where iron salts showed a protective influence)

Liquid phase interactions-

Changes in pH and viscosity-

The soluble salts used indicated acidic salts (copper sulphate and manganese sulphate) and basic (potassium iodide) while the insoluble salts included alkaline earth metal salts (magnesium oxide and dicalcium phosphate) and iron salts (RO/ FF). In case of acidic and basic salts, any interaction between gelatin and the action would bring forth changes in the pH. The decrease in pH with stored gelatin solutions containing copper sulphate and an increase in pH with those containing potassium iodide support interaction. The interaction possibly even increased the viscosity of the samples as observed from the viscosity data.

Insignificant change in the pH indicated lower degree of interaction (as also observed from atomic absorption spectral data given under formulation studies). Also, the insignificant changes in viscosity value supports this statement.

CONCLUSION-

The minerals employed in sot gelatin hematinic capsules show migration into the gelatin shell due to the higher water and humectants content of soft gelatin capsules shell than the hard gelatin shell which subsequently end up in interaction between the gelatin and the captions resulting in protracted disintegration or rupture. These interactions in the capsules could lead to noncompliance with the official disintegration tests standards. However, the effect of this interaction on the bioavailability of the content has not been reported so far.

REFERENCES-

1. Amstrong NA, James K.C., Pugh W.K, “ Drug migration into soft gelatin capsules shells and its effect on in vitro availability “, J.Pharm.Phamacol; 1983, 36, 36-365.

2. Berry I.R. “ Improving bioavailabilty with soft gelatin capsule “ ; Dugs and Cosmetic Indus., 1993, 102, 32-33, 102, 105, 106-108.

3. Chowhan Z.T., Chi, L.H.,”Drug – excipient interactions resulting from powder mixing possible mechanism of interaction with starch and its effect on drug dissolution”, Pharm.Tech., 1985, 9(3), 84-97.

4. Chowhan Z.T., Chi, L.H. “ Drug – excipient interactions from powder mixing, II: possible mechanism of interaction with cros povidone and its effects on in vitro dissolution “, ibid, 1985,9(4), 28-41.

5. Chowhan Z.T., Chi. L.H. “ Drug –excipient interactions resulting from powder mixing III: solid-state properties and their effect on drug dissolution “; J. Pharm. Sci., 1986, 75, 534-541.

6. Cooper J.W., Ansell, H.C., Cadwelder D.E., ‘ Liquid and solid solution interactions of preliminary certified colorants with pharmaceutical gelatins “, J.Pharm.Sci. 1972, 62, 1156-1164.

7. Lalla J.K., Bhalla D.V.; “ Chewable tablets acetaminophen; prodrug approach.” drug. Dev. Ind. Pharm. 1990, 11. 115-135.

8. Lalla, J.K., Nair, G.K., Ahuja P.L., Gurnaney R, Bhat Shruti U,” Disintegration of hard gelatin capsules- Role of pH, enzymes and other additives present in the disintegration medium in reducing the disintegration time of stored samples”, Indian Drugs, 1993, 30, 11-18.

9. Ludwig A, Van Oeteghem M, “ Disintegration of hard gelatin capsules Part 1- Composition and structure of capsule wall”, Pharm.Ind, 1979, 41, 796-798.

10. Ludwig A, Van Oeteghem M, “Disintegration of hard gelatin capsules Part 2- Disintegration mechanism of hard gelatin capsules investigated with a stereoscopic microscope” ibid, 1980, 42,405-406.

11. Ludwig A, Van Oeteghem M, “ Disintegration of hard gelatin capsules Part 3- Penetration and diffusion of liquid through the capsule wall investigated by scanning electron microscopy, Part 4- Method for measuring the time of rupture of the capsule.” Ibid, 1980, 42,10404-1043, 1140-1141.

12. Ridgeway K, “Hard capsule”; The Pharmaceutical Press London, 1987, p 31.

For clarifications or inquiries, contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com

Discussion on Solid Phase interaction of gelatin- mineral interactions-

2009-05-05T19:24:00.000-07:00

by Dr. Shruti bhat

(i) Formulation studies :

When freshly prepared, all the capsules ruptured within 10 mins and disintegrated/ dissolved completely within 30 mins. However, storage of the above capsules for 2 months (at 40 and 50 degrees centigrade) showed significant changes in their rupture dissolution times.

The capsules containing copper sulphate, manganese sulphate and potassium iodide (both alone and in presence of RO), refrigerated (control) sample of capsules containing manganese sulphate + RO, KI and KI+ RO indicated a rupture time of more than 15 mins and a DT of more than 60 mins after storage for one month. The refrigerated capsules of copper sulphate and copper sulphate + RO however, complied with the tests for rupture and DT when stored for a period of one month.

Hence, to further investigate the reason for such protracted disintegration, the capsules shell was analyzed for evidence of possible migration of metal ions from the capsules contents to the shell. The shells of both freshly prepared and stored capsules were analyzed quantitatively for copper, potassium and manganese ions using an atomic absorption spectrophotometer.

It was observed that copper ions migrated into the shells after storage at 40 degC for 7 days. The rate of migration of copper ions increased on increasing the temperature to 50 degC. Also, a 3- fold increase in concentration of the copper salt brought about a 16- fold rise in the rate of migration. But, the rate of migration under accelerated temperature and increased storage period was independent of the presence of RO. At the refrigeration temperature, the rate of migration decreased 4- fold in case of capsules containing RO thereby indicating that RO had a protective action on the migration of copper ions from the content into the shell.

Similar behavior was exhibited by potassium ions. However, unlike capsules containing copper sulphate, these containing KI stored in a refrigerated did not show any decrease in the rate of migration. Capsules containing manganese sulphate (alone and with RO) did not show any migration even under accelerated conditions of temperature. This could be because the ions with larger diameter may not fit into the void in the gelatin molecules.

For inquiries please contact me at 1- 514- 743- 6159 or email at drshrutibhat@gmail.com

Gelatin - mineral innteractions- solution and film studies

2009-05-04T16:39:00.000-07:00

by Dr. Shruti Bhat

(II) Film studies-

Preparation of gelatin solutions-

A typical composition employed was as follows-
__________________________________________________
Gelatin 10.0 g

Metallic salt * 2.0 g

Glycerin 5.0 g

Methyl paraben (sodium salt) 0.18

Propyl paraben (sodium salt) 0.02

Demineralized water q.s. 100.0g (freshly boiled and cooled)
__________________________________________________

The study included the use of R.O (red oxide) at 1 %, 3% and 4 % w/w concentrations.

The required soluble and insoluble metallic salts including copper sulphate, potassium iodide, manganese oxide, zinc sulphate and dicalcium phosphate were added before adjusting the weight. Additional mixtures containing above components with mineral salts added to (a) R.O 1 % (w/w) and/or ferrous fumarate 1 % (w/w) were also prepared.

(i) Casting of films-

Free films 90.2 mm thick) of different compositions formulated as mentioned above were cat on a flat glass plate and were peeled. The films were conditioned in a desiccators at 30 + 1degC and 40 +1 degC at 72.8 % and 90.0 % RH. Moisture content of the films was determined by aquametry.

(ii) Dispersive infra- red spectra in Attenuated total reflectance (ATR) mode-

ATR-IR spectra of the films were recorded between 2000 and 615 cm-1 in IR spectrometer (Jasco model 810) previously validated using polystyrene standard) equipped with an integrating sphere using a krypton internal reflecting crystal. Film strips (3x1 sqcm ) to fit the crystal dimensions were place on both sides of the crystal. An angle of incidence of 45 degree with minimal plate pressure were used to obtain the spectra at a scan of 1 cm/sec –1.

(iii) Thermal analysis – DSC studies-

Shimadzu DT- 40 Thermal analyzing system equipped with Chromatopac CR 6A integrator was employed using DSC module. Sample (5.0 mg) was taken in an aluminum cup (against an empty aluminum cup as reference) and was heated at a rate of 5 degK/min in an atmosphere of nitrogen (flow rate 30.0 ml/min) using temperature program of 35- 300 degC.

(iv) Rupture time dissolution tie of shell-

These were determined by suspending the conditioned fresh and aged films in 600 ml of modified dissolution medium comprising of 0.5 % alcalase and 1 % calcium chloride in demineralized water in 1.0 L beaker under stirring (100rpm).

Liquid phase interactions-

(i) pH changes-

pH of 6.67 % w/w gelatin gel containing 2 % w/v metallic salts under study was determined using a pH meter ( Elico model 101 ). The pH was recorded both for fresh samples as well as for those stored at 37 + 1 degC for 7 days.

(ii) Viscosity-

Viscosity of selected solutions was determined at 30 + 2 degC in an Oswald viscometer (BSS-C) employing 6 % w/w aqueous solution containing 2 .0 % w/v of the salts under study. These determinations were made on the freshly prepared solutions as well as on those stored at 30 + 2 degC for a period varying between 3.0- 6.0 months.

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Gelatin- mineral interactions- Experimental and solid phase interaction studies:

2009-05-03T06:11:00.000-07:00

by Dr.Shruti Bhat

EXPERIMENTAL-

Materials-

All the chemicals employed were procured from the indigenous manufacturers and were use without further purification.
Gelatin (type A, Protein products of India), copper sulphate pentahydrate, zinc sulphate heptahydrate, magnesium oxide, potassium iodide, managanese sulphate tetra hydrate and ferrous sulphate heptahydrate were of analytical grade (Qualigens). Other materials used included, dicalcium phosphates anhydrous USP (Enar chemie), red oxide of iron [RO] (SD chemicals), ferrous fumarate IP (Bakul products), sodium methyl and propyl p-amino benzoates IP (Ben Chem), calcium chloride dihydrate (E.Merck), enzyme alcalase (Novo industry A/S, Denmark), glycerine IP (Godreig soaps), hydrochloric acid (Qualigens) and demineralised water.

