Regulatory aspects of pharmaceutical excipients

Pharmaceutical excipients are inert substances used as diluent/Vehicle/Fillers/Binders/bulk agent/lubricants for drug formulation. They are responsible for product performance and enable the drug to give desired pharmacological action. The regulatory guidelines have made it mandatory that all constituents of a drug formulation should be compliant and tested as per current cGMP regulations for safety and efficacy of drug. Increasing focus on excipients is due to past incidents, where patients had died due to contaminated excipients, used by pharma companies. It is the responsibility of the pharma manufacturer suppliers to use high quality pharma ingredients in the respective formulation.

Regulatory bodies governing the standards of excipients are as per international and national guidelines. International guide lines are as per ICH Q7A GMP applicable to API's. Use of any new excipient in formulation should be assisted with quality and safety data.

Excipients are classified as per the source of origin:

1.Animal origin
2. Plant origin
3. Mineral origin
4. Synthetic origin

Risks associated with non-GMP manufactured excipients

Documented evidence:

Fraudulent product obtained from broken supply chain and distribution routes leading to contamination cases:
1990 Nigeria: Cough syrup contaminated with solvents (47 reported deaths)
1986-1998 India and Bangladesh: Paracetamol syrup contaminated with diethylene glycol from propylene glycol origins (236 reported deaths)
1996 Haiti: Glycerine contaminated with diethylene glycol (88 reported deaths)

Adulterated excipients causes failure of drug batches during manufacturing and may also result in hazardous products and thus it is risky for drug manufacturers and the patients.

Thus due to the above associated risks and subject to mandatory requirements, excipients must be manufactured, processed, packaged and held in conformity with Current Good Manufacturing Practice (cGMP).

Excipients with cGMP Conformance should be based on ICH Q7A GMP Guidance for APIs as regulatory bodies have not developed regulations or specific guidance on cGMP conformance for excipients. However, FDA is supportive of the IPEC GMP Guide for Bulk Pharmaceutical Excipients. Quality characteristics of excipients are significant to the overall quality of the drug products in which they are used.

Drug product manufacturers rely on excipient manufacturers to provide excipients of uniform quality, physical and chemical characteristics, eg., levels of impurities.

As per 21 CFR 211.84(d)(2), the user/drug product manufacturer is required to test every batch of drug excipient for conformity with written specifications, for purity, strength and quality. However, drug product manufacturers can rely on their suppliers for this testing, provided that the reliability of the suppliers' test results is validated at appropriate intervals

The most important thing to note is that testing as per USP/NF/BP/Ph Eur does not replace compliance to GMP.

Regulation of excipients

Excipients can be classified as official in pharmacoepia or non official in pharmacoepia. Compendial excipients have composition consistent with monographs published in compendia such as USP-NF, BP, Ph Eur, and JP. The non pharmacoepial excipient usage should be justified with safety and quality data.

Increasing focus on excipients is based on several parameters:

1)Excipients help deliver final drug formulation performance and are also considered to be major part of the formulation

2)As per the cGMP, quality can be introduced in final formulation, and thus GMP is applied right from incoming of materials to distribution in market

3)Understanding variation of excipients properties as they relate to product quality attributes

4)Building robustness and flexibility into manufacturing process

5)Lack of guidelines Specific to Excipients

US-FDA perspective

An excipient is defned by the US FDA as ''any component of a drug product other than an active ingredient''. In the US, the FDA assesses and permits use of excipients as part of a New Drug Application (NDA). In the US guidelines relating to preclinical data for NDA submission, excipients are not mentioned. Under US law, a new pharma excipient, unlike an active drug, has no regulatory status unless it can be qualified through one or more of the approval mechanisms available for components used in ?nished drug dosage forms.

EU - EMEA perspective

Within the EU there is a directive that makes it clear that new excipients will be treated in the same way as new actives. In Europe, the need for companies to fully consider the types of excipients in new drug formulations has been the focus of a guideline released recently by the European Commission on drug label and package leaflet excipient information for all MAA. This guideline indicates that all excipients must be listed on the drug label for parenteral, topical, inhalation, and ophthalmic products. For other medicinal products, only those excipients with a defined and recognised action of effect need to be declared on the label. In drug package leaflets, all excipients must be included. European regulations and guidelines also require that a full statement of the excipients used be given in the Summary of Product Characteristics (SPC) document for new drug formulations.

Japan - MHW perspective

The formal structure for regulating pharma excipient is quite complex. Responsibilities are divided among several divisions in the MHW and National institutes for Hygienic Sciences (NHS) and Central Pharmaceutical Affairs Council (CPAC) play key roles in the regulation of excipients.

There are two compendia containing monographs that describe Japanese standards for pharma excipients.

• Pharmacopeia of Japan (JP)
• Japanese Standards of Pharma Ingredients (JSPI)

Excipient evaluation

Excipients are important in assuring drug product quality and stability. Understanding and controlling the functionality of excipients can lead to more robust, flexible processes. Excipient specifications should be appropriate to assure product performance. Continual monitoring can assist in continual assurance of product quality. Understanding variation of excipient properties as they relate to product quality attributes are dependent on following parameters:

Physical

• Particle morphology, powder property, polymorph, Hygroscopic, aqueous solubility and density

Chemical

• Identity, purity, incompatibility with drug substance or other excipients

Mechanical

• Flow ability, compressibility

Excipient evaluation for a drug formulation should be based on following approaches:

Drug-Excipient Compatibility

Advantages: Maximised stability of a formulation, enhanced understanding of drug excipient interactions

Formulation Robustness

Advantages: Desired pharmacological action achieved, facilitates the development of novel drug delivery systems

Functionality

Advantages: Minimises formulation processing problems, facilitates safer/more efficient manufacturing processes

Excipient supplier qualification

Apart from the above facts, it is very important that the pharma manufacturer, during sourcing of excipients for drug formulation should qualify the vendor on the following parameters:

1. A comprehensive assessment of

• Excipient quality
• The manufacturing process to make the excipient
• The distribution controls used to deliver the excipient to the drug product manufacturer

2. Supplier systems and capability

3. Physical audit at manufacturing site

The purpose of this qualification is to ensure that the safety of the drug product is not compromised by the excipient. Both manufacturing (GMP) and distribution (GDP) aspects need to be covered. Failures at any point in manufacturer in the supply chain may put patients at risk. The modern pharma paradigm requires a Quality by Design (Qbd -ICH Q8) and a risk management approach (ICH Q9) to determine the details of that qualification. Those excipients posing the greatest risks require the most thorough controls.

Industry formed committees /Groups 1. EFCG — European Fine Chemical Group 2. IPEC — INTERNATIONAL PHARMACEUTICAL EXCIPIENT COUNCIL -Europe 3. IPEC — INTERNATIONAL PHARMACEUTICAL EXCIPIENT 4. COUNCIL America 5. EXCIPACT 6. European association of chemical distributors 7. The Pharmaceutical Quality Group 8. Rx-360 Mission

Advancement of industry initiatives

Pharma excipients have no official regulatory status independent of the finished dosage form in which they are used. As a result, the mechanism for regulation of these ingredients is not fixed.

Conclusion

Excipients form an integral part of medicinal products deserving quality management systems and appropriate regulations. Thus the days of treating excipients like commodities and buying them without fully qualifying the source and the entire distribution chain are over. Some excipients are also being used as API's by pharma companies when they were never intended by the manufacturer to be an API grade and are not made in an FDA registered facility using ICH Q7A GMP guidelines.

This adds to the risk of the pharma company and poses a safety risk to patients. Pharma companies need to take steps to guard against such practices and reduce their risk at all stages of the manufacturing process, even the processes that take place outside their premises. In the light of more stringent regulatory practices, and more complex supply chains, finding the right excipient manufacturer thus takes on additional significance.

For more details.....

http://www.expresspharmaonline.com/20110215/market03.shtml

Ranbaxy inks consent decree & prepares for $500m penalty

Ranbaxy has signed a consent decree with the US FDA and set aside $500m for penalty payments to settle its longstanding dispute.

For Details follow the link below.....

http://www.in-pharmatechnologist.com/Processing-QC/Ranbaxy-inks-consent-decree-prepares-for-500m-penalty

European Medicines Agency and United States Food and Drug Administration to share manufacturing site inspections

The European Medicines Agency and the United States Food and Drug Administration (FDA) are launching an initiative to share work on inspections of manufacturing sites in each other's territories.

The initiative, starting in January 2012, will enable the two authorities to rely on each other's inspection outcomes rather than carrying out separate inspections in duplicate. This is expected to:

• enable better use of the two authorities' inspection resources;
• reduce the burden of inspections for medicines manufacturers;
• shift the authorities' inspection capacity to other regions.

The initiative will apply to inspections of manufacturing sites of human or veterinary medicines in the European Economic Area or United States of America. It will focus on sites that are already known to the two authorities and have a history of compliance with good manufacturing practice (GMP) following previous inspections.

This is the latest step in increased collaboration between European authorities and the FDA. In August this year, the authorities announced the successful completion of two pilot projects involving the sharing of information on inspections.

The outcomes of the initiative will be reviewed after three years.

Lipitor And The Future Of Pharmaceutical Innovation

Grace-Marie Turner is president of the Galen Institute, a non-profit research organization that promotes market-based health policy solutions.
Today, nearly 80 percent of all prescriptions in the U.S. are filled with generics, and the percentage will rise when more than 10 major drugs go off patent in 2012.  Late last month, the most popular drug in history, Lipitor, went off patent, allowing a generic version of the cholesterol-lowering drug to enter the market and be sold at lower prices.

Pfizer has developed a novel program that lets people stay on Lipitor, even as more competitors prepare to enter the market.  Patients can sign up to get a $4 co-pay card that will allow them to get their prescription filled at generic prices through the company’s new program, “Lipitor For You.”  They can have their prescription filled at a local participating pharmacy, or they can get the medicine delivered by mail.

“They are setting up a Pfizer pharmacy, if you will,” said Everett Neville, vice president of pharmaceutical strategy and contracting at Express Scripts., one of the nation’s biggest pharmacy benefit managers. That is something that no pharmaceutical company “has done to date,” he said.

In the U.S., the company is offering to sell Lipitor at generic prices to health plans and to pharmacies and pharmaceutical distributors who agree to fill prescriptions with its product instead of an unbranded version.

The effort is part of a broader push by Pfizer to keep patients on the brand-name drug.  The blockbuster medicine generated tens of billions of dollars in revenue for Pfizer over its patent life, boosting resources available to invest in research into the next generation of new drugs.
Generic companies are allowed to sell copies of brand-name drugs once the patent expires.  The Federal Hatch-Waxman Act, passed in 1984, allows a ramp-up to this generic competition in the first 180 days after a drug patent expires;  during this time, competition is limited to the company that is “first to file” an application to sell the generic version of the drug.
This provides only a six-month reprieve.  Pfizer will reassess the program once more competitors enter the market next year.
“Previously, Big Pharma has tended to walk away” from top-selling drugs once they lose patent protection, Pfizer Chief Executive Ian Read said in an interview. “Now, we have a flat-out different culture.”

Medco Health Solutions Inc., which manages the benefits for 60 million Americans, says it plans to sell brand-name Lipitor at generic prices to the million-plus customers in its mail-order program. Another pharmacy benefit manager, Catalyst Rx, has told pharmacists that brand-name Lipitor will function as the generic during the next six months, with a generic’s $10 co-pay.

All generic versions of the drug must contain the same active ingredients as the original formulation, but that doesn’t mean it will work the same in every patient.
Different drugs with the same active ingredient do work differently for different patients, as everyone who has taken maintenance drugs knows.  This gives patients a chance to stay on Lipitor if that works best for them without being automatically switched to a generic.  Patients also value the certainty of having a brand-name drug and the supply-chain integrity the company provides.
Seems like an attractive deal for many patients. Pfizer’s deal is a little like GM telling people they can have a Cadillac at Chevy prices.
With the growing difficulty of getting drugs through the FDA labyrinth and the rising cost of drug approval, Pfizer musts produce revenue for continued research – the lifeblood of pharmaceutical companies.  Without this research, the pipeline would run dry, delaying or even killing new medicines for Alzheimer’s, Parkinson’s, and countless other diseases.
It now costs about $1.8 billion to bring a new drug to market, and only a fraction of the drugs that are approved actually recoup the investment.  According to a recent McKinsey study, unless pharmaceutical companies can develop creative ways to generate revenue to fund research, “we would expect Big Pharma’s current level of R&D spending to become a luxury that investors no longer tolerate. We already see these signs today, as some investors and analysts believe that many of Big Pharma’s R&D investments destroy value.”
That would be bad news for today’s and especially tomorrow’s patients.

Supreme Court Takes a Look at Medical Patents-USA

What if your doctor couldn’t use scientific research about the drugs she was prescribing to you in order to ensure that you received the proper dosage of medication? What if a doctor had to navigate a complex thicket of procedural patents simply to treat her patients?
Well, according to Tim Lee, the Supreme Court is on the verge of making medical patents a reality, allowing drug companies to not only patent their drugs, but also the way doctors prescribe them to patients:

This should make the nation’s doctors extremely nervous. For two decades, the software industry hasstruggled with the harmful effects of patents on software. In contrast, doctors have traditionally been free to practice medicine without worrying about whether their treatment decisions run afoul of someone’s patent. Now the Supreme Court seems poised to expand patent law into the medical profession, where it’s unlikely to work any better than it has in software.
The case focuses on a patent that covers the concept of adjusting the dosage of a drug, thiopurine, based on the concentration of a particular chemical (called a metabolite) in the patient’s blood. The patent does not cover the drug itself—that patent expired years ago—nor does it cover any specific machine or procedure for measuring the metabolite level. Rather, it covers the idea that particular levels of the chemical “indicate a need” to raise or lower the drug dosage.
The patent holder, Prometheus Labs, offers a thiopurine testing product. It sued the Mayo Clinic when the latter announced it would offer its own, competing thiopurine test. But Prometheus claims much more than its specific testing process. It claims a physician administering thiopurine to a patient can infringe its patent merely by being aware of the scientific correlation disclosed in the patent—even if the doctor doesn’t act on the patent’s recommendations.

The American Medical Association’s brief on the matter argues that ”If claims to exclusive rights over the body’s natural responses to illness and medical treatment are permitted to stand, the result will be a vast thicket of exclusive rights over the use of critical scientific data that must remain widely available if physicians are to provide sound medical care.”
“Conscientious physicians will be unwilling and unable to avoid considering all relevant scientific information when reviewing test results. Thus, as medical knowledge accumulates, patent licenses increasingly will be required for physicians to conduct even well established diagnostic tests.”

Sounds a bit like the patent trolling we’ve been encountering in the software universe in recent years, as an increasingly bizarre and burgeoning patent system weighs down innovation and stymies growth.
Of course, in medicine the stakes are somewhat higher. Already drug patents give the prescription industry far too much cushioning from competition. Add this to the mix and you create all sorts of bad incentives, lawsuits, and other obstacles to good patient care.
Now obviously this is totally insane, but the Supreme Court doesn’t seem to realize just how insane:

Justices Scalia and Breyer showed some skepticism that patents could cover the use of scientific correlations in medical practice. But the other justices expressed no such skepticism. At one point, Justice Kagan offered some advice to Prometheus’s lawyer. “What you haven’t done is say at a certain number you should use a certain treatment, at another number you should use another treatment,” she said. “I guess the first question is why didn’t you file a patent like that? Because that clearly would have been patentable. Everybody agrees with that.”
Of course “everyone” does not agree with that. In particular, the American Medical Association (and, presumably, many of the nation’s doctors) doesn’t. Neither does the ACLU, the AARP, or the Cato Institute. Yet if any members of the high court disagreed with Kagan, they didn’t speak up.

We’ve long argued that the Supreme Court should overturn the lower courts’ de facto legalization of software patents. Instead, the Supreme Court appears poised to take a step in the opposite direction and expand patent law to cover the medical profession. And they seemed oblivious to how dramatic a step that would be.

The world, it appears, is determined to turn me into a full-fledged libertarian. What with SOPA, PIPA, the NDAA, software patent trolling, police violence, and now patents on how doctors provide treatment to their patients, it’s becoming more and more clear how pernicious the law can be when it’s designed for powerful special interests, national security hawks, and big corporations.
There may indeed be a place for patents, but the way they’ve been used to stifle competition and innovation in software shows how limited their utility really is – at least for the majority of people. A small handful of patent-entrepreneurs make loads of money. They just don’t produce anything in order to make that money. It’s a sort of legal banditry. Loophole highwaymen waiting to waylay the unfortunate software engineer or doctor.

9 Things That Motivate Employees More Than Money

Don't show 'em the money (even if you have it). Here are nine better ways to boost morale.

The ability to motivate employees is one of the greatest skills an entrepreneur can possess. Two years ago, I realized I didn’t have this skill. So I hired a CEO who did.
Josh had 12 years in the corporate world, which included running a major department at Comcast. I knew he was seasoned, but I was still skeptical at first. We were going through some tough growing pains, and I thought that a lack of cash would make it extremely difficult to improve the company morale.
I was wrong.
With his help and the help of the great team leaders he put in place, Josh not only rebuilt the culture, but also created a passionate, hard-working team that is as committed to growing and improving the company as I am.
Here are nine things I learned from him:

1. Be generous with praise. Everyone wants it and it’s one of the easiest things to give. Plus, praise from the CEO goes a lot farther than you might think. Praise every improvement that you see your team members make. Once you’re comfortable delivering praise one-on-one to an employee, try praising them in front of others.  
2. Get rid of the managers. Projects without project managers? That doesn’t seem right! Try it. Removing the project lead or supervisor and empowering your staff to work together as a team rather then everyone reporting to one individual can do wonders. Think about it. What’s worse than letting your supervisor down? Letting your team down! Allowing people to work together as a team, on an equal level with their co-workers, will often produce better projects faster. People will come in early, stay late, and devote more of their energy to solving problems.  
3. Make your ideas theirs. People hate being told what to do. Instead of telling people what you want done; ask them in a way that will make them feel like they came up with the idea. “I’d like you to do it this way” turns into “Do you think it’s a good idea if we do it this way?”  
4. Never criticize or correct. No one, and I mean no one, wants to hear that they did something wrong. If you’re looking for a de-motivator, this is it. Try an indirect approach to get people to improve, learn from their mistakes, and fix them. Ask, “Was that the best way to approach the problem? Why not? Have any ideas on what you could have done differently?” Then you’re having a conversation and talking through solutions, not pointing a finger.  
5. Make everyone a leader. Highlight your top performers’ strengths and let them know that because of their excellence, you want them to be the example for others. You’ll set the bar high and they’ll be motivated to live up to their reputation as a leader.  
6. Take an employee to lunch once a week. Surprise them. Don’t make an announcement that you’re establishing a new policy. Literally walk up to one of your employees, and invite them to lunch with you. It’s an easy way to remind them that you notice and appreciate their work.  
7. Give recognition and small rewards. These two things come in many forms: Give a shout out to someone in a company meeting for what she has accomplished. Run contests or internal games and keep track of the results on a whiteboard that everyone can see. Tangible awards that don’t break the bank can work too. Try things like dinner, trophies, spa services, and plaques. 
8. Throw company parties. Doing things as a group can go a long way. Have a company picnic. Organize birthday parties. Hold a happy hour. Don’t just wait until the holidays to do a company activity; organize events throughout the year to remind your staff that you’re all in it together. 
9. Share the rewards—and the pain. When your company does well, celebrate. This is the best time to let everyone know that you’re thankful for their hard work. Go out of your way to show how far you will go when people help your company succeed. If there are disappointments, share those too. If you expect high performance, your team deserves to know where the company stands. Be honest and transparent.