Pharma blog

Beta-lactam antibiotic

2009-02-10T08:17:00.000-08:00

From Wikipedia, the free encyclopedia

Core structure of penicillins and cephalosporins . Beta-lactam ring in red.
β-lactam antibiotics are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, carbapenems, and β-lactamase inhibitors,[1] that is, any antibiotic agent that contains a β-lactam nucleus in its molecular structure. They are the most widely-used group of antibiotics.

History

The first synthetic β-lactam ever was prepared by Hermann Staudinger in 1907 by reaction of the Schiff base of aniline and benzaldehyde with diphenylketene ^[2] ^[3] in a [2+2]cycloaddition:

Clinical use
β-lactam antibiotics are indicated for the prophylaxis and treatment of bacterial infections caused by susceptible organisms. At first, β-lactam antibiotics were mainly active only against Gram-positive bacteria, yet the recent development of broad-spectrum β-lactam antibiotics active against various Gram-negative organisms has increased their usefulness.

Mode of action
β-Lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin-binding proteins (PBPs).
β-lactam antibiotics are analogues of D-alanyl-D-alanine - the terminal amino acid residues on the precursor NAM/NAG-peptide subunits of the nascent peptidoglycan layer. The structural similarity between β-lactam antibiotics and D-alanyl-D-alanine facilitates their binding to the active site of penicillin-binding proteins (PBPs). The β-lactam nucleus of the molecule irreversibly binds to (acylates) the Ser403 residue of the PBP active site. This irreversible inhibition of the PBPs prevents the final crosslinking (transpeptidation) of the nascent peptidoglycan layer, disrupting cell wall synthesis.
Under normal circumstances peptidoglycan precursors signal a reorganisation of the bacterial cell wall and, as a consequence, trigger the activation of autolytic cell wall hydrolases. Inhibition of cross-linkage by β-lactams causes a build-up of peptidoglycan precursors, which triggers the digestion of existing peptidoglycan by autolytic hydrolases without the production of new peptidoglycan. As a result, the bactericidal action of β-lactam antibiotics is further enhanced.

Modes of resistance
By definition, all β-lactam antibiotics have a β-lactam ring in their structure. The effectiveness of these antibiotics relies on their ability to reach the PBP intact and their ability to bind to the PBP. Hence, there are 2 main modes of bacterial resistance to β-lactams, as discussed below.
The first mode of β-lactam resistance is due to enzymatic hydrolysis of the β-lactam ring. If the bacteria produces the enzymes β-lactamase or penicillinase, these enzymes will break open the β-lactam ring of the antibiotic, rendering the antibiotic ineffective. The genes encoding these enzymes may be inherently present on the bacterial chromosome or may be acquired via plasmid transfer, and β-lactamase gene expression may be induced by exposure to beta-lactams. The production of a β-lactamase by a bacterium does not necessarily rule out all treatment options with β-lactam antibiotics. In some instances, β-lactam antibiotics may be co-administered with a β-lactamase inhibitor.
However, in all cases where infection with β-lactamase-producing bacteria is suspected, the choice of a suitable β-lactam antibiotic should be carefully considered prior to treatment. In particular, choosing appropriate β-lactam antibiotic therapy is of utmost importance against organisms with inducible β-lactamase expression. If β-lactamase production is inducible, then failure to use the most appropriate β-lactam antibiotic therapy at the onset of treatment will result in induction of β-lactamase production, thereby making further efforts with other β-lactam antibiotics more difficult.
The second mode of β-lactam resistance is due to possession of altered penicillin-binding proteins. β-lactams cannot bind as effectively to these altered PBPs, and, as a result, the β-lactams are less effective at disrupting cell wall synthesis. Notable examples of this mode of resistance include methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. Altered PBPs do not necessarily rule out all treatment options with β-lactam antibiotics.

