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HEMACORD becomes the first cord blood product approved by US FDA.

2012-01-01T07:57:00.000-08:00

The first US FDA approved cord blood product

Stem cells have great importance in regenerative medicine , they can be used to regenerate a lost tissue or to restore a hampered function of a tissue or to completely or partially replace a defective tissue, for example, stem cells are been successfully used in treatment of certain blood cancers and disorders.

Now HEMACORD is a first US FDA approved hematopoietic progenitor cells-cord (HPC-C) cell therapy product, which was approved by US FDA in the month of NOV 2011.

HEMACORD is used in treating disease of blood forming and blood cells (hematopoietic stem cell transplantation) , immune cells , to correct the auto immune diseases to replace over activated immune cells which are responsible for autoimmune diseases, as well as blood disorders like thalassemia major. Certain metabolic disorders like over activated enzyme system or completely absence of an enzyme in metabolic process too are treated by stem cell transplantation.

In 2009 US FDA had put two years time frame as phase in period for HPC-C product and had required their manufacturers to submit an ANDA or IND for such products after Oct. 20, 2011. And now HEMACORD is first US FDA approved hematopoietic progenitor cells-cord (HPC-C) cell therapy product.

HEMACORD is made up of stem cells (hematopoietic progenitor cells (HPCs) isolated from human cord blood.

There are three sources for basal stem cells 1. Bone marrow 2. Chord blood 3. The tissue it self , in case of blood cells it would be blood it self can be used as source of stem cells, first three sources are considered good sources as in last source the amount of tissue required to collect stem cells is very much higher.

The product is provided a boxed warning cautioning doctors about possibility of passing on host diseases, genetic disorders and anaphylactic and allergenic reactions to receiving individual, graft failure. This must be verified with the usefulness of the drug against the risks involved. Patients are also required to be monitor closely after HEMACORD administration.

New York Blood Center, Inc.from New York, USA is the manufacturers of HEMACORD.

Stem Cells use in regenerative medicine

2011-11-26T04:13:00.000-08:00

Stem cell and regenerative medicine: What is stem cell therapy ?

There are certain cells in our body known as stem cells can differentiate in to many different organ tissue cells and connective tissues (puripotent cells), which make stem cells one of great tool in regenerative medicine in fact it is looked as wonder medicine, stem cell derived from chord blood cell or bone marrow can differentiate in to , neural cell , liver cell, muscle cells or ostioblast (bone cells), blood corpuscles and so on eventually they can develop in to all types of organs and connective tissue cells, blood cells in human body.

Even stem cells are capable of rendering normal life to a patient affected with disorders like blood cancer and other degenerative diseases by virtue of replacing faulty tissue cells with normal cells originated through transplanted stem cells.

Stem cells develop in to a particular tissue basal cell which are called as pluripotent stem cells and progenitor cell which further develop in to cells of particular organ . This is one of our natural repair system of our body tissue. Stem cells can also be artificially grown in laboratory in to specific required tissue basal cells and injected in to damaged tissue where they bring repair of that damaged tissue, because this stem cells are used as source of regeneration of any damaged tissues or undeveloped tissues Or to bring about repair of an abnormal or the faulty tissue, as that in blood cancer.

Stem cells are classified in to two types
1) Embryonic stem cells are obtained from blastocysts (embryo)
2) Adult stem cells are present in all tissues.

Source of stem cells in human body:
Bone marrow and umbilical cord blood are main source of stem cells.

Cord blood stem cells:
Cord blood is a rich source of stem cells as well as hematopoietic cells , it is collected from the blood tissue in placental blood in umbilical cord after child birth, it is used in treatment of genetic disorders and hematopoietic disorders (blood disorders) as well as for regenerative therapies in tissue damages cord blood stem cells contains can be used to treat hematopoietic , degenerative disorders to some extent and genetic disorders.

Umbilical cord blood cells can be stored in cord blood stem cell banks, immediately after child birth, and can be used as a rich source of stem cells in future in event of any degenerative or hematopoietic disorders.
Adult stem cells are stem cells which are derived from the

Bone marrow stem cells mesenchymal:
Stroma in bone marrow consist of stem cells which are capable of differentiating in to basal cells (progenitor cell) of any organ or tissue in human body, and function as repair system in our body.
As the bone marrow stem cells also known as mesenchymal stem cells are capable of differentiating in to many different functional cells including osteoblasts (bone cells) which can develop in to particular tissues, therefore they are called as multipotent cells.

The cord blood stem cells are used to treat following disease
1) Hematological malignancies
2) Beta Thalassemia
3) Failure of Bone marrow
4) Adrenoleukodystropy Nerous system damage of mylin sheet damage to peripheral nerous system and adrenal gland.( X-linked Adrenoleukodystropy)
5) Inherited Immunodeficiency
6) Globoid Leukodystrophy
7) mucopolysaccharidosis type I disease a genetic disorder where there is lack of enzyme responsible for breakdown of mucopolysaccharides in lysosomes which gradualy results in glycosaminoglycans buildup and organ damage.

Regulatory aspects of human tissue cell products

In united states chord blood cell and similar cell therapy and tissue products are regulated through CFR 21 Part 1271.
Also following regulatory requirements are mandatory for human tissue and cell products.
1)Lableing as under 21 CFR Parts 201, and 610 Subpart G
2) Regulations for Prescription Drug Advertising as under 21 CFR Part 202
3) Current good manufacturing practices regulations as under 21 CFR Parts 210 and 21 CFR Part 211
4) General Regulations for Biological Products: 21 CFR Part 600 –; and
5) Regulation of General Biological Products Standards as under 21 CFR Part 610.

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First artificial aortic heart valve which can be placed in heart with out open heart surgery :

2011-11-15T13:22:00.000-08:00

Innovative Transcatheter Heart Valve (THV) can now be placed in to heart with the help of catheter.

Senile aortic valve stenosis shortens life expectancy greatly in patients suffering from senile aortic valve stenosis if they are not treated with surgery to correct or replace aortic valve, which is done with an open heart surgery, some patients health condition poses great risk for open heart surgery, for such patients now US FDA has approved an innovative Transcatheter device which can replace aortic valve with an artificial valve with the help of a delivery catheter artificial valve is placed in to the defective valve , and it starts functioning within seconds after it is replaced , the innovative device is known as The Sapien Transcatheter Heart Valve (THV).

This device is approved only for patients which can not be considered for open heart surgery .
Heart is very important organ in human body, which requires working through out ones life. There are valves in our heart which regulate closing and opening of heart in a synchronized manner in different mode of contraction and relaxation of different heart chambers so as to facilitate normal blood supply or pumping of blood to all tissues in our body without causing back flow or mixing of blood.When ever there is a defect in heart valves it can lead to serious life threatening consequences like congestive cardiac failure and cardiac arrhythmias.

Senile aortic valve stenosis disease gradual deposition of calcium occur over aortic valve which causes defect in its functioning by making its opening narrow or making its opening smaller, because of which heart has to pump blood with more force than the regular normal force otherwise in a normal aortic valve. This leads to serious lifethretehning consequences like chest pain, cardiac arrest , heart failure, cardiac arrhythmias. Life expectancy of the patients affected with Senile aortic valve too becomes very short.

US FDA has now approved an innovative drug device an Innovative Transcatheter Heart Valve (THV) for patients which has greater risk in open heart surgery . It is made up of cow tissue and polyester supported with a mesh frame of stainless steel.

Catheter carrying a Transcatheter Heart Valve is inserted in to femoral artery by giving a small cut in leg and then it is placed and fixed by expanding it with balloon at the site of defective heart valve it is then functional immediately

There are risks also associated with this Transcatheter Heart Valve like stroke due formation of blood clot due to damage to blood cells by Transcatheter Heart Valve it self , perforation in blood vessel and ventricular structure and risk of developing impairment in nerve conduction of heart muscles.

Person with infection in heart and who can not take anticoagulant drugs should not be treated with the Transcatheter Heart Valve. Edwards Lifescience, is the manufacturer of the Sapien Transcatheter Heart Valve.

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List of drugs which are approved by FDA in liposomal drug delivery systems.

2011-11-03T03:39:00.000-07:00

Drugs available in market as liposomal drug delivery systems :

Amphotericin B :
Amphoterecin B is an antibiotic and is an antifungal drug , it is required to be injected intravenously and have some seriously bad side effects like acute reaction and fever with chill , nausea, anorxia and weekness, all these side effects depend up on the concentration of Amphoterecin B available directly to all biological receptors in our body , along with fungal cells.
Formulating amphoterecin B in lyposomes prevent its diret contact with biological receptors where its action is not requires where as its action against fungal cell remain intact.

Cytarabine (Ara-C ) :
is an anticancer drug it is an nucleotide anti metabolite drug , and is cytotoxic , it also brings damage to other tissue cells when it come in contact with other normal tissue cells , along with cancer cells .
Formulations of Cytarabine (Ara-C ) in liposome reduce its untoward toxic effect on other tissue cells , and it can be specifically delivered to only cancerous cells only when the are tagged with antibodies against the cancer cells . the therapeutic concentration of drug to be administered in the body of patient also comes to lower side.