Method-

Characterization of gelatin-

Gelatin was characterized by determination of-

(i) Isoelectric point – IEP-

The IEP of gelatin was determined using 30 g of 1 % w/w gelatin solution (prepared in demineralized water) and measuring its zeta potential before and after addition of one drop of 0.1 N HCl. The IEP was found to be 4.85

(ii) Bloom strength- and

(iii) Viscosity of the gel.

The bloom strength (using previously calibrated Boucher electronic jelly tester) and viscosity (using Oswald viscometer BSS-C) were determined on 6.67 % w/w gel. The bloom strength was found to be 192.5 bloom grams and the viscosity value was 0.0304 poise.The results indicated that gelatin used was of Type A.

Solid phase interactions-

Preliminary studies-

In the preliminary studies, interactions between gelatin and minerals was investigated using different techniques. Based on these results, formulation studies were carried out employing only those combinations, which showed probable interactions.

Formulation studies-

Study design-

A low (-) and high (+) value of each salt (except DCP, zinc sulphate and magnesium oxide which were eliminated on the basis of preliminary data) was selected depending on the concentrations of these salts occurring in commercial brads of hematinic soft gelatin –mineral capsules. Copper sulphate (+/-:30.0 mg/ 3.0 mg), potassium iodide (+/- : 2.5 mg /0.1 g) and manganese sulphate (+/-:2.5/0.5 mg) were suspended and along with RO/ FF (1 % w/w) in groundnut oil and later encapsulated in soft gelatin shells on a rotary die machine, Scherer model (Tool Tronics Ltd). About 5000 capsules were manufactured for the study.

Stability studies-

The capsules were placed in stoppered amber colored glass bottles protected from light and stored under exaggerated conditions of temperature viz. 40 + 2 oC and 50 + 2 oC for 2 months. Control samples were maintained at refrigeration temperature (8 degC) for the same period rupture and dissolution time of both fresh and stored capsules were evaluated in 600 ml of 0.1 N HCl (pH 1.6 + 0.2) using apparatus II in a 6- station USP XXII dissolution rate test apparatus. The medium was stirred at 100 rpm. The capsules were evaluated both for the shell rupture time and the dissolution time.

Few shells of the stored capsules were investigated for their ionic content using atomic absorption spectrophotometer (Perkin Elmer model 3100). Standard solutions of copper, potassium and manganese were made. A calibration curve was plotted for each metal ion employing following parameters viz. Cu+2 (30 mA, λ=324.7nm), Mn+2 (4mA, λ = 278.9 nm) and K+1 (8mA, λ = 766.6 nm). The results were statistically analyzed using 3-point regression analysis.

For inquiries, please contact me at 1-514-743-6159 or email drshrutibhat@gmail.com

Protracted disintegration of soft gelatin haematinic capsules due to gelatin shell- mineral interaction ?

2009-05-01T13:35:00.001-07:00

by Dr. Shruti Bhat

Introduction-

The behavior of aged soft gelatin based hematinic capsules may be attributed to gelatin- mineral and gelatin – vitamin interactions reflected subsequently in the non-compliance with the official disintegration test standards as seen from their rupture/ dissolution time. Both these terms refer to these properties associated with the shell. This article evaluates gelatin- mineral interaction based on a case study I did during my postgraduate days for a well-known company. To make the scientific community abreast of the research findings with out divulging or any way comprising confidentiality with the company or anybody else associated with the work, I have extracted the relevant details for community learning.

The work was initiated after conducting an exhaustive literature survey. Glimpses from some of the prior art is presented here. Ludwig and Ooteghem (1979 and 1980) report on the mechanism of disintegration of hard gelatin capsules. Ridgeway (1987) described the chemistry and reactions of gelatin. Cooper et al (1972) investigated liquid and solid solution interactions of primary certified colorants with pharmaceutical gelatin. The author used ultraviolet (UV) and attenuated total reflectance (ATR) infrared spectroscopy for evaluating this film. Bhalla and Lalla (1990) and Chowhan et al (1985 and 1986) employed thermal analysis for evaluating drug-excipient compatibility.

Drug migration into the soft gelatin shells and its influence on (1) in vitro availability of the drugs has been reported by Amstrong et al (1983) and Berry (19893) respectively. However, there are no literature reports on the bioavailability of minerals / vitamins from fresh and stored hematinic soft gelatin capsules. An observation that the soft gelatin based hematinic failed to comply with the Indian Pharmacopoeia disintegration test after storage led us (1993) to study the reasons for this behavior, because of the large-scale use of hematinic capsules in soft gelatin shells all over the world.

REFERENCES-

1. Amstrong NA, James K.C., Pugh W.K, “ Drug migration into soft gelatin capsules shells and its effect on in vitro availability “, J.Pharm.Phamacol; 1983, 36, 36-365.

2. Berry I.R. “ Improving bioavailabilty with soft gelatin capsule “ ; Drugs and Cosmetic Indus., 1993, 102, 32-33, 102, 105, 106-108.