Common β-lactam antibiotics

Penicillins
Main article: penicillin

Narrow-spectrum
Beta-lactamase sensitive
benzathine penicillin
benzylpenicillin (penicillin G)
phenoxymethylpenicillin (penicillin V)
procaine penicillin
oxacillin
Penicillinase-resistant penicillins
methicillin
oxacillin [2]
nafcillin
cloxacillin
dicloxacillin
flucloxacillin
β-lactamase-resistant penicillins
temocillin

Moderate-spectrum
amoxycillin
ampicillin

[edit] Broad-spectrum
co-amoxiclav (amoxicillin+clavulanic acid)

Extended-spectrum
azlocillin
carbenicillin
ticarcillin
mezlocillin
piperacillin

Cephalosporins
Main article: cephalosporin

First generation

Skeletal formula of cefalexin, a first-generation cephalosporin
Moderate spectrum.
cephalexin
cephalothin
cefazolin

Second generation
Moderate spectrum with anti-Haemophilus activity.
cefaclor
cefuroxime
cefamandole

Second generation cephamycins
Moderate spectrum with anti-anaerobic activity.
cefotetan
cefoxitin

Third generation
Broad spectrum.
ceftriaxone
cefotaxime
cefpodoxime
Broad spectrum with anti-Pseudomonas activity.
ceftazidime

Fourth generation
Broad spectrum with enhanced activity against Gram positive bacteria and beta-lactamase stability.
cefepime
cefpirome

Carbapenems
Main article: carbapenem

Skeletal formula of imipenem
Broadest spectrum of beta-lactam antibiotics.
imipenem (with cilastatin)
meropenem
ertapenem
faropenem
doripenem

Monobactams
Unlike other beta-lactams, the monobactam contains a nucleus with no fused ring attached. Thus, there is less probability of cross-sensitivity reactions.
aztreonam (Azactam)

Beta-lactamase inhibitors
Although they exhibit negligible antimicrobial activity, they contain the beta-lactam ring. Their sole purpose is to prevent the inactivation of beta-lactam antibiotics by binding the beta-lactamases, and, as such, they are co-administered with beta-lactam antibiotics.
clavulanic acid
tazobactam
sulbactam

Adverse effects

Adverse drug reactions
Common adverse drug reactions (ADRs) for the β-lactam antibiotics include diarrhea, nausea, rash, urticaria, superinfection (including candidiasis).[3]
Infrequent ADRs include fever, vomiting, erythema, dermatitis, angioedema, pseudomembranous colitis.[3]
Pain and inflammation at the injection site is also common for parenterally-administered β-lactam antibiotics.

Allergy/hypersensitivity
Immunologically-mediated adverse reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent (a small fraction of which are truly IgE-mediated allergic reactions, see amoxicillin rash). Anaphylaxis will occur in approximately 0.01% of patients.[3][4] There is perhaps a 5%-10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems; but this figure has been challenged by various investigators.
Nevertheless, the risk of cross-reactivity is sufficient to warrant the contraindication of all β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic.

Production of beta-lactam antibiotics and its regulation

2009-02-10T08:09:00.000-08:00

Demain AL.
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
The discovery of penicillin was announced over 60 years ago. It was the first beta-lactam antibiotic and the importance of this group is greater today than it has ever been. It is clear that even at 60 years of age, beta-lactams are going strong and no one contemplates their early retirement. Currently, sales of beta-lactam compounds form the largest share by far of the world's antibiotic market. The beta-lactam antibiotics include penicillins such as penicillin G, penicillin V, ampicillin, cloxacillin, and piperacillin; cephalosporins such as cephalothin, cephaloridine, cephalexin, and cefaclor; and cephamycins such as cefoxitin. In addition, beta-lactam antibiotics include the more recently developed nonclassical structures such as monobactams, including aztreonam; clavulanic acid, which is a component of the combination drug augmentin; and thienamycin, which is chemically transformed into imipenem, a component of the combination drug known as primaxin (or tienam). The classical beta-lactam antibiotics can be divided into hydrophobic and hydrophilic fermentation products. The hydrophobic members, e.g. benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V), contain non-polar side chains, e.g. phenylacetate and phenoxyacetate, respectively, and are made only by filamentous fungi; the best known of these is Penicillium chrysogenum. The antibacterial spectrum of the hydrophobic penicillins is essentially Gram-positive. The hydrophilic types are penicillin N, cephalosporins and 7-alpha-methoxycephalosporins (cephamycins) which are made by fungi, actinomycetes and unicellular bacteria. They all contain the polar side chain, D-alpha-aminoadipate. We can draw a sequence of reactions which describes the biosynthesis of all penicillins and cephalosporins, however the total sequence exists in no one microorganism. All penicillin and cephalosporin biosynthetic pathways possess the first three steps in common and all cephalosporin pathways go through deacetylcephalosporin C. However, there are many subsequent biosynthetic reactions which vary in the different producing organisms. Production of beta-lactam antibiotics occurs best under conditions of nutrient imbalance and at low growth rates. Nutrient imbalance can be brought about by limitation of the carbon, nitrogen or phosphorus source. In addition to these factors, amino acids such as lysine and methionine exert marked effects on production of penicillins and/or cephalosporins by some microorganisms. Induction of some of the synthetases, especially the first enzyme, ACV synthetase, by methionine is the basis of the methionine stimulation of cephalosporin C synthesis in C. acremonium. Inhibition of homocitrate synthase is the mechanism involved in lysine inhibition of penicillin synthesis in Penicillium chrysogenum.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 1815263 [PubMed - indexed for MEDLINE]