Cyclophosphamide :
It is a anticancer drug , like cytrabin it too has cytotoxicity it belonging to category cyclic nitrogen mustard These drugs are very unstable in biological fluids in fact it is a prodrug which when come in contact with biological fluid at ph 5 to 7 becomes active and exert their effect and kill cancer cell by alkylating DNA and thus making it inactive for any activity they are called as alkylating agents , it is also used in certain auto immune diseases as it reduces the activity of hyperactive immune cells. They too have untoward cytotoxic effect on normal cells as well .
Formulating cyclophosphamid in liposomes help in reducing its cytotoxic effects , as the drug concentration required for desired anticancer effect .

Doxorubicin
It is also an anticancer drug it is an antibiotic drug and has similar cytotoxic effects of anticancer chemotherapy, formulations of liposome formulations of these drug help in bringing down their cytotoxicity andand help in optimizing therapeutic efficacy.

Hepatitis A and Influenza vaccines :
Vaccines are developed in liposome to render their untoward effect sensitizing effect on immune system, further they can be combined with polyethylene glycol which further render vaccines less immunogenic and specific.

Liposomal Morphine in pain management in cancer patients it is formulated as controlled release , delayed release liposome with which it reduces the need of frequent intrathecal injections of painkiller morphine in cancer patients.

Verteporfin :
It is a drug used as photosesitizer in photodynamic therapy for macular degeneration, it is used to treat and eliminated damaged tissue in macular region in macular degeneration these drug absorb energy from light 693 nm and produce reactive oxygen , which help in treating damaged blood vessels in eye. Liposome help in optimizing the therapy with minimal concentration of drug and and targeting the damaged tissue.

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Gastro retentive drug delivery system.

2011-10-31T11:30:00.000-07:00

What is gastro retentive drug delivery system or floating tablets floating capsules , what is a mucoadhesive dosage form?

When a drug is administered in a oral dosage form, and has very less bioavailability in lower intestine, then the absorption and bioavailability of the drug very much depend on gastric emptying time, which is very much unpredictable variable.

Gastro retentive drug delivery systems are drug delivery systems which are intended increase gastric retention time of a dosage form and to deliver a drug in stomach, there are certain conditions when delivering a drug in gastric environment helps to increase its therapeutic efficiency in case a localized drug delivery in stomach is intended.

For example famotidine is used to treat peptic ulcer but it has very low bioavailability when famotidine is delivered in conventional tablet dosage form as it is less soluble in alkaline ph which is encountered in small intestine immediately after a dosage form passes out from stomach.

In order to achieve retaining of a dosage form in to gastric acid, following methods are employed
1. Floating, raft, tablets and capsules.
In this method dosage form is designed so that it floats over gastric juice , method to achieve this include formation of raft , by swelling, expanding , to impart low density to the dosage form , which can be achieved with gas forming systems , sachet systems and hollow microspheres .
2. Bioadhesive or mucoadhesive tablets and capsules:
In this method dosage form is formulated with certain mucoadhesive polymers of hydroxy propyle methyl and propyl cellulose derivatives, and their sodium salts, which up on coming in contact with water swell and stick to mucus wall of stomach, both floating and Bioadhesive or mucoadhesive approaches can also adapted , and exciepients used are Agar , sodium alginate, carbopol and polyvinyl acetate, HPMC and polyacrylate polymers.

Which are the drugs formulated in gastro retentive dosage forms

Aspirin, griseofulvin, cinnarizine, diltiazem,,chlordiazepoxideHCL , acetaminophen, verapimil hydrochloride , pepstatin, ampicillin, amoxycillin trihydrate,, fluorouracil,, benserazide,diazepam, theophylline,furosemide, misoprostol, L-Dopa, ursodeoxycholic acid, atenolol, isosorbide mononitrate, para aminobenzoic acid, piretamide.

Advantages of gastroretentive dosage form
1.Gastrict emptying time which is a major factor in case a drug has absorption window in stomach , absorption and thus bioavailability is increased , which may further reduce the subsequent required number of dosage and drug concentration in a therapy.
2.Local drug delivery to attain localized action can be achieved in stomach.
3.Drug can be formulated as a sustained release or prolonged release dosage form with Gastro retentive dosage form
4.Gastroretentive drug delivery system has good result in case lower intestinal movement is increase like in case of diarrhea .
5.Drugs with low solubility in alkaline PH and which rapidly degrade in alkaline ph or in colon when formulated as gastric floating tablets or capsules or gastroretentive dosage form they are absorbed better. Example famotidine

Disadvantages of gastroretentive dosage form
1.Some drugs like aspirin which breakdown in to salicylic acid which is also has capability of damage stomach lining and form ulceration , which can be dangerous.

2.Drug like ibuprofen , can cause sever acidity , and ulceration in case it stick to gastric lining for longer time.

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Letrozole banned in India for its use to treat infertility as ovulation inducer.

2011-10-24T13:06:00.000-07:00

The drug letrozole is now banned in India by Indian ministry of health and family welfare for its use to treat infertility in women as it may cause teratogenic effects like defective bone formations, cardiac stenosis and even cancer too, to babies born to mothers who used drug letrozole .

Drug letrozole was approved in India for use as ovulation inducer in women with anovulatory infertility and it is now banned for manufacture for sale, or sale or distribution for indication anovulatory infertility. An official notification with this regard was published in The Gazette of India on 12th of oct 20011

The drug letrozole is banned for its use as ovulation inducer as the drug letrozole has teratogenic effect and may cause defects in babies born to mothers taking drug letrozole. In a clinical trial it was found that the baby born to mothers who had consumed letrozole for treating their infertility have developed bone malformation, cancer and cardiac stenosis.

Letrozole’s use in treatment of breast cancer:
In US the drug letrozole is approved only to treat non metastatic as well as metastatic breast cancer. Breast cancer cells when dislodge form the its origin and when mobilize or spread to other tissue is called as metastatic, and these cancer cells growth is fasten or depends on stimulation from hormone estrogens the female sex hormones.

Estrogens are synthesized in human body from androgens after action of enzyme aromatase.The drug Letrozole competitively blocks enzyme aromatase, thereby blocking the symntesis of estrogens which prevent breast cancer cell from multiplication and further growth.

Though the drug Letrozole is a choice of drug for the indication for breast cancer it has some serious side effects like osteoporosis (loss of bone mass because of which bones become fragile and get fractured more often) and hypoestrogenism, therefore to counter act osteoporosis after use of Letrozole drug like Bisphosphonates are always priscribe along with Letrozole. The drug letrozole is also used off the label by some to counteract gynecomastia induced by anabolic steroids.

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What is drug master file?

2011-10-22T07:22:00.000-07:00

What is drug master file?

Drug master file (DMF) is set of documents submitted to FDA by a pharma manufacturer, the drug master file may also provide information which may be confidential for the company but may be required to be presented to regulatory authority for complete understanding of their product, facility, and the processes, systems, equipments and articles adapted for various of process of manufacturing and quality control and quality assurance, or storage and distribution.
A holder can permit or authorize other person to rely on data and information for various applications submissions.

It is not mandatory document for US FDA, but it is submitted by a pharmaceutical manufacturer to support their export application or (ANDA) Abbreviated New Drug Application, IND Investigational New Drug Application , or (NDA) New Drug Application. FDA reviews DMF only in context with these applications and an application for marketing a new drug in market.

These applications may reference the content to DMF wherever it is applicable. The drug master file is submitted to FDA in two copies, one copy must be retained by the person or holder who is submiting DMF.

US FDA classifies DMF in to five types:
Type I
DMF provides information about manufacturing facility or Site, technical personnel’s working for the company and Operating Procedures.
This type of DMF is required from conducting on site inspections out side of USA
It should describe
1. Site of manufacturing, actual address of site , and a map showing its geographical location.
2. Operational layout, with diagram of main processing or production arias.
3. Equipments and capabilities. Complete description about equipment capabilities and their applications.
Organization diagram, highlighting key on site and corporate Quality control and Quality assurance positions.

Type II
Type II Drug master file give information about drug molecule, its Intermediates, and starting material and intermediates used in the manufacturing of drug molecule and drug product.
For each packaging material complete information about their use, composition and components, and how they are controlled and released.
Details about name of supplier, their manufacturer too are required to be provided.
If required by drug product, one should also provide toxicological data about packaging material.

Type III
Drug master file provides information about packaging material used for packaging drug product.

Type IV
Provides information about colorants additives, exceipients and flavors essences or substances used for manufacturing them.

Type V
Contains the information references which are accepted by FDA.It is required that a DMF to provide only one type of information and all data to support, different DMF’s may be cross referenced amongst themselves.

Though US FDA does not make it a mandatory document for any approval or disapproval , they have provided guidelines in section 21CFR314.420 about how DMF should be prepared and submitted .

21CFR314.420 states that A DMF for application in support of application for approval for marketing a new drug in market. should provide information about
1.) Drug molecule
2.) Drug molecule intermediates
3.) Packaging materials
4.) Excipients
5.) Flavors
6.) Essence
7.) Colorants
8.) Or substances used to make them
9.) It also states that it should also provide complete list of persons who are authorized to incorporate any change in the DMF, and DMF holder may restrict a person to only a particular drug product.
10.) Stability data of drug product.

Different terms used for Drug master file
For submit ion to European countries it is called as Active Substance Master File (ASMF) European Drug Master File (EDMF) and it is also called US-Drug Master file (US-DMF) in United States.

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Clinical study reveals that Selenium and Vitamin E supplement increase the risk of prostate cancer.

2011-10-20T01:37:00.000-07:00

We often consume food supplements containing multivitamins and minerals which purport to provide health benefits, and we even don’t come to know that they actually have harmed our health.

One of such fact is that Selenium and Vitamin E which are extensively used as food supplements are found to be increasing risk of prostate cancer in men.

These facts about vitamin E were revealed from a clinical study conducted in USA and Puerto Rico, and Canada in multicenter clinical trial which involved about 400 sites and 35000 men, the study began in 2001.
4 Groups were formed comprising more than 8000 participants in each group,

Group 1 was given selenium and vitamin E
Group 2 was given selenium and a placebo for vitamin E;
Group 3 was given vitamin E and a placebo for selenium;
Group 4 was given given only placebo of selenium and vitamin E.

Finally it was found that, the patients taking selenium or vitamin E only and vitamin E and selenium both together were more likely to develop prostate cancer, than patients who took only placebo.
The clinical research named as SELECT was actually began to find out if selenium and vitamin E impart protection from prostate cancer , a 25 % reduction in risk was the goal which was never achieved but actually it was found that about 17 % increase in cases of prostate cancer were observed in group taking vitamin E
The study was conducted by SWOG which is a network of research institutions around the world , and was funded by National Cancer Institute (NCI) & institutions of National Institutes of Health.

Selenium and chromium extensively used in many food supplements claiming to be their beneficial effects on diabetes and many other disease conditions , and surprisingly those claims are not supported with any of prompt clinical studies revealing their beneficial effects and their usefulness in the claimed indications.

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New drug for treating excess iron load in patients affected with Thalassemia receiving regular blood transfusion and who do not respond to standard chelation therapy

2011-10-16T14:37:00.000-07:00

The fight for life for patients affected with Thalassemia does not stop with regular blood transfusion. Regular blood transfusions are required for patients affected with the disease Thalassemia major, and blood transfusion it self may cause life threatening diseases like cardiac arrhythmia and liver damage, hepatitis and heart failure, diabetes and arthritis.

These disease may develop as a result of toxic effect of accumulation of iron in to body tissue, this iron is received from transfused blood from regular blood transfusion therefore patients receiving regular blood transfusion are required to be treated with iron chelating drugs like Deferoxamine , which bind to excess iron in tissue and excrete it in urine and feces. Deferoxamine molecule was discovered from bacteria Streptomyces pilosus which produced and used Deferoxamine for transportation of iron in to bacterial cell.
Some patients do not respond favorable for chelation therapy with the standard drug Deferoxamine and overloaded iron is are not completely removed from patients body.

Deferoxamine is given in IV or subcutaneously in a high dose and for very long period ranging from 12 hours to 24 hours to get desired chelating effect , drug Deferoxamine also is irritant and must be diluted several times. It rapidly get degraded in to body. Therefore a high concentration too is required to get the desired chelating effect, allergic and anaphylactic reactions too occur in rare cases.

Some patients even do not respond favorably to chelation therapy with the standard drug.

US FDA has approved a new drug which can now be used for treating patients which do not respond favorably to standard chelation therapy. Name of the newly approved drug is Ferriprox (deferiprone).
Drug Ferriprox (deferiprone) can be administered orally, dose is 75 mg per kg of body weight per day split in to three doses. Three molecule of deferiprone form chelate with one mol of iron which is then excreted through urine and feces.

Drug Ferriprox is the first drug after 2005 to get approval from US FDA for treating patients affected with Thalassemia.

Iron from hemoglobin in RBCS from transfused blood keep on accumulating in body tissue leading to toxicity to all the tissue where ever it get accumulated like in liver leading to liver damage, in heart muscles leading to fibrosis of heart muscles causing arrhythmia and heart failure, in pancreases suppressing the formation of insulin, also other hormones like growth hormone production too is suppressed, which suppress all other hormonal levels and endocrine system hormones too.

Twelve clinical trial were conducted to evaluate safety and efficacy of drug Ferriprox and it was observed that in patients who did not respond to conventional chelation therapy , about 20% reduction in serum ferritin was observed a 20 % decrease in ferritin levels were observed.

The excess iron in our body binds with proteins and form a iron proteinate which is stored in muscles and tissues allover the body and can be broken later on and iron can be used from this source when ever it is needed.

Side effects of Ferriprox are as follows :
Neutropenia, Join pain , abdominal pain , nausea and vomiting.
One of the serious side effect is agranulocytosis , the white blood cell count goes down rendering body susceptible for other serious infections.

US FDA has approved the drug Ferriprox (deferiprone) in an accelerated drug approval process as the disease Thalassemia has very little options for treatment when standard chilation therapy is not favorable.

Drug Ferriprox (deferiprone) is marketed by Toronto based pharmaceutical company ApoPharma, US FDA has also asked ApoPharma to conduct post market studies to evaluate safety and efficacy further. And to evaluate efficacy and safety in patients with sickle cell anemia too.

Current Good manufacturing practices regulations for manufacturing of penicillin and betalactum antibiotics.

2011-10-14T12:47:00.000-07:00

Current good manufacturing practices requirements for manufacturing of penicillin and betalactum antibiotics and non penicillin betalactum antibiotics.

Both penicillin and other non penicillin beta lactum antibiotic are capable of producing severe lifethretehning anaphylactic reactions and shock .

A non betalactum antibiotic can sensitize an individual for other non betalactum antibiotic and can produce cross reactivity which can be equally serious.

Also read here
Why beta lactum and penicillin produce allergic and anaphylactic reaction?
Chemistry and mode of these reactions.

Regulatory requirements for manufacturing of penicillin and non penicillin betalactum antibiotics

Controlling of cross contamination:
21 CFR 211.42 Subpart (c) : States Requirements about building and facility for control and its required for manufacturing or even repacking of drug containing penicillin for manufacturing process, packaging and holding. Penicillin production process, handling storage or repackaging or holding must be done in an aria of adequate size and which is defined or assigned only for penicillin.
The facility must be such that it controls as well as prevent cross contamination to other product, while process like, receipt, issuing, storage holding or rejection packaging or labeling or before sampling, while in quarantine, before or after release, during sampling or testing by QC.

Prevention for contamination in other products with dedicated facility:
21 CFR 211.42 Subpart (D), Says that all operations for manufacturing and packaging or repackaging of penicillin antibiotics must be done in a facility separate from other facilities which are used for manufacturing of non penicillin and non betalactum drugs.

However FDA says that it is not necessary to provide a complete separate building, but the aria where manufacturing packing and filling and processing of penicillin happens must be strictly and completely isolated from the rest of arias completely so as to control and prevent cross contamination of other drug products, it can be with providing separate air handling systems, and other dedicated ancillary systems and arias.

Testing of drugs for traces of penicillin and betalactum cross contamination:

21 Cfr 211.176 regulation:
US FDA has provided process for detection of cross contaminations of penicillin in other drug products which are incorporated with reference.

21 Cfr 211.176 requires that drug manufacturer must test all drugs being manufactured in facility for traces of penicillin with the procedures provided and if the traces are found to detectable level with the process of detection those products must not be sent to market.

There is no separate or specific good manufacturing practice guidelines for API (penicillin) or non penicillin betalactum antibiotics, manufacturing , processing , or repacking or holding rather FDA’S Good manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7 guidance) are required to meet these guidelines are more or less similar to drug products containing penicillin. which require a separate production aria , which completely isolated so as to avoid cross contamination to other product , and be provided with separate dedicated equipment and air handling systems.

As betalactum ring has property to produce a anaphylactic reactions , similar to penicillin , the good manufacturing practices regulations for penicillin also applies to all antibiotics containing beta lactum ring and antibiotics having similar property to sensitivity as beta-lactum though it may not contain exact close ring of beta lactum a open ring similar to beta lactum too is required to comply with good manufacturing practices regulations for penicillin and beta lactum .

Also there is observed that sensitization with traces of one beta lactum antibiotic may produce sever anaphylactic reactions when encountered with other beta lactum or penicillin antibiotics (cross reactivity).

Following are the classes of beta lactum antibiotics
Penicillins (oxacillin, ampicillin)
Cephalosporins(cefaclor, cephalexin)
Penems(meropenem, imipenem)
Carbacephems (loracarbef)
Monobactams(aztreonam).
These class of antibiotics are required to be manufactured in a separate and completely isolated manufacturing place or a facility with dedicated equipment , air handling systems and units.

Type of cross contaminations must be avoided:

FDA recommends that manufacturer must ensure that following types of cross contamination do not occur

1.Non penicillin beta lactum to Non penicillin non betalactum drug
2.Non penicillin beta lactum to other non penicillin betalactum

Therefore arias where penicillin betalactum antibiotics are manufactured must be completely separated and isolated with dedicated and isolated equipments and aria.

OTC drugs containing chloroflouorocarbons (CFCs) will not be available in US after 31-dec 2011

2011-10-14T07:49:00.000-07:00

So far there is only one drug in USA which is being sold as OTC drug and which contain chloroflouorocarbons (CFCs) as a propellant and containing ephinephrine it is used for getting temporary relief from symptoms of mild asthma, it will be now phased out and will not be available for patients using them after this years end, after 31-Dec- 2011, as it contains chloroflouorocarbons (CFCs) a substance which is known to deplete ozone.

Though all manufacturers of inhalers and other drug delivery systems which were using CFC have changed it to other environment friendly propellant system, there is no non CFC propellant system based inhaler which contain drug epinephrine is available.

Where as other drugs can be used to get temporary relief from symptoms of asthma require a prescription for its sale.

The only OTC epinephrine inhaler containing CFCs is marked by Armstrong Pharmaceutical Inc the product or brand name of the inhaler is Primatene Mist which is the only OTC epinephrine containing inhaler , US FDA had reminded about nearing of its phase of date 31-Dec-2011 to public who still use epinephrine inhaler Primatene Mist , also the product itself mention on its label about the same. US FDA in have asked general public to get other drug prescribed from healthcare provider and in event they don’t have a asses to a prescriber for same visit nearest community health center and get a non CFC propellant based inhaler prescribed as all of such inhalers are not OTC they require prescription for its sale.

US FDA stated in its press release that this is required to comply with the obligations of USA as per the Montreal Protocol for restricting use of substances which deplete ozone layer in atmosphere.

Why Betalactam Antibiotics require a separate manufacturing aria in a pharmaceutical manufacturing company?

Good manufacturing practices

Liposomal drug delivery system

What is First Pass effect of First Pass Metabolism

Why water for pharmaceutical use is always kept in close loop in continuous circulation

Insuline now provides hope for treatment of Alzheimer’s disease

2011-10-10T10:09:00.000-07:00

Insulin is a drug which is used in treatment of diabetes but it has also shown promising results when used to treat alzheimer’s disease in a clinical research findings, Insulin was given as nasal spray to patients affected with alzheimer’s disease.

So far there is no drug or treatment available which can halt the progress of Alzheimer’s disease, also it is most widely affected disease worldwide.

What is Alzheimer’s disease?
Alzheimer’s disease is a disease which affects mostly aged person; typical symptoms include dementia (loss of cognitive ability) and irritability, confusion, and mood swinging, impairment in using language, and aggressiveness. In sever cases some body functions too are lost and the disease last for life of person affected with it.

Research on insulin and its beneficial effect for treating Alzheimer’s disease:
Study is conducted by Dr. Suzanne Craft and her colleagues at the Veterans Affairs Puget Sound Health Care System to find the effect of insulin on brain function in patients affected with Alzheimer’s disease, as insulin hormone is responsible for mobilization of glucose from blood to other body tissue in our body which also include brain, and glucose is a main source of energy for brain, insulin help in making glucose available inside brain tissue which can be used as source of energy for proper normal functioning of brain tissue.
In a clinical trail consisting about 104 patients affected with Alzheimer’s disease a daily dose of 20 IU and 40 IU was given in the form of nasal spray containing insulin hormone to affected patients and it was found that this it helped in preserving patient’s abilities for general activities. The dose of 20 IU was able to improve memory where as dose of 40 IU did not showed any improvement in improving memory may be because it may be crossing the optimal concentration for desired effect.

What causes Alzheimer’s disease?
Alzheimer’s disease is caused because of degenerative or deformative changes in brain tissue, like shrinking or abnormal folding of tau and a-beta proteins and excusive folding of cortex and deformation enlargement of cerebral ventricles in brain, which are related with aging and its degenerative effects. Stressful life style and food habit smoking and uncontrolled diet and other lifestyle is also one of reason for development of Alzheimer’s disease.

New drug for treatment of atypical Hemolytic Uremic Syndrome (aHUS)

2011-10-09T07:03:00.000-07:00

New drug for atypical Hemolytic Uremic Syndrome (aHUS), which blocks the protein responsible for breakdown of RBC which lead to sever lifethreatening conditions like stroke and renal failure.

Atypical Hemolytic Uremic Syndrome (aHUS ) disease is causes because of genetic disorder because of which uncontrolled breakdown of red blood cells occur (RBCs) leading to anemia ,which does not only stops at that but further develops in to severe life threatening conditions like kidney failure and thromboembolic conditions, which may cause stroke and paralysis too.

Atypical Hemolytic Uremic Syndrome (aHUS ) affects mostly children and it is a rare disease.
There are very few treatments available for (aHUS ), now US FDA has approved a drug Soliris (eculizumab) which can now used to treat atypical Hemolytic Uremic Syndrome(aHUS).

How atypical hemolytic uremic syndrome is caused:
C5 protein is a protein which is a part of complement system of our immune system, it fix to antibodies and help in phagocytosis or destruction of unwanted infected cells or an unwanted antigen in our body .
In case of individual affected with atypical Hemolytic Uremic Syndrome C5 protein formed is abnormal due to mutation in gene which produce C5 protein and thus malformed C5 (complement system) causes destruction of RBCS in person affected with atypical Hemolytic Uremic Syndrome (aHUS ) .

How drug Soliris (eculizumab) act:
Drug Soliris (eculizumab) consist of humanized monoclonal antibodies IgG4 , which work against malformed complement system protein the C5 protein, it binds with it and stop its destructive action on RBCs.
Earlier solaris was also approved for treatment of paroxysmal nocturnal hemoglobinuria (PNH), where a affected persons red blood cells are destroyed and red urine is formed due to excretion of hemoglobin in urine. Drug Soliris (eculizumab) is classified as an orphan drug

The results out of clinical trial of drug Soliris (eculizumab) was able to demonstrate that it improves condition of kidney and also other blood count were improved and plate late count too was increased.

Side effects of drug Soliris (eculizumab):
Are as follows : High BP , infections in upper respiratory tract, infection of urinary tract diarrhea, vomiting , nausea and headache and decreased wbc count.

Alexion Pharmaceuticals in Cheshire, Conn market this Drug Soliris (eculizumab)

Also see

what is heamolytic anemia ?

New analog of antibiotic vancomycine which even work in case bacteria develop and activate antibiotic resistance

2011-09-30T12:09:00.000-07:00

Vancomycine analog molecule can even work against vancomycine resistant virulent microorganisms.

When a last resort life saving drug too don't work in patients because of development of drug resistance, patients life may get seriously affected, but now one of such a life saving drug too is designed to even work in such situation by not allowing virulent bacteria to develop antibiotic resistance.

Antibiotic vancomycine, is used as a last resort drug in critical situation in patients infected with gram positive bacteria and for individuals on dialysis, virulent strain of staphylococcus aureus which is resistant to drug methicillin (MRSA methicillin resistant s.a ) and to one who have not responded to methecill and all other antibiotics have failed to provide their antimicrobial activity because of development of antibiotic resistance by disease causing microorganisms.

It was observed that vancomycine too develop antibiotic resistance in some cases, resulting in life threatening situations.

The challenge is now answered by the scientists from The Scripps Research Institute have successfully developed a molecule which is a synthetic analog of vancomycin, which has antibiotic properties of vancomycin and do not develop resistance against vancomycine while providing its desired antimicrobial effect .
They have designed the molecule of vancomycin so that the molecule stays intact even in the event of mechanism of resistance is activated by disease causing bacteria with a small molecular change.

How it works:
Mechanism of action of Vancomycin and mechanism of development of resistance
Gram positive bacteria consist of a outer cell wall which is made up of peptidoglycan a complex of carbohydrate and protein which protects bacteria from chemical as well as from physical strain. Vancomycin owing to its structural properties is capable of forming a hydrogen bonding with peptidoglycan proteins , D-alanyl-D-alanine, aminoacids sequence in the process of cell wall synthesis, it forms hydrogen bonding with amide groups in vancomycin molecule resulting in to halting cell wall synthesis killing bacterial cell.

The bacterial resistance occurs as bactria now replace D-alanyl-D-alanine with D-alanyl-D-lactate or D-alanyl-D-serine because of mutation in genes.

Because of changes in amino acid sequence in mutant, the formation of hydrogen bonding of these amino acids in cell wall synthesis steps with vancomycin is hampered because of stearic hindrance(special arrangement in a molecule or clustering of molecules so as to hinder the activity around the active point).
Now the altered analog of Vancomycin molecule is developed by replacing amide with thioamide a one point change in molecule, replacing oxygen with sulfur now shows activity even in case bacteria produces resistance.

Professor Dale L. Boger is the senor author of the research he is from The Scripps Research Institute.

Also See:

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Transdermal drug delivery system new requirements for quality and for regulatory submissions

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Transdermal drug delivery system new requirements for quality and for regulatory submissions

2011-09-18T12:36:00.000-07:00

US FDA issued new guidelines for Transdermal drug delivery system and related drug delivery systems.

US FDA stated in its new guidelines on transdermal drug delivery system and related drug delivery systems that the initial drug load concentration has tremendous potential for impacting quality of product its safety and efficacy and it has great potential for drug abuse.

There are many advantages and disadvantages of transdermal drug delivery system TDDS , like a drug can be administered without pain to patient, patients to like the dosage form greatly as they wont feel as they are on medication, and a constant plasma drug concentration can be easily achieved for a drug for a longer period of time without giving the untoward effect of initial higher plasma level of a drug as in case of conventional dosage forms, also drug escape the first pass metabolism through transdermal drug delivery , some a critical drugs which are known to save life are also administered as Transdermal patches for example nitroglycerin in congestive cardiac diseases.

There are some serious effects observed in resent time, like accidental high dose of a drug up on accidental sticking on handling or accidental contact with skin which has lead individual serious and to fatal conditions some times a life threatening one.

The fatal untoward effects are also seen in health care providers which accidentally handled the patches and got drug dose from remaining drug load from the used transdermal drug delivery patch.

The important factor.

The drug concentration which is required to be loaded on to a Transdermal drug delivery or related drug delivery systems is very high than that of the actual drug being absorbed and required to be achieved in to plasma of a patient.

US FDA guidelines for Transdermal drug delivery patches and related drug delivery systems

In order to finally achieve consistent low residual drug with the desired quality of the Transdermal drug delivery systems ,

1. US FDA requires a drug manufacturers to submit the initial loaded drug concentration in the transdermal drug delivery patch and related drug delivery systems , be provided in the application for investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplemental new drug applications (sNDAs) for TDDS, TMDS, and topical patch products.

2.US FDA now requires that the all justifications for initial drug load or concentration should be included in the application.

3.It also states that a proper scientific risk based approach must be taken to minimize the drug residue in the system so that a lowest possible concentration remains in the system.

4.The amount of residual drug in the transdemanl drug delivery system must not exceed than those already approved by FDA .

5. US FDA also requires that the information of product and process development and how the final formulation is justified should be given in the common technical document (CTD) formatted application in section for Pharmaceutical Development.

US FDA has put emphasis on following points

1.) Quality By Design Concept
2.) Minimizing Residual Drug

The transdermal drug delivery patches and related products , be developed with the intention of giving efficacy and safety as well,
The quality by design concept basically requires a formulator to plan for a desired quality, quality of a drug can be best achieved when it is planed than when it monitored.

Planing of quality of a drug product through logical application of past findings and research data and chemistry of drug molecule and exceipients being used, to achieve minimum drug load and this can lead to achieve minimum residual drug in transdermal drug delivery systems after use. Which will ensure that the abuse potential of the transdermal drug delivery systems are taken care of.

Also see

Good Manufacturing Practices

Liposome drug delivery system

Transdermal drug delivery system

2011-09-18T11:08:00.000-07:00

Transdermal drug delivery system, Transmucosal drug delivery system:

There are many instance where some drugs are required to be administered to patients in a steady and continuous form usually for longer duration directly in to their systemic circulation, many are benefitted bypassing first pass metabolism, therefore transdermal drug delivery systems have immerged as very useful dosage forms for some patients, life saving drugs like nitroglycerin are available transmucosal and transdermal drug delivery systems.

A typical transdermal drug delivery system (TDDS) consist of drug patches or reservoirs formed with mechanical supports and barriers and support provided by liners and frames, a patch of a drug being delivered is formed which can be applied over skin with a help of suitable adhesive.

As the transdermal drug delivery system (TDDS) consists of both mechanical units and drug reservoir systems formed and controlled with mechanical barriers , they are classified under combination drug products required to comply with all requirements of a combination drug products.

Components of transdermal drug delivery system (TDDS) are as follows:

1.Drug:
Drug is loaded in the form of suspension or solution with suitable co-solvents and held in a reservoir held in to a support frame which is then separated and protected from outer environment with a protective liner . Drug blended in to suitable adhesive , or can be formed in to a matrix system as drug releasing matrix.

2.Liners
Help in maintaining the transdermal drug patch intact while in storage from outer environments , the are removed before application transdermal drug delivery system (TDDS) on skin.

3.Adhesive:
Help in fixing drug layers over applied skin surface , drug can also be mixed in the adhesive substance.

4. Drug release enhancers, drug permeation enhancer:
Co solvents like terpins , alcohols surface active agents like sodium lauryl sulfate , and pyrrolidones in varying proportions are used to enhance and control the drug permeation from drug reservoir or drug matrix system.

5. Backing layer: Silicon rubber , cellulose derivatives , Polypropylene is used to protect drug patch environment.

Advantages of transdermal drug delivery system (TDDS)
1.Patients acceptance or compliance for transdermal drug delivery system is good as they do not feel that they are taking drug as in conventional dosage forms as in tablet and injections.

2. Steady and content delivery of a drug can be achieved for a longer duration, without sudden rise and dropdown in plasma concentration of drug.

3. This route of drug administration is further developed in to transmucosal drug delivery systems TMDS, with which a drug can be absorbed as quickly as that of injectable dosage form, maintaining a steady concentration throughout the application even large peptide molecules can be delivered by transmucosal drug delivery system with the help of drug loaded liposome

Disadvantages of transdermal drug delivery system (TDDS):
1. The drug required to be loaded in the transdermal drug delivery system patch and related drug delivery systems is usually very higher than the actual required drug dose to be administered.

2. Accidental exposure of used transdermal drug delivery systems has resulted in to some fatal incidences in children’s and for healthcare professionals.

3. Drug absorption in to skin is a zero order, though drug absorption skin does not depend on the concentration beyond a particular concentration, but it largely depends on the aria of the applied skin and contact time.

Evaluation of transdermal drug delivery system (TDDS):
Following tests are used to evaluate transdermal drug delivery system (TDDS):
Interaction studies:
Interaction studies carried out and required to be reported to evaluate interactions between drug and adhesives and other components of system which will have its effect on bioavailability of drug in the system up on application.
Thickness of the patch:
Measured at different points on the patch with micrometer, and it is required that the thickness do not vary beyond allowed limit so that a uneven delivery of drug from different point is avoided so that the system remains optimized.
Folding endurance:
Is found by repeated folding after cutting the patch appropriately and applying repeated folding, this gives an idea how good is the patch to bare and remain intact for folding while in storage and during usage.

Following are some important tests used in evaluation of transdermal drug delivery system.

Percentage Moisture content:
Percentage Moisture uptake
Water vapour permeability (WVP) evaluation
Drug content:
Rolling ball tack test:
Quick Stick (peel-tack) test:
Probe Tack test
In vitro drug release studies
In vitro skin permeation studies
Uniformity of dosage unit test
Polariscope examination
Shear Adhesion test
Peel Adhesion test
Thumb tack test
Flatness test
Percentage Elongation break test
Skin Irritation study
Stability studies

Also see
Good Manufacturing Practices

Liposomal drug delivery system

What is First Pass effect of First Pass Metabolism

Liposomal drug delivery system

2011-09-08T09:11:00.000-07:00

What is liposome:
Liposomes are small vesicles made up of phospholipids , the very similar constituent of cell membrane, so that the pospholipid vesicles behave more or less as a micro cell inside which drug molecules can be loaded .
The phospholypid molecule is made up of hydrophylic head( containing choline, phosphate, and glycerol) , to which two long lypopylic chains(essential fatty acid chain) are attached, because of which these molecule aline themselves together in water in a very peculiar manner so as to form a membrane like bilayer.

Formation of phospholypid bilayer.
When phospholypid come in contact with aqueous solution,first they form film like alignment, water soluble head of molecule (hydrophylic ) aline and attache with water molecule, the fat soluble (hydrophobic fatty acid chains ) part of molecule is stay away from water molecules , projecting outwards.
This is a peculiar monolayer formation , up on which anther layer of phospholypid molecule aline themselves , hydrophobic chains attache to hydrophobic chains in first film , now in second layer of phospholypid hydrophobic heads are projecting outwards , this is a peculiar billayer of phospholypid.

All lypopilic heads of pospholipid molecule are aligned inside forming a spherical capsules of varying size, these vesicles may be single layered pospholipid or multi layered pospholipid.They are further categorised in to MLV (multilamellar vesicles) SUV (Small Unilamellar Vesicles) and LUV (Large Unilamellar Vesicles) each one has its unique application, depending up on the requirements of drug delivery and required targeting.

Application of liposome:
1) Drug delivery: Both water soluble and water insoluble, and peptide drug molecules can be delivered with the help of liposome. Liposome’s are used for delivering drug directly in to cells, owning to the property of liposomal membrane which is similar in properties with that of cell wall, liposome’s tend to fuse with the cell wall and can deliver a drug directly inside the cells.

How drug is carried by liposome:
Hydrophilic drug (water soluble) can be encapsulated inside the hydrophilic inner core of liposome, from where it can not come out easily as outer core is hydrophobic , which serves as a protective membrane. A hydrophobic drug can be trapped inside the lipid bi layer of liposome.

Targeted drug delivery system:
Liposome’s can be attached with antibodies against particular cells or tissue, these antibodies along with liposome’s wherein drug is loaded are then attracted by those cells or tissue against which the antibodies work, after attachment of the antibodies with the particular cell, liposome membrane fuses with cell wall and drug molecules entrapped inside the liposome are delivered inside the cell.

Application of liposome’s in anticancer drug delivery system:
Liposome’s of size smaller than 200 nm can enter cancer cells in the tumor and deliver anticancer drug directly in to affected cells, by mechanism explained above.
Liposome’s can be tagged with antibodies against cancerous tissue , and a drug against those cancer cell can be entrapped inside the liposome , these antibody tagged liposome’s get attracted to cancerous cells wall get fused with liposomal wall, and anticancer drug entrapped inside liposome’s is delivered directly inside affected cells.

Application of liposome’s in gene therapy in gene delivery RNA, DNA peptide drug delivery:
Liposomes have great application in gene therapy, as genes can be successfully delivered inside cells for desired incorporation of a gene. Also DNA and RNA and peptide drugs can be delivered directly in to cells for their desired effect on those cells.

Application of liposome’s in protecting drug from external environment:
Drugs which are highly sensitive for external environment, like PH and oxygen, and get degraded easily can be formulated in to liposome’s, for example vitamins can be formulated in liposome’s, which enhances self life of these drugs.

Optimization of cytotoxic drug treatments:
Some drugs are very toxic , for example anticancer drugs like doxorubicin, cisplatin, cytarabine, these drugs when given in conventional dosage form also have cytotoxic side effect on other body tissues and cells, therefore produce more undesired toxic side effects, with liposomal drug delivery systems , the concentration of drug required for desired effect is reduced to very low concentration , which also keeps other body tissue and cells away from such drugs harmful cytotoxic effects.

Long circulation Liposome’s:
Liposome’s can be treated with polyethylene glycol , so that they keep them selves intact for long time in blood circulation with which we can achieve long duration of drug delivery.

Phospholipids used in liposome formulation:
Natural origin: Sphingomyelin , Egg yolk Phospholipids , Soybean Phospholipids
Synthetic origin: Phosphatidylcholine, Lyso-Phosphatidylcholine , Phosphatidylserine ,Phosphatidylethanolamine , Phosphatidic Acid, Phosphatidylglycerol.

New treatment discovered for making kidney transplant successful.

2011-09-08T09:05:00.000-07:00

Kidney transplant will see more success rate than earlier.

Patients suffering from kidney failure are required to go for treatment like regular dialysis and kidney transplant, and that to be not all kidney transplants are successful , 1 out of every 3 kidney transplants are rejected by patients body (because of patients immune system) , it is because of the human body recognizes difference between its own body tissue and other persons body tissue and human body reject others persons body tissue by producing antibodies against the transplanted tissue , ultimately damaging and rejecting the transplanted kidney.

Dr. Robert A. Montgomery and his team from the Johns Hopkins University School of Medicine have found new technique , which has shown promising method which has greatly lowered the kidney rejection and has done kidney transplants successfully with their method.

They identified that there is an antigen on cells in human called as human leukocyte antigen, a person sensitized by human leukocyte antigen (HLA sensitized ) help human immune system to identify its own body tissue and incoming foreign tissue and trigger antibodies against transplanted kidney transplant and further leads to kidney rejection.

Therefore they developed a method to desensitize patients by filtering out anti-HLA antibodies they removed the anti-HLA antibodies from patient’s body by process of plasmapheresis. Patients were given
Low-dose intravenous immune globulin (antibody preparation made from pooled donor blood) as substitute for anti-HLA antibodies. The procedure of plasmapheresis was repeated several times before the actual kidney transplant was done , these patients were also given other immuno suppressant drugs which are normally given before kidney transplant.

More than 80% of the patients which received kidney transplant and plasmapheresis treatment were still alive after 8 years. Compared to observed lower life period for patients on either dialysis or HLA compatible kidney transplant ad dialysis.
The method is bit costly but is cost effective compared to the total other costs of regular dialysis are considered in kidney failure patients, and success rate.

What is plasmapheresis:
Plasmapheresis is a method of removing toxic or unwanted component from blood , by removing part of blood out of body and processing it in centrifuge to separate blood cells and plasma , the plasma containing toxic or unwanted antibodies is discarded and is replaced with donor plasma , albumin , or 70% albumin and 30% saline , a suitable anticoagulant drug is given to patient before the plasmapheresis procedure .

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New drug approved by US FDA for treatment of angioedima:

2011-09-02T15:04:00.000-07:00

Angioedima is a condition which causes spontaneous swelling of soft tissues dermis, subcutaneous tissue, submucosal tissues, mucosa, with typical symptoms of inflammation, swelling occurs typically over face and around throat, and tongue, it is painful and eatchy , some times blocking air way , which result in lowering oxygen level in blood (Asphyxia) , which may become life threatening if not treated.

Angioedima occure because of : Heredetory, Drug induced, because of allergy.
Angioedima caused by drug induced, because of allergy can be treated or ceases on discontinuation of causative agent or after treatment of antiallergic drug. Hearidetory angio edema , which is caused due to deficiency of C1 inhibitor protein , is treated with injecting intravenously C1-esterase (C1-inhibitor or C1INH) concentrate obtained from suitable donor blood, which is always not feasible.

Angioedima

Heredetory Angioedima HAE : Occur due to absence C1-inhibitor or partly or completely loss of capability to produce C1-inhibitor an ezyme which is responsible for inhibitory action on bradykinine which is responsible for process of inflammation , Bradykinin brings about vasodialation and is responsible for edematous condition, as vascular fluid keeps on accumulating in surrounding tissue which result in to edema.
US FDA has approved a new drug which can be used fro treatment of Angioedima, name of drug is Firazyr (icatibant) Injection which is approved for use in patients of age 18 and above.

Mode of action of Firazyr (icatibant):
Firazyr (icatibant) is a drug which resembles protein molecule (peptide), owing to its similarity to bradykinin peptide , it blocks bradykinin B2 receptors antagonistically , thereby reducing the edematous and inflammatory effect of bradykinin.

Other two drugs approved by US FDA for Heredetory Angioedima HAE
Berinert for facial HAE
Kalbitor for treating patients of age sixteen and above.

Side effects of Firazyr are as follows : Redening at the site of injection, increase in enzyme level in liver, fiver, rash, and dizziness. Shire Human Genetic Therapies Inc. of Cambridge, markets the drug Firazyr.

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CFR 21 part 11 and its application on computarised systems used in clinical trials US FDA guidelines
Pharmaceutical Validation

Types of validations in pharmaceutical manufacturing

Requirements of documents for validation of sterilisation process

Clean Room Classification

Find a Job in Pharmaceutical Company -->JOBS IN PHARMA INDUSTRY<---

Quality assurance in pharma industry

Quality by design concept for pharmaceutical industry

Quality by design concept in pharmaceutical industryan explanation

Ion exchange resin and its application in pharmaceutical dosage forms, and drug delivery systems.

2011-09-02T13:40:00.000-07:00

Ion exchange resins are cross linked polymers of polystyrene, up on which a negatively charged or a positively charged functional group can be added to get an anion exchange resin (Resin- )or a cation exchange resin Resin + (Resin + Or Resin- ). When these resins are mixed with drug molecule which has a negative charge in its one or more functional group as a result of polarity, or as in salt form, or as a result of resonance, such a drug can form a complex with a resin as follow.

1.) Resin + Drug-
2. ) Resin- Drug+
*The resulting resin drug complex stability depends on how strong are the acidic or basic functional groups on resin, stronger functional group result in to formation of very stable resin drug complex, and vice a versa , both has its applications in sustained release drug delivery systems, a resin with strong acidic or basic functional group tend to provide a much more delayed drug release, where drug release is bit faster with weak acidic and basic functional group resins.

When Resin- Drug+ or Resin + Drug- complex (drug resinate ) comes in contact with acid(in stomach) or base(in intestine), it start releasing drug molecule in exchange of similar charged ion for example if drug molecule is positively charged, then it is released from Resin- Drug+ complex when it come in contact with Hydrogen Ion( H+) , similarly a Resin + Drug- or basic drug resin complex will start releasing drug when it comes in contact with basic ions ( in intestine ) OH – NH3- .
Release of drug molecule from Resin +Drug complex takes place due to higher concentration of replacing ions (H+ , or OH – NH3- ).

Masking Taste of drug with ion exchange resin:
There are some drugs which are very bitter in taste like Bromhexin and Quinine, patients has very low acceptability for such drugs some time patients vomit and expelling all of the consumed dose which may result in to dosing error, therefore when such drugs are formulated with ion exchange resins which binds such drugs they do not release drug on taste buds over tongue as a result taste of drug is masked, and when it come in contact with gastric acid bromhexin is released in to gut.

Sustained-release drug delivery system:
Ion exchange resins may not alone give capability to formulate it in to a sustained release dosage form , to make it a good sustained release drug delivery system , proper selection of resin is important a resin with strong acidic or basic functional group provides strong complexation with drug therefore are good candidates for delayed drug release, likewise when early release is intended a weaker acidic or basic functional group resins are useful . Drug resinate is also required to be coated with semipermiable film forming polymers, as drug resinate complex can not be solely relied up on for the intended use. ( ethylcellulose ). In order to maintained the sustained release property of ion exchange resin drug complex it is pretreated with polyethylene glycol so that it do not swell and break open the film coating when it come in contact with gastric juice.

Ion exchange resins are required to be washed with, suitable organic solvent, to remove residual organic or chemical impurities in ion exchange resin, followed by washing with purified water, and regeneration if required, before using for actual process. Ion exchange resin are required to comply with requirements listed in 21 CFR 173.25 by US FDA.

Ion exchange resins have many other applications in pharmaceutical dosage form and drug delivery systems like , localized drug release, stabilization of drug molecule for chemical degradation .
Ion exchange resins are widely used in pharmaceutical industry for purification or raw water and in preparation of water for pharmaceutical use.

DM water plant water purification system unit operations.

2011-09-01T14:18:00.000-07:00

A typical water purification system or demineralisation plant (DM water plant ) in a pharmaceutical company consist of following unit operations or components.

1.Prefiltration:
Pre filtration in water purification system is a process of removing of solid contaminant from the water which is required to be processed further with water purification system.
Water from source which must comply with specification of drinking water is used to produce water for pharmaceutical use, pre filters comprises of coarse filtration units like cartridge pre filters of pore size 5 µm followed by next online 1 µm cartridge pre filter is found useful, or a sand filter can be used in unit which handles high volume of water, purpose these filters is to remove most of the solid dirt if at all from the water to be processed, it is often used before , passing water through activated charcoal bed which is situated prior to ion exchange resins.

Following points must be considered for pre filter.
It can support formation of biofilm therefore filter itself may affect the quality of water, therefore following points are important for pre filtration units or cartridge filters.
1.Periodic cleaning , Periodic disinfection /sanitization
2. Inspection for loss of filter media after washing.
3.Monitoring of flow rate and pressure while in operation and during back washing.
4.Selection of proper pore size , and periodic replacement of filter media.

Activated charcoal filter:
Activated carbon has a very peculiar and has a very useful property it can adsorb any organic molecule or bio molecules , gases and atoms, the process is called as adsorption . Adsorption is a phenomenon where a atom or a molecule adheres to the surface of adsorbent here adsorbent is activated carbon. Therefore activated charcoal is used for removal of unwanted organic molecular impurities in source water. There are following attractive forces and bonding are responsible for phenomenon of adsorption 1.Van der waals forces. 2.Hydrogen bonding 3.Ionic bonding and some times 4.covalent bonding in case of chemical sorption. Adsorption is a surface phenomenon and it depends up on the surface aria of adsorbent and contact period of molecules with adsorbent and temperature, more is the contact time higher is adsorption, more is the temperature less is adsorption, activated carbon has good surface aria, with respect to weight as well as it has good physical molecular attractive force over its surface, therefore it serves as a good adsorbent .Because of this property activated charcoal is also used as anti dot for chemical poisoning in human.
Water is passed through activated carbon bed before it goes to ion exchange resins where removal of excess acidic or basic ions and mineral ionic impurity takes place.

Important factors must be considered for activated carbon filter are:
It can develop microbial biofilms therefore it must be sanitized periodically; a validated procedure and frequency must be adapted for this purpose.

Sanitization of activated charcoal
Steam can be used for disinfection and sanitization of activated charcoal, but sanitization with hot water is most of time preferred.Carbon can loose its activity of adsorption due to saturation of its surface, and it can leach out some adsorbed molecule, therefore a periodic backwashing of carbon is required.
Activated carbon it self can get contaminated due to formation of biofilm or due to repeated use , it become less active up on repeated use , in such event it must be replaced by fresh one, the frequency of replacement must be validated.

How activated charcoal is prepared:
Activated charcoal is prepared from by Carbonization of coir, lignite, coal ,nutshells, peat, wood, where it is burned at high temperature at 600–900 °C in absence of oxygen, which is followed by process of activation by subjecting to heating carbon formed in process of carbonization at 250 °C in presence of carbon monoxide or oxygen or steam.

3.Water Softerners :
Softeners are used in water system , their main purpose is to provide a feed water which contains very low level of calcium and magnesium , and other cations, as these ions are also responsible for scale formation and blocking further unit operations , like anion exchange resin or it may generate scaling where distillation is required. Softeners are basically cation exchange resins , which exchange sodium ion for calcium and magnesium or fe++ , it also can remove ammonium ions , which are generated as degradation byproduct of chloramine , a compound which is used as source of chlorine for water as antimicrobial agent.Softners are regenerated with concentrated solution of sodium chloride, it must be sanitized and decontaminated with chlorine and UV light.

4. Ion exchange , what is ion exchange resin how they work:

Water is passed through ion exchange resins to remove excess anionic impurities, anion exchange resin can also remove bacterial endotoxins(pyrogen) as they are negatively charged.
Ion exchange resins are cross linked polystyrene , up on which a required functional group can be added get an anion exchange resin or a cation exchange resin.
1.Anion exchange resin :
Anion exchange resins contain hydroxyl ions as functional groups which when come in contact with strong anion like chlorine, this hydroxyl ion group is replaced for strong anion like chlorine ect, from feed water. water thus collected contains no or very less anions

Anion exchange resins get saturated with extraneous anions like chlorine ect , and tend to reduce its capacity of ion exchange , therefore when it is acted up on by a strong base like NAOH , again the bound anions are replaced with hydroxyl ions, this process is called as regeneration of ion exchange resin, appropriate washing must be given to remove excess alkali as well as salt formed in regeneration process.
2. Cation exchange resin
Water is passed through cation exchange resin to remove cations like calcium magnesium , iron , ect. Cation exchange resin work with the similar principle as described for anion exchange resin , cation exchange resin has hydrogen ions over resin when they come in contact with strong cations like calcium and magnesium , fe++ ect , resin exchange H+ ion for cation impurities in feed water thus collected contains no or very less cations, Again when cation exchange resin is saturated with captured cation impurities from feed water, when it is treated with strong acid like HCL hydrogen ion replaces those cations , a appropriate washing must be given to remove excess acid as well as salt formed in regeneration process.

3. Mixed bed ion exchange resin:
Contains both anion and cation exchange resins , they are comparatively more efficient than individual resins, one can make use of all three columns , where a final ion exchange column is of mixed bed ion exchange resin, this to require regeneration , which is done in the same way as that of anion and cation exchange resin columns.
5. Continuous Electrodeionization (CEDI) :
In this process ion exchange resin are regenerated continuously with hydrogen and hydroxyl ions from water itself, which are generated by application of electric charge , which causes elecrohydrolysis of water in to Hydrogen and Hydroxyl ions , which sits on resin as ions which are exchanged with cation and anion impurities from feed water , these impurities bind with resin strongly than Hydrogen and Hydroxyl ions. Resultant water collected is free from cationic and anionic impurities from feed water. Advantage of Continuous Electrodeionization (CEDI) is that there is no chemical used for regeneration of ion exchange resins. Continuous elctrodeionization (CEDI) are required to feed initially with purified water instead of actual water to be processed.
There should be maintained a standard operating procedure for operation of DM water plant , all procedures should be validated , there should be a exhaustive water sampling plan, and operators must be trained .

Also see:

Why water for pharmaceutical use is always kept in close loop in continuous circulation?

Microbial load limits for water for pharmaceutical use

Ultraviolet light as antimicrobial disinfectant in water for pharmaceutical use

Reverse Osmosis Membrane Technology RO Water Purification system information on RO membrane technology.

Water system validation

Pharmaceutical Water System Validation Sample Document

Preparation of Water for Injection

Pharmaceutical Validation in detail

Pharma Revalidation how and when

Botox approved by US FDA for urinary incontinence associated with nervous system damage

2011-08-31T08:48:00.000-07:00

Botox can be used in treatment of urinary incontinence because of damage in nervous tissue.

Urinary incontinence is a condition where a patient’s bladder can not hold urine, it may be because of certain surgeries like removal of prostate gland or because of certain neurologic conditions like spinal chord injury or multiple sclerosis (condition which develops due to damage in nerves in brain and spinal chord).

US FDA has approved Botox (onabotulinumtoxinA) injection for treatment of urinary incontinence developed due to neurological diseases which makes urinary bladder overactive.So fare urinary incontinence was treated with catheter to remove urine from bladder and drugs which act by bringing relaxation in muscles of bladder because of bladder can store urine.

Botox injection containing onabotulinumtoxinA is injected in to bladder, which brings about relaxation of bladder muscle, so that bladder can store more urine and reduce the effect of urinary incontinence, which other wise is very difficult to manage in case if it is associated with neurological damages. Injection of Botox is done with a procedure called as cystoscopy with which doctor can see inner surface of bladder , general anesthesia may be required to carryout cystoscopy.

In urinary incontinence associated with effect of Botox on bladder muscle lasts up to ten months.
Botox has showed good improvement in a clinical study which involved 691 patients affected with urinary incontinence due to spinal chord injury or multiple sclerosis study was compared with placebo group.
US FDA has also approved Botox for treatment of chronic migraine headaches. Botox is also used to treat facial frown lines and to treat contraction and stiffness in some muscles, it is also used to treat twitching of eyelid and improper aligned eyes because of muscular contractions.

Adverse effects of Botox when used for urinary incontinence are urinary tract infection, urine retention, it is required to carryout self catheterization to empty bladder.

Botox is marketed by Allergan Inc., of Irvine, Calif USA.

What is Therapeutic Index ?

What is Narrow Therapeutic Range Drug?

What is High Efficiency Particulate Air( HEPA ) filter ?

What is a Laminar Air Flow Cabinet.

What is an Isolator in pharmaceutical manufacturing.?

What is 21 CFR Part 11, US FDA compliance and CFR 21 Part 11?

CFR 21 part 11 and its application on computarised systems used in clinical trials US FDA guidelines
Pharmaceutical Validation

Types of validations in pharmaceutical manufacturing

Requirements of documents for validation of sterilisation process

Clean Room Classification

Find a Job in Pharmaceutical Company -->JOBS IN PHARMA INDUSTRY<---

Quality assurance in pharma industry

Quality by design concept for pharmaceutical industry

Quality by design concept in pharmaceutical industryan explanation

Microbial load limits for water for pharmaceutical use:

2011-08-20T20:09:00.000-07:00

With optimized water purification system at the final user point it is observed that water has very low microbial load or microbial counts, to avoid a step rise in microbial load with any sudden change in water purification system, step wise validation and monitoring of microbial loads at each points in water system should be undertaken, with which one can set up narrow alert and action limits so as to maintain the final quality of water for pharmaceutical use.

Following is the limits for microbiology at different points in water purification system:

Raw water : It must be of quality of drinking water with complying with
Targeted limit for Microbial load in CFU = Equal or less than 200 cfu/ml
Alert limit for Microbial load in CFU = 300 or readings nearing 300 cfu/ml
Action limit for Microbial load in CUF = 500 or reading nearing to 500 cfu/ml

After prefiltration thought multimedia filters:
Targeted limit for Microbial load in CFU = Equal or less than 100 cfu/ml
Alert limit for Microbial load in CFU = 250 to 300 cfu/ml select one figure
Action limit for Microbial load in CUF = 500 or reading nearing to 500 cfu/ml

After passing through water softner :
Targeted limit for Microbial load in CFU = Equal or less than 100 cfu/ml
Alert limit for Microbial load in CFU = 250 to 300 cfu/ml select one figure
Action limit for Microbial load in CUF = 500 or reading nearing to 500 cfu/ml

After passing through activated charcoal filter:
Targeted limit for Microbial load in CFU = Equal or less than 50 cfu/ml
Alert limit for Microbial load in CFU = 250 to 300 cfu/ml select one figure
Action limit for Microbial load in CUF = 500 or reading nearing to 500 cfu/ml

Limits for feed water for reverse osmosis unit:
Targeted limit for Microbial load in CFU = Equal or less than 20 cfu/ml
Alert limit for Microbial load in CFU = 150 to 200 cfu/ml select one figure
Action limit for Microbial load in CUF = 400 or reading nearing to 400 cfu/ml

Water treated with reverse osmosis:
Targeted limit for Microbial load in CFU = Equal or less than 10 cfu/ml
Alert limit for Microbial load in CFU = 20 to 50 cfu/ml select one figure
Action limit for Microbial load in CUF = 100 or reading nearing to 100 cfu/ml

Water for injection must be sterile there should not be any microbial count of any kind , as well as it is required to be free from bacterial endotoxin or pyrogen.

Water for injection must be discarded if it is stored for more than 24 hours , that means it must be used with in 24 hours for further process in injectable dosage form manufacturing.

What is CFU:
colony forming unit (CFU) is a unit to express the number or microorganism in any given sample for microbiological examination for its bio burden or total microbial count, it based on the principle that a single viable microbial cell when grown in a suitable dilution in a microbial enrichment media gives rise to one single colony on agar plate, which can be seen with magnifier of with naked eyes..

One ml of water sample is inoculated in microbiological enrichment mediums which can promote microbial growth, a single viable microorganism (bacteria as well as fungi) in a microbiological enrichment medium grow and form a continuous growth , a single viable microorganism give rise to a single visible microbial colony counting such colony gives number which is very much near to the total number of microorganisms in given 1 ml of sample water being tested, dilution factors and sample preparations must be considered before arriving at the final count.

Also see:

Ultraviolet light as antimicrobial disinfectant in water for pharmaceutical use

Reverse Osmosis Membrane Technology RO Water Purification system information on RO membrane technology.

Pharmaceutical Water System Validation Sample Document

Preparation of Water for Injection

Pharmaceutical Validation in detail

Pharma Revalidation how and when

Ultraviolet light as antimicrobial disinfectant in water for pharmaceutical use

2011-08-18T06:49:00.000-07:00

Ultraviolet lamp in processing of water for pharmaceutical use:

Ultra violate lights lamps are very useful in reducing the bioburden of water for pharmaceutical use. Ultra violate lamps are used at various points in purification and distribution process of water for pharmaceutical use, they can be installed at points starting from first inlet point in to deionization or demineralization ion exchange resin columns or reverse osmosis, and at the point of last point of distribution at pharmaceutical manufacturing point.

How ultra violate light work as antimicrobial :

Ultraviolet light consist of electromagnetic radiation of wavelength shorter than the visible light, which are capable of destructing DNA by disrupting hydrogen bonding between nucleic acids and by disrupting intermolecular bond in vital proteins and enzymes which are responsible for growth of microorganisms.

UV light of wavelength 254 nm is used for reducing microbial count in water for pharmaceutical use.

UV light of wavelength 150nm to 185nm are ionizing therefore it also help in reducing total organic content by degrading organic carbon to Co2 (254nm also can be used for this purpose). It also help in removing excessive chlorine from water by process of ionization and inonexchange in subsequent deionization or demineralisation step.

UV light of wavelength 150nm to 185nm also help in removal of excessive ozone pumped during disinfection or sanitisation of DM water plant

Excision repair:

Why UV light can not be relied up on as complete antimicrobial option:

UV light disrupts DNA and nucleic acid hydrogen bonding in DNA , these disruption are always not permanent a bacterial spore or a bacteria when allowed to stand in favorable condition , these disruptions are restored back to normal, and bacterial cell becomes viable again, this process is known as nucleotide excision repair.

Important points should be considered for UV light in water system in pharmaceutical as follows:

1. Intensity of UV light keeps on reducing over the usage period, therefore a particular UV light should be assigned particular burning hours , and should be monitored for its utilization of burning hours. Up on nearing to its limit of burning hours UV light should be replaced with appropriate one.

2. Material of construction many plastic material are not recommended , as they tend to absorb UV light , stainless steel too absorb UV light and tend to get heated up as a result, which also reduce the total dose of UV light available for antimicrobial action on water, but nevertheless it is advantageous over other material , stainless steel of grade ss 316 L is considered appropriate.

3. A ultra violate light chamber for water treatment are also available which do not absorb UV light as efficiency of UV light largely depend on this factor as well.

4.Uniform and laminar flow of water through UV light tubing should be maintained so that contact time of UV light is with a particular point is increased and loss of UV light do not occur, uniform flow of water through UV light tubing enhances efficacy of UV light sterilisation.

5. A film may form over the surface of UV light and chamber which may absorb UV light and lower the dose of UV light available for antimicrobial action on water.

6.UV light chamber or tubing inner surface must be highly reflective, which increases efficacy of UV light as it is not absorbed by the surface but is reflected back , more will be the number of reflection, more will be the microorganisms coming in the path of UV light for its antimicrobial action.

Validation of efficacy of online UV light sterilization in water purification plant:

Efficacy of online UV light units should be evaluated by validation, form a suitable validation master plan to evaluate their actual ability to lower microbial load in water being treated, microbial load before UV treatment and after UV treatment should be monitored and a correlation between both must establish the efficacy of UV light in online water purification units, it can be adapted as a daily / routine sampling point for ongoing validation of water purification plants.

Scientists found the gene responsible for uncontrolled growth of body parts.

2011-08-18T06:48:00.000-07:00

Drug or a gene therapy can be developed to control abnormal protein (AKT) activity responsible for uncontrolled body parts in Proteus Syndrome.

Life goes on with the hope of better tomorrow and our scientists and institutions too are tested by challenges of finding a treatment for diseases which still do not have any medicine or treatment to treat life threatening diseases, one of such disease is Proteus Syndrome.

It’s a great pain for parents and relatives of a child who’s body do not grow in the proportion it has to grow as normal, some children’s one limb grow larger than other or a hand palm growing in to its size beyond control, such disease also bring about deformities in bones and many times require amputation leading to permanent disability, one of such disease is known Proteus Syndrome.

Scientists from United States, National institute of health’s National Human Genome Research Institute (NHGRI) have found out the gene responsible for the Proteus Syndrome, after analyzing regions on DNA and exoms by whole-exome sequencing from affected patient and their family member , it was observed that a misspelled region in gene was found to be responsible for mutation.This misspelled gene is called as AKT1 which is also responsible for cancerous growths.It was also found that AKT proteins were more active in tissues of affected patients, with defective gene than in normal, the affected gene was also compared with huge DNA sequence data in libraries, and with affected patients, defective gene was a peculiar in affected patients only.Proteus Syndrome is believed to be developed after a spontaneous mutation in the gene.

There are now new possibilities open for such patients to treat them with gene therapy to replace affected gene, a drug can be developed to arrest the activity of AKT proteins in affected patients.

New biomarker identified which is linked to increased risk of kidney failure.

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Protein which is responsible for cancer spread discovered