5. Chowhan Z.T., Chi. L.H. “ Drug –excipient interactions resulting from powder mixing III: solid-state properties and their effect on drug dissolution “; J. Pharm. Sci., 1986, 75, 534-541.

6. Cooper J.W., Ansell, H.C., Cadwelder D.E., ‘ Liquid and solid solution interactions of preliminary certified colorants with pharmaceutical gelatins “, J.Pharm.Sci. 1972, 62, 1156-1164.

7. Lalla J.K., Bhalla D.V.; “ Chewable tablets acetaminophen; prodrug approach.” drug. Dev. Ind. Pharm. 1990, 11. 115-135.

9. Ludwig A, Van Oeteghem M, “ Disintegration of hard gelatin capsules Part 1- Composition and structure of capsule wall”, Pharm.Ind, 1979, 41, 796-798.

For clarifications / information, contact me at 1- 514- 743- 6159 or email at drshrutibhat@gmail.com .

Isolation of bacteria and testing of microbial contamination in dye and lake colors used in the pharmaceutical drug products-

2009-04-26T09:37:00.000-07:00

by Dr. Shruti Bhat

Isolation and identification of bacteria-

The isolation was done by transferring the colonies from nutrient agar plated to sterile enrichment broth media. These included MacConkeys broth (for detection of Staph.aureus) and Cetrimide broth (detection of P.aeruoginosa). The specimen tubes were incubated for 48 hours at 37 + 1 oC in inverted position for 24 hours and 507 days.

Allocation of mannitol-salt agar B30-

The colonies grown on Vogel –Johnson’s medium was streak plated on sterile mannitol –salt agar medium for confirmation regarding presence/ absence of Staph. aureus . Pure staphylococcus culture ATCC 12600 was simultaneously streaked on separate plates to serve as positive control.

Further study of culture on selective media-

The colonies grown on Vogel- Johnson’s medium and MacConkeys medium were tested for Gram reactions and motility characteristics.

Biochemical tests-

In order to further ensure that the organisms cultured on Vogel- Johnson’s and Mac Conkeys agar were probably E.coli, Staph. aureus or Salmonella species, the inoculums of the colonies from respective agar medium were employed in biochemical tests comprising of hydrolysis of starch, nitrate reduction, oxidase and catalase activity, liquefaction of gelatin, IMVic, Oxferm reaction etc.

The contents of this article belong to extensive laboratory work done by me to assess microbial contamination on few brands of dye and lake colors available in the market. For additional information, please contact me at drshrutibhat@gmail.com

Evaluation of some marketed dye and lake colors for microbial contamaination-

2009-04-26T09:29:00.000-07:00

by Dr. Shruti Bhat

EXPERIMENTAL-

Materials-

Marketed samples of indigo carmine, sunset yellow, erythrosine and ponceau 4R dye and their aluminum lakes. Materials used in the preparation of the lakes including aluminum hydroxide powder (batch nos. 103,374,AD3 and paste P61). Nutrient agar, Vogel-Johnson’s medium, Mac Conkeys medium, Cetrimide medium and agar media of these and mannitol salt agar were from M/s Hi media, India. Other stains and chemicals employed were of highest purity.

Methods-

Sampling and sample handling-

Sample condition-

All the samples obtained were powders, excepting aluminum hydroxide, which was supplied also as a paste. The samples were received in tightly closed glass bottles.

Sample treatment-

The surface of the sample container was disinfected with an aqueous mixture of 80 % alcohol v/v and 1 % v/v. The surface was dried with sterile gauze before opening and removing the contents in laminar air flow cabinet.

Microbial evaluation-

(i) Preparation of stock inoculums-

One-gram test sample was aseptically inoculated in 25 ml of sterile nutrient broth. The inoculated medium was kept undisturbed for about 15 minutes, to ensure complete transfer of microbes from sample to the medium. The clear supernatant liquid was then used a sample for performing the tests.

(ii) Determination of MPN by serial dilution method-

One ml of stock inoculums prepared as mentioned under (i) was diluted with 9.0 ml nutrient broth to give a dilution of 1:10. this was further serially diluted with sterile nutrient broth to give 1:100, 1:1000 and 1: 10000 dilutions.

The labeled tubes were inoculated at 37 + 1 deg.C for 24- 48 hours and 5-7 days after which they were observed for the presence or absence of growth. The tube in which the growth was not clear from appearance was sub-cultured into fresh sterile nutrient broth tubes (0.1 ml was inoculated into 10 ml sterile nutrient broth). Negative and positive (E.coli ATCC 11775) control was maintained to test the effectiveness of sterilization procedures and growth promoting property of the nutrient media respectively.

(iii) Determination of bacterial count by plate count technique-

The stock inoculums prepared under (i) was serially diluted with sterile physiological saline to give 1:10,1:100,1:1000,1:10000 ,1:1,00,000 ,1: 10,00,000 dilutions. Depending on the MPN count values determined above in (1) 1.0 ml of the last two dilutions of the sample showing growth were pour plated using 15.0 ml of sterile nutrient agar. The plates were then incubated at 37 + 1 oC for 24 hours and 5-7 days and the MPN values were determined.