Facility Design and Layout of Penicilin

2009-02-10T07:41:00.000-08:00

3.1 Facility Design and Layout
This page will address various regulatory issues related to this section of the GMP Institute framework. Click below to view the issues that are relevant to you.

Penicillin Issues
What do the CGMPs mean by separate facilities? Must the buildings be totally separated, or are the CGMPs satisfied when the floors are physically separated with separate air filtration units installed?
Is it acceptable to manufacture penicillin and non-penicillin products in the same facility on a campaign (i.e., the conversion of production facilities to a different product line on a routine basis) basis, with adequate cleaning validation procedures in place?
Is it acceptable to manufacture penicillin products in the same facility as cephalosporin?
Can a facility that produced penicillin dosage forms be decontaminated and renovated for production of non-penicillin solid dosage forms provided there is no further penicillin production in the renovated facility?
Is there an acceptable level of penicillin residue in non-penicillin drug products?
If a firm's only operation is performing finished packaging operations for bulk tablet and capsule drug products, must it still maintain separate facilities and equipment for packaging penicillin products?
What do the CGMPs mean by separate facilities? Must the buildings be totally separated, or are the CGMPs satisfied when the floors are physically separated with separate air filtration units installed?
References: 21 CFR 211.42(d) Design, and construction features 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling 21 CFR 211.176 Penicillin contamination Federal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the CGMPs at comment 142

more.......

2009-02-09T01:44:00.001-08:00

Oral formulations
The way a drug is formulated can avoid some of the problems associated with oral administration.
Drugs are normally taken orally as tablets or capsules.
The drug (active substance) itself needs to be soluble in aqueous solution at a controlled rate. Such factors as particle size and crystal form can significantly affect dissolution. Fast dissolution is not always ideal. For example, slow dissolution rates can prolong the duration of action or avoid initial high plasma levels.

Tablet form
A tablet is usually a compressed preparation that contains:
5-10% of the drug (active substance);
80% of fillers, disintegrants, lubricants, glidants, and binders; and
10% of compounds which ensure easy disintegration, disaggregation, and dissolution of the tablet in the stomach or the intestine.
The disintegration time can be modified for a rapid effect or for sustained release.
Special coatings can make the tablet resistant to the stomach acids such that it only disintegrates in the duodenum as a result of enzyme action or alkaline pH.
Pills can be coated with sugar, varnish, or wax to diguise the taste.
Some tablets are designed with an osmotically active core, surrounded by an impermeable membrane with a pore in it. This allows the drug to percolate out from the tablet at a constant rate as the tablet moves through the digestive tract.

Capsule form
A capsule is a gelatinous envelope enclosing the active substance. Capsules can be designed to remain intact for some hours after ingestion in order to delay absorption. They may also contain a mixture of slow- and fast-release particles to produce rapid and sustained absorption in the same dose.

2009-02-06T07:29:00.000-08:00

Good manufacturing practice
From Wikipedia, the free encyclopedia
(Redirected from Current good manufacturing practice)
Jump to: navigation, search
Food safety

Terms
Foodborne illness
HACCP
Critical control point
Critical factors
FAT TOM
pH
Water activity (Wa)
Pathogens
Clostridium botulinum
E. coli
Hepatitis A

This article does not cite any references or sources. Please help improve this article by adding citations to reliable sources. Unverifiable material may be challenged and removed. (December 2007)
Good Manufacturing Practice or GMP (also referred to as 'cGMP' or 'current Good Manufacturing Practice') is a term that is recognized worldwide for the control and management of manufacturing and quality control testing of foods, pharmaceutical products, and medical devices.
Since sampling product will statistically only ensure that the samples themselves (and perhaps the areas adjacent to where the samples were taken) are suitable for use, and end-point testing relies on sampling, GMP takes the holistic approach of regulating the manufacturing and laboratory testing environment itself. An extremely important part of GMP is documentation of every aspect of the process, activities, and operations involved with drug and medical device manufacture. If the documentation showing how the product was made and tested (which enables traceability and, in the event of future problems, recall from the market) is not correct and in order, then the product does not meet the required specification and is considered contaminated (adulterated in the US). Additionally, GMP requires that all manufacturing and testing equipment has been qualified as suitable for use, and that all operational methodologies and procedures (such as manufacturing, cleaning, and analytical testing) utilized in the drug manufacturing process have been validated (according to predetermined specifications), to demonstrate that they can perform their purported function(s).
In the US, the phrase "current good manufacturing practice" appears in 501(B) of the 1938 Food, Drug, and Cosmetic Act (21USC351). US courts may theoretically hold that a drug product is adulterated even if there is no specific regulatory requirement that was violated as long as the process was not performed according to industry standards. By June 2010, the same cGMP requirements will apply to all manufacture of dietary supplements.[1]
Contents

The World Health Organization version
The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over one hundred countries worldwide, primarily in the developing world. The European Union's GMP (EU-GMP) enforces more compliance requirements than the WHO GMP, as does the Food and Drug Administration's version in the US. Similar GMPs are used in other countries, with Australia, Canada, Japan, Singapore and others having highly developed/sophisticated GMP requirements. In the United Kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as "The Orange Guide", because of the colour of its cover, is officially known as The Rules and Guidance for Pharmaceutical Manufacturers and Distributors.
Since the 1999 publication of GMPs for Active Pharmaceutical Ingredients, by the International Conference on Harmonization (ICH), GMPs now apply in those countries and trade groupings that are signatories to ICH (the EU, Japan and the US), and applies in other countries (e.g., Australia, Canada, Singapore) which adopt ICH guidelines to the manufacture and testing of active raw materials.
GMP is designed to help assure the quality of drug products by ensuring several key attributes, including correctness and legibility of recorded manufacturing and control documentation. Data transfers must be performed in specific ways to avoid mistakes (e.g., writing down a reading on a balance and requiring a second person to also check the balance reading to assure accuracy). Methods have been developed to make this process easier (e.g., links between equipment and central data storage facilities for direct transfer of important data).

Enforcement
GMPs are enforced in the United States by the FDA; within the European Union, GMP inspections are performed by National Regulatory Agencies (e.g., GMP inspections are performed in the United Kingdom by the Medicines and Healthcare products Regulatory Agency (MHRA); in the Republic of Korea (South Korea) by the Korea Food and Drug Administration (KFDA); in Australia by the Therapeutical Goods Administration (TGA); in South Africa by the Medicines Control Council (MCC); in Brazil by the Agência Nacional de Vigilância Sanitária (National Health Surveillance Agency Brazil) (ANVISA); in Iran, India and Pakistan by the Ministry of Health[1] and by similar national organisations worldwide). Each of the inspectorates carry out routine GMP inspections to ensure that drug products are produced safely and correctly; additionally, many countries perform Pre-Approval Inspections (PAI) for GMP compliance prior to the approval of a new drug for marketing.
Regulatory agencies (including the FDA in the US and regulatory agencies in many European nations) are authorized to conduct unannounced inspections, though some are scheduled. FDA routine domestic inspections are usually unannounced, but must be conducted according to 704(A) of the FD&C Act (21USC374), which requires that they are performed at a "reasonable time." Courts have held that any time the firm is open for business is a reasonable time for an inspection.

Other good practices
Other 'Good Practice' systems, along the same lines as GMP, exist:
Good Laboratory Practice (GLP), for laboratories conducting non-clinical studies (toxicology and pharmacology studies in animals);
Good clinical practice' (GCP), for hospitals and clinicians conducting clinical studies on new drugs in humans;
Good Regulatory Practice (GRP), for the management of regulatory commitments, procedures and documentation.
Collectively, these 'Good Practice' requirements are referred to as 'GxP' requirements, all of which follow similar philosophies. This is far from a complete list, other examples include Good Agriculture Practices, Good Guidance Practices, and Good Tissue Practices. In the US, medical device manufacturers must follow what are called "Quality System Regulations" which are deliberately harmonized with ISO requirements, not cGMPs.

www.who.int

2009-02-06T07:09:00.000-08:00

Traditional medicine

Key facts
In some Asian and African countries, 80% of the population depend on traditional medicine for primary health care.
Herbal medicines are the most lucrative form of traditional medicine, generating billions of dollars in revenue.
Traditional medicine can treat various infectious and chronic conditions: new antimalarial drugs were developed from the discovery and isolation of artemisinin from Artemisia annua L., a plant used in China for almost 2000 years.
Counterfeit, poor quality, or adulterated herbal products in international markets are serious patient safety threats.
More than 100 countries have regulations for herbal medicines.
Traditional medicine is the sum total of knowledge, skills and practices based on the theories, beliefs and experiences indigenous to different cultures that are used to maintain health, as well as to prevent, diagnose, improve or treat physical and mental illnesses.
Traditional medicine that has been adopted by other populations (outside its indigenous culture) is often termed alternative or complementary medicine.
Herbal medicines include herbs, herbal materials, herbal preparations, and finished herbal products that contain parts of plants or other plant materials as active ingredients.
Who uses traditional medicine?
In some Asian and African countries, 80% of the population depend on traditional medicine for primary health care.
In many developed countries, 70% to 80% of the population has used some form of alternative or complementary medicine (e.g. acupuncture).
Herbal treatments are the most popular form of traditional medicine, and are highly lucrative in the international marketplace. Annual revenues in Western Europe reached US$ 5 billion in 2003-2004. In China sales of products totaled US$ 14 billion in 2005. Herbal medicine revenue in Brazil was US$ 160 million in 2007.

Challenges
Traditional medicine has been used in some communities for thousands of years. As traditional medicine practices are adopted by new populations there are challenges.
International diversity: Traditional medicine practices have been adopted in different cultures and regions without the parallel advance of international standards and methods for evaluation.
National policy and regulation: Not many countries have national policies for traditional medicine. Regulating traditional medicine products, practices and practitioners is difficult due to variations in definitions and categorizations of traditional medicine therapies. A single herbal product could be defined as either a food, a dietary supplement or an herbal medicine, depending on the country. This disparity in regulations at the national level has implications for international access and distribution of products.
Safety, effectiveness and quality: Scientific evidence from tests done to evaluate the safety and effectiveness of traditional medicine products and practices is limited. While evidence shows that acupuncture, some herbal medicines and some manual therapies (e.g. massage) are effective for specific conditions, further study of products and practices is needed. Requirements and methods for research and evaluation are complex. For example, it can be difficult to assess the quality of finished herbal products. The safety, effectiveness and quality of finished herbal medicine products depend on the quality of their source materials (which can include hundreds of natural constituents), and how elements are handled through production processes.
Knowledge and sustainability: Herbal materials for products are collected from wild plant populations and cultivated medicinal plants. The expanding herbal product market could drive over-harvesting of plants and threaten biodiversity. Poorly managed collection and cultivation practices could lead to the extinction of endangered plant species and the destruction of natural resources. Efforts to preserve both plant populations and knowledge on how to use them for medicinal purposes is needed to sustain traditional medicine.
Patient safety and use: Many people believe that because medicines are herbal (natural) or traditional they are safe (or carry no risk for harm). However, traditional medicines and practices can cause harmful, adverse reactions if the product or therapy is of poor quality, or it is taken inappropriately or in conjunction with other medicines. Increased patient awareness about safe usage is important, as well as more training, collaboration and communication among providers of traditional and other medicines.

WHO response
WHO and its Member States cooperate to promote the use of traditional medicine for health care. The collaboration aims to:
support and integrate traditional medicine into national health systems in combination with national policy and regulation for products, practices and providers to ensure safety and quality;
ensure the use of safe, effective and quality products and practices, based on available evidence;
acknowledge traditional medicine as part of primary health care, to increase access to care and preserve knowledge and resources; and
ensure patient safety by upgrading the skills and knowledge of traditional medicine providers.