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

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:

1. Remedial corrections of an identified problem.
2. Root cause analysis with corrective action to help understand the cause of the deviation and potentially prevent recurrence of a similar problem.
3. 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.

Http://www.drshrutibhat.com
Expert at leading Pharmaceutical R&D.
Translates innovative concepts to PROFITS.
YouTube Channel : Http://www.youtube.com/user/ShrutiBhat10

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.


Do you have questions for the author?

Diabetes drug may increase fracture risk in women.

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.
Do you have questions for the author?

QA updates on new drug research-

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-

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-

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-

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-

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.