(iv) Detection of fungi-

One ml of the stock inoculums mentioned under (i) was added to 90 ml of Saborauds broth. Positive control (Candida albicans ATCC) and negative controls were maintained side by side. The tubes were incubated at room temperature (RT) for a period of 7-15 days.

In the next chapter, we shall discuss further on the experimental and isolation procedures of the microbes.

For additional information, please contact me at drshrutibhat@gmail.com

Microbial contamination in dye and lake colors - an Introduction

2009-04-26T09:18:00.000-07:00

by Dr. Shruti Bhat

With the advent of out-sourcing of pharmaceutical products especially by Americas and the western world, pharma products have to meet international standards. This is not possible if quality is built into the product all the way through its trajectory from birth i.e. production development till marketing and administration to patients.

Therefore, all materials that get into a pharmaceutical product need to be closely scrutinized for its quality aspects. A commonly used excipients in formulation is color. Although, the percentages of color used in pharma products is quite low, the effect of color on formulation stability or ability of coloring ingredient for destabilizing products is well known.

Presence of microorganisms in large numbers in drugs and cosmetics preparations is undesirable since it may lead to spoilage of products. The product can change in color, consistency or manifest visible growth. Furthermore, presence of microbial contaminants would constitute a potential hazard to public health although reports on contaminated cosmetics are rare.

A critical component involved in color stability is the microbial load. Some preliminary work on microbial contamination in cosmetics has been reported absent twelve years back from this laboratory. The earlier work in this field has been reported by Doren , Woodward , Riger , Wederburn, Kalings and Bruck . (Ref 1-8)

Various sources of contamination by microorganisms have been enumerated . Raw materials are likely sources of microbial contamination and should be examined microbiologically on a routine basis. Even IP, BP and USP have recognized this fact and have set standards for total number of aerobic bacteria in a variety of products for e.g. gelatin, aluminum hydroxide gel etc. A published report by FIP working party indicated presence of high levels of microorganism not only in substances of animal and vegetable origin but also of synthetic or purified substances including talc, kaolin, vitamins, lactose etc.

Dye colors and their lakes used for improving the elegance of the medicines and cosmetic products could become a potential source of microbial contamination in these formulations. Although the colorants are evaluated for their toxicity, their safety as regards the microbial contamination has attracted very little attention of the regulatory authorities. The methods for evaluation of medicinal preparations are given in official compendia while those for cosmetic preparations have been adequately described by Lucas (Ref 9-12).

With this background and the fact that, the regulatory authorities might include the limits of microbes in colorants work on lakes manufactured by one company has been undertaken. The contents of the case study disclosed here is authentic. This article is published here in to give an update of our research findings to the scientific community at large with out compromising in any way the confidentiality of the matter with all associated with this work.

REFERENCES-

1. Wilson J.W. and Moore R.J. N. “ Cleanliness, hygiene and microbiological control manufacture in “, Harry’s cosmeticology 7th Edition.” Longman Scientific and Technical Pub.1982, p 877.

2. Gupta R.M and Lalla J.K., Indian J.Microbiology, 1980, 19(4),202.

3. Doren L.W., American Perfumer and Cosmetics (1980), 85 (3), 40.

4. Woodwards C.R. ibid, 85 (3), 73.

5. Rigler N.E., Schimmel J. “Cosmetics science and technology” Interscience Pub. London 1966.

6. Wederburn D.L. “ Harry’s cosmetiology “, 6th Edition, Leonard Hill Books, London 1973.

7. Kalinga L.W., Acta Pharma Suecia, (1966),3,219.

8. Bruch C.W., American Perfumer and cosmetics, (1971),86 (4),45.

9. “Six general requirements for the sterility of biological substances “, WHO Technical report,Sr. 200,Geneva World Health Organization.

10. FIP working party report, J.Mond.Pharm, (1972), 15,88.

11. Danial N.M. in “Handbook of US colorants”, Wiley Intersceince Pub.1979,p 30.

12. Lucas J.P. in Newburger’s Manual of Cosmetics Analyst by Senzel A.J. 1977,p 132.

In the next chapter we shall discuss details of experimental and evaluation procedures.

For inquiries and clarification on formulation development & Quality assurance, please contact me at drshrutibhat@gmail.com

Estimation of api by quantitative HPTLC - Results and Discussion

2009-04-24T05:53:00.000-07:00

by Dr. Shruti Bhat

Identification test-

Mass, IR spectral data and DSC thermo gram indicated that the pseudoephedrine test sample had high purity and compared well with the reference standard.

Method validation-

Under the chromatographic conditions described, the migration distance obtained in the case of both the reference as well as the test samples of pseudoephedrine hydrochloride was 34.0 mm (Rt – 0.41). the reference standard sample showed a single band. The test for selectivity employing mixture of pseudoephedrine HCl and phenylephrine showed sharp separation of HPTLC plate in the solvent system containing formic acid as mentioned earlier and compared well with the respective reference standard. The migration distance of pseudoephedrine HCl and phenylephrine were 34.0 mm (Rt – 0.41). and 51.0 mm (Rt – 0.62). respectively.

Observation on the limits of detection and quantification, selectivity, linear range and ruggedness of the proposed method were as follows-

Limit of detection (μg) 5

Limit of quantification (μg) 10

Linear range (μg), regression coefficient, r= 0.999 35-140

Sensitivity (units) 11.2

Ruggedness (%CV) between analysts 1.224

Ruggedness (%CV) between laboratories 2.32

Comparing the accuracies (%CV calculated over the linear range) of the HPLC and HPTLC method, It was found that the accuracy of the former was 1.362 units, while that of the latter was 3.002 units.

Application to stability studies-

The results of the stability studies indicated that there was probably no interference of degradation products during the assay. The degradation products however, were not identified since the reference standards for the same were not available.

CONCLUSION-

A simple, selective and rugged HPTLC method has been developed and validated for determining pseudoephedrine HCl powder. The proposed method is comparable to the HPLC method (reported earlier in the literature). The HPTLC method can be applied for studying the stability of the pseudoephedrine HCl and sulphate samples stored under stress conditions of temperature and humidity. The method further needs to be tried for the analysis of pseudoephedrine in solid and liquid dosage forms.

REFERENCES-

1. Martindale, J.E.F., Reynolds Ed, The Pharmaceutical Pres London, 1989, p1478.

2. J.E. Haley, D.A. Sheuwood and S.T. Brennanm, J.Liq. Chromat., 1989, (1296), 907-917.

3. F.T. Delbebe and M. Debackere, Priopham. Drug Dispos., 1991, 12 (1),37-48

4. R.G. Achari and R. Stillman, LC-GC, 1986,4(5), 454-456.

5. R.C. George and J.J. Conario, J.Liq. Chromatogram., 1988, 11(2), 475-488.

6. S. Ebel, M. Herboth, Proceedings of the IVth International symposium on Instrumental HPTLC Selvino/ Bergamo , Italy, 1987, 27-33.

7. P.K. Shrivastava, R. Paraksh, Orient J.Chem, 1989, 5(2), 135-138.

8. J.T.H. Schiller, V. Graef, S.W. Golf and W. Funk, Proceedings of the IVth International symposium on Instrumental HPTLC, Selvino/ Bergamo, Italy, 1987, 369-378.

9. G. Szepesi, J.Planar Chr. Mod.TLC., 1992, 5(6), 396-407.

10. R. Bhusan, G.P. Reddy, Proceedings of the IVth International symposium on Instrumental HPTLC, Selvino/ Bergamo, Italy, 1987, 53-59.

11. K. Scheide, F. Wonst, Th.Prey and E. Baneher, Anal. Hem. 1981, 428-430.

12. J. Allowohn, S. Ebel, J.S. Kang, Proceedings of the IVth International symposium on Instrumental HPTLC, Selvino/ Bergamo, Italy, 1987, 27-33.

13. A.C. Moffat, J.V. Jakson, M.S. Moss and W, Widdop in “ Clarke’s Isolation and identification of drugs”, 1986, The Pharmaceutical Press London, p 167.

14. P.D. Sethi, “ Identification of dugs in Pharmaceutical formulations by Thin Layer Chromatography “, CB Publishers and Distributors, India, 1993,0 84, 206 and 214.

The information on actual results has been abridged. For reprints of this article or information on HPTLC, QA techniques and audits, please forward your inquiries at drshrutibhat@gmail.com .

API estimation using quantitative HPTLC- contd.

2009-04-23T20:31:00.000-07:00

by Dr. Shruti Bhat

Method validation: selectivity, limit of detection, limit of quantification, linearity range and sensitivity-

The selectivity of the method was checked by spotting 50μg x μl –1 of pseudoephedine HCl (a structurally related drug) individually and as a mixture (in 1:1 proportion) on a plate. Rest of the procedure followed was a described above under, “preparation of calibration curve”. The limit of detection, limit of quantification, linearity range of the calibration curve and sensitivity (which is the slope of the calibration curve) were also determined

Accuracy-

Accuracy of the assay was determined following standard procedure; the results obtained by spotting known amount of drug applied on the plate were compared with the experimental values. The accuracy was expressed in terms of % basis using the following equation-

% Bias = Observed value – Original concentration
--------------------------------------------------------- x 100
Original concentration

Precision-

The inter- day assay variability was calculated for all concentrations in the linearity range (35,70,105 and 140 μg). The intra- day variation was determined on six replicate samples of a low (35 μg) and a high (140 μg) of the concentration curve.

Ruggedness-

Ruggedness of the analytical method was determined by the analysis of the same sample of pseudoephedrine HCl in two separate laboratories having similar equipments by three different analysts on consecutive days for a week. The coefficient of variation (%CV) amongst the results obtained was calculated.

Comparison of HPTLC with HPLC-

The accuracy of the proposed HPTLC method was compared with a reported HPLC method of estimation of pseudoephedrine HCl (detected at 210 nm) using Partisil SCX (10μm) HPLC column (25cm x 4.6 mm). The mobile phase comprised of 24 mM phosphate buffer (pH=2.3) in 50 % aqueous acetonitrile solution (1.5 ml per min.).

Applicability to stability studies-

The proposed HPTLC technique was applied in evaluating the stability of pseudoephedrine HCl samples stored under exaggerated conditions of temperature (40,50 and 60 + 1 deg.C) with relative humidity of 58,75 and 90 %. The standard samples (70 μg /ul) during the analysis were spotted after every 10 tests samples during the analysis. The method was also applied in the analysis of aged pseudoephedrine sulphate samples stored under similar conditions; the details of the stability studies are being published elsewhere.

Tomorrow, we shall take up discussion on results and discussion of these experiments.

For further information on HPTLC, QA techniques and audits, please forward your inquiries at drshrutibhat@gmail.com

Estimation of api by HPTLC : article contd.- Experimental

2009-04-23T11:45:00.000-07:00

by Dr. Shruti Bhat

Instruments-

Camag HPTLC system comprising of Camag IV sample applicator Linomat, Hamilton syringe 100 micro liter, Camag twin trough chamber (20x10 cm2), Camag scanner Ii V3.14 with ACTS software version 3.12, HPLC unit (Jasco PV 980) equipped with intelligent sampler (Jasco 851), Intelligent UV-Vis detector (Jasco model 875) and integrator (Jasco model 870 IT), Mass spectrometer (Schimadzu QP 1000) equipped with EI mode, FTIR spectrophotometer (Jasco model FT/IR- 45300), Differential scanning calorimeter (Schimadzu model DT040 thermal analyzer equipped with chromatopac CR 6A integrator).

Drugs, chemicals and other materials-

Silica gel 60 F 254 HPTLC plates (20x 10 cm, Merck), pseudoephedrine hydrochloride USP, pseudoephedrine sulphate USP, (from a reputed Indian company), pseudoephedrine hydrochloride reference standard (B.Knoll, Germany), phenyl ephedrine reference standard (B.Knoll, Germany), ethylene dichloride and benzene (HPLC grade, Spectra Chem., India), toluene, ethyl acetate, cyclohexane, acetone, methanol and chloroform (HPLC, E.Merck India grade), potassium hydroxide GR and ammonia (Qualigens, India) and formic acid 98/100 % (BDH grade, India ). All the chemicals were used without further treatment. All volumetric glassware used for the study was calibrated.

Stock solution of pseudoephedrine hydrochloride (reference standard) 7 μg x ul –1 (A) was prepared by dissolving 70 mg of the material in degasses distilled water in a 10 ml volumetric flask.

Identification and purity of pseudoephedrine hydrochloride test sample-

Mass spectrum, IR spectrum and DSC thermo gram of pseudoephedine (test sample) were recorded using the instruments mentioned earlier and the data obtained were compared with those of the reference sample. Due to some difficulties, the impurity profile of the pseudoephedrine HCl could not be determined.

HPTLC of pseudoephedrine hydrochloride-

Preliminary experiments-

Pseudoephedine HCl was spotted on HPTLC plate using Linomat IV. The plate was developed in a twin trough chamber. A single band was obtained indicating high purity of the test sample. However, the bands either failed to migrate from the base line or they almost migrated to the solvent front. Amongst all the reported systems employed including ethylene chloride – methanol- benzene (70:25:5 v/v/v) showed good movement of the band except that it showed tailing. Further studied on this has been presented here.

Preparation of calibration curve, sample application, plate development and densitometric evaluation-

Stock solution A was prepared as mentioned above 1,2,5,10,15 and 20 μl of this solution corresponding to 7,14,35,70,105 and 140 μg respectively of pseudoephedrine HCl were spotted as individual bands using Camag Linomt IV sample applicator equipped with a 100 μl Hamilton syringe. The plate was developed to a distance of 80-85 mm (35-40 min) in a solvent system consisting of ethylene dichloride- methanol-benzene- formic acid (14 :4:2:1 v/v/v/v) in a Camag twin trough chamber pres-saturated with the solvent system for a period of not less than 45 minutes.

The developed plates were scanned densitometrically observing the following conditions: [I] lamp deuterium. [ii] Scanning speed 4.0 mm/s, [iii] slit dimensions 4x3 mm2, [iv] detection wave length 254 nm, [v] sensitivity 230 units and [vi] span 40 units.

The migration distance (MD) of the band was taken as the response standard during the scanning and integration of the developed bands. Peak area (AUC) was then plotted against the concentration values to obtain a calibration curve.

In the next chapter, we shall take up discussion on method validation and its results.

For further information on HPTLC, QA techniques and audits, please forward your inquiries at drshrutibhat@gmail.com .

Quality Assurance in pharmaceutical industry- Is quantitative HPTLC method a useful tool ? Part I: Estimation of api.

2009-04-22T16:58:00.000-07:00

by Dr.Shruti Bhat

INTRODUCTION-

Analysis is a critical and integral part of the pharma business. Its only up on clearance of products on analysis can the products be even released into the market. Hence, systems of analysis as well as the analytical tools assume prime importance. Several well known analytical tools viz. HPLC, GC, IR, UV-Vis, atomic absorption spectrophotometer etc. are available to a pharmaceutical analyst. However, to my mind, pharmaceutical analyst has still not utilized all analytical techniques science has offered to us. To name few, are Near Infra red- NIR, Raman spectroscopy and HPTLC.

With the process analytical technique- PAT, claiming importance in quality control departments of several established pharmaceutical companies especially in the US, one has to rethink on easy yet accurate ways of content measurement in pharmaceutical products. HPTLC is another such easy analytical technique that is precise, speedy and easy to work with but has not become very popular in the analytical field

To elucidate the merits of HPTLC, without promoting any brand of the analytical equipments, I have mentioned herein few cases (published in serial order). This work was done during my postgraduate days wherein we attempted to study use of HPTLC in the analysis of assay of active pharmaceutical ingredients- API, formulations and from plasma samples of a bio-equivalence study.

This article attempts to depict merits of HPTLC in estimation of assay of API. Pseudoephedrine hydrochloride is a model drug for this study.

Pseudoephedrine hydrochloride, a stereoisomer of ephedrine belongs to the class of sympathetomimetic drugs 1. Its main clinical use being a nasal decongestant. It is employed alone or in combination with other agents.

Analytical methods reported for estimation of pseudoephedrine include thin layer chromatography [TLC], gas chromatography [GC] and high performance liquid chromatography . However, quantitative high performance thin layer chromatography [HPTLC] estimation for this drug has not been reported hitherto.

The GC and HPLC assay procedure although, possess good sensitivity are tedious. TLC on the other hand is easy but lacks the sensitivity and selectivity necessary in the analysis of pharmaceutics. HPTLC possess the advantages of being simple, rapid (since 10 –20 sample can be estimated on a single plate), and easy to operate giving rapid performance with high resolution. The method has widely been accepted for qualitative and quantitative evaluation of drugs belonging to various classes viz. vitamins, steroids, amino acidic , alkaloids , antibiotics etc.

The objective of this study was (i) to develop HPTLC method for determination of pseudoephedrine and (ii) to apply the method to the quantitative estimation of pseudepherdine hydrochloride samples stored under stress conditions.

REFERENCES-

1. Martindale, J.E.F., Reynolds Ed, The Pharmaceutical Pres London, 1989, p1478.

2. J.E. Haley, D.A. Sheuwood and S.T. Brennanm, J.Liq. Chromat., 1989, (1296), 907-917.

3. F.T. Delbebe and M. Debackere, Priopham. Drug Dispos., 1991, 12 (1),37-48

4. R.G. Achari and R. Stillman, LC-GC, 1986,4(5), 454-456.

5. R.C. George and J.J. Conario, J.Liq. Chromatogram., 1988, 11(2), 475-488.

6. S. Ebel, M. Herboth, Proceedings of the IVth International symposium on Instrumental HPTLC Selvino/ Bergamo , Italy, 1987, 27-33.

7. P.K. Shrivastava, R. Paraksh, Orient J.Chem, 1989, 5(2), 135-138.

8. J.T.H. Schiller, V. Graef, S.W. Golf and W. Funk, Proceedings of the IVth International symposium on Instrumental HPTLC, Selvino/ Bergamo, Italy, 1987, 369-378.

9. G. Szepesi, J.Planar Chr. Mod.TLC., 1992, 5(6), 396-407.

10. R. Bhusan, G.P. Reddy, Proceedings of the IVth International symposium on Instrumental HPTLC, Selvino/ Bergamo, Italy, 1987, 53-59.

11. K. Scheide, F. Wonst, Th.Prey and E. Baneher, Anal. Hem. 1981, 428-430.

12. J. Allowohn, S. Ebel, J.S. Kang, Proceedings of the IVth International symposium on Instrumental HPTLC, Selvino/ Bergamo, Italy, 1987, 27-33.

Tomorrow, we shall take up discussion on detailed experiments and its results.

For further information on HPTLC, QA techniques and audits, please forward your inquiries at drshrutibhat@gmail.com .

Using Quality-by- design in manufacturing processes and facilities, what is the impact -

2009-04-12T16:22:00.000-07:00

The present business climate looks upon QbD as an approach or option for filing of NDAs, however, many fail to leverage the opportunity to use aspects of QbD to focus business and development plans.

This article if to provide you with more in-depth insight into QbD, its manifestations and worthiness to the business of making quality medicines.

Benefits of Quality-by design - QbD provides
· Increased assurance of product quality
· Design space information captures process understanding for operational implementation
· Quality risk management is critical in development of product quality control strategy.

What does this mean for pharma industry business especially during times of receeding economy ?

Please do visit me tomorrow for further reading.............

Dr.Shruti Bhat