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Commerce Ministry to Implement Online System for Tracing & Authentication of Export From April, 2020

The Union Ministry of Commerce, through the Centre for Development of Advanced Computing (C-DAC), will implement online system for tracing and authentication of pharmaceutical export packages from April 1, 2020.

The online system is envisaged to help manufacturers and merchant traders to generate and utilise tertiary and secondary level coded data in a user-friendly manner. 

“Industry is very happy with the government initiative which will solve problems for track and trace,” says Nipun Jain, chairman, SME panel, Pharmexcil.

Simplified tracing system for authentication of drug packages will act as a single window integrated system that will enable the tracing of an exported pharmaceutical product. It has the provision to upload product and production data.

It also has provisions to create virtual tertiary and secondary packages and generation of unique identification for manufacturers,  merchant exporters (Labeler Code), products (Product Code), and Packages (Package Code- Primary, Secondary, Tertiary Packs). 

It will also help in tracing of pharmaceutical product exported using Unique ID and QR Code. 

System is based out of simplistic workflow and hence takes care of both manufacturers and merchant exporters. 

With this system, tertiary and secondary packing will be taken care with their corresponding unique serial numbers and there is no need of duplication of SSCC and tertiary generated by proposed system.

The proposed system is for Indian government’s tracing and tracking mechanism for export purposes, therefore it is independent of the product coding systems used by a manufacturer.

It facilitates ease of tracking of packages and products using Unique ID. An App shall be provided to verify product details upon entering unique Id.

The proposed system shall provide feasibility of generation of primary codes from software to printing systems directly and avoid manual or third party intervention. E-sign of Government of India shall be used (Aadhar based) instead of digital signatures. For products verification, the listing may be taken from authentic source like SUGAM, Central Drugs Standard Control Organisation (CDSCO). 

"Digital Link Syntax” - A new #GS1 Standard for Product Authentication

GS1 has recently published their technical guideline for Verification Router service where they intended to provide a simple standardized lightweight messaging framework for verification of saleable return and enables wholesaler/distributor to determine what immediate action should be taken based on authentication check.

Under the Drug Supply Chain Security Act, beginning November 27, 2019, wholesaler distributors are required to verify the product identifier of returned product before placing them into inventory for resale. A manufacturer who receives a verification request from a repackager, wholesale distributor, or dispenser must respond to that request within 24 hours. Supply chain parties are expected to exchange information in “a secure, interoperable, electronic manner in accordance with the standards

 GS1 advances with Digital Link Syntax

First time GS1 standard is including JSON as a message response syntax; it is also the first GS1 “Share” standard to leverage the new GS1 Digital Link (Web URI) standard for the request syntax.

GS1 technical standard to make use of the new GS1 Digital Link syntax in order to enable a basic automated authenticity check of a serialized product identifier with batch and expiry date via a lightweight web-based request/response message pair, initiated by a simple HTTP/HTTPS GET request and returning a lightweight machine-readable response message formatted in JavaScript Object Notation (JSON). 

In current practice, a product is uniquely identified by following elements and encoded in GS1 2D DataMatrix barcode.



The GS1 Digital Link (Web URI) syntax provides an alternative way to express GTIN, serial number, lot/batch and expiry date within a single Web URI format. GS1 element strings can also be translated into a GS1 Digital Link Web URI with the following structure or URI template:{gtin}/lot/{lot}/ser/{ser}?exp={exp}


{gtin}, {exp}, {lot} and {ser} are placeholders for the actual values, such as:

Example E1908672/ser/721234567872?exp=220228

The GS1 Digital Link syntax is simply an alternative way of expressing a concatenation of one or more GS1 element strings but formatted in a way that functions as a web address. It is important to note that the GS1 Digital Link syntax does not require any changes whatsoever to current practices of marking products with GS1 barcodes, whether 1-D or 2-D; pharmaceutical packages will continue to be marked using GS1 DataMatrix symbols that encode the four elements above.

As part of the adoption strategy for GS1 Digital Link, GS1 is currently developing free open source translation functions (in JavaScript, PHP and Java) that will enable translation between GS1 element strings and the GS1 Digital Link / Web URI syntax, in both directions. This can then be included within the software / firmware of barcode scanners or further downstream, within information systems, so that the GS1 Digital Link / Web URI syntax can always be generated on demand, whenever it is required, without requiring any change to how GS1 identifiers are currently encoded and marked on product packaging. In other words, it will be possible to scan a set of four element strings (GTIN, Lot/Batch, Serial Number and Expiry Date) from an existing GS1 DataMatrix barcode on a product package, and have that GS1 element string translated into a GS1 Digital Link Web URI format whenever it is useful to do so.

The 5th Generation of Cephalosporins

Since their discovery in the 1950s, cephalosporins have become one of the largest classes of antibiotics. The class is divided into generations or subclasses, which are grouped by chemical properties and subsequent generalized microbiologic spectra.

Cephalosporins have been used to treat a variety of infections, from mild to life-threatening; however, like all antibiotics, resistance has been identified in bacteria. This typically occurs when the medications bind to an active site serine that is located on all functional penicillin-binding proteins (PBPs). The resulting inactive enzyme slowly hydrolyzes the antibiotic so that it forms an inactive entity compared with the bacteria.1

To address antibacterial resistance, the Generating Antibiotic Incentives Now provision of the FDA Safety and Innovation Act (FDASIA; Public Law 112-144) created the designation of “qualified infectious disease products” (QIDPs).2 This status is granted to agents that are intended to treat dangerous or life-threatening infections caused by resistant, novel, or emerging pathogens or those listed within the FDASIA. The agents receive an additional 5 years of patent exclusivity and priority and fast-track FDA review. In 2015, ceftolozane/tazobactam (Zerbaxa) became the fourth and ceftazidime/avibactam (Avycaz) became the fifth QIDP to receive FDA approval.3,4 Together, these new cephalosporins have been referred to as fifth-generation cephalosporins, or new-generation cephalosporins (NGCs).


Both NGCs are bactericidal agents that bind to PBPs, the essential enzymes involved in the final step of cell wall biosynthesis in both Gram-positive and Gram-negative organisms. 1,3,4 Each is attached to a beta-lactamase inhibitor that does not possess clinically relevant in vitro activity against bacteria but does serve to protect the cephalosporin from degradation. Tazobactam, combined with the novel cephalosporin ceftolozane, is an irreversible inhibitor of class A penicillinases and class C cephalosporinases and forms covalent bonds to some chromosomal and plasma-mediated beta-lactamases. 2,6 Avibactam, a novel beta-lactamase inhibitor combined with ceftazidime, the established third-generation cephalosporin, inhibits class A penicillinases, extended-spectrum beta-lactamases (ESβLs), class C cephalosporinases, class D oxacillinases, and serine carbapenemases.1,5,7


Ceftolozane/tazobactam and ceftazidime/avibactam have shown efficacy against a large number of pathogens. Both NGCs demonstrate in vitro activity against enterobacteriaceae in the presence of certain beta-lactamases and ES Ls and are effective against Pseudomonas aeruginosa, including some resistant isolates.6,7 Only ceftazidime/avibactam, however, is effective against Klebsiella pneumoniae carbapenemases. 7 Ceftolozane/tazobactam also has shown efficacy against Streptococcus species and the anaerobic pathogens Bacteroides fragilis and Fusobacterium species.6 Neither NGC is effective against the Enterococcus species and therefore may not provide adequate empiric coverage for all patients with a nitrate-negative urinalysis.


The NGCs are FDA approved for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intraabdominal infections (cIAIs).6,7 cIAIs include intraabdominal abscesses, peritonitis, gastric or duodenal perforation, intestinal perforation, appendicitis, cholecystitis, and diverticulitis. When treating cIAIs, metronidazole must be used with the NGCs to provide coverage against anaerobic organisms. The NGCs should be used only in patients 18 years old or older, when treating infections known or strongly suspected to be caused by susceptible organisms, and reserved for patients with no or limited antibacterial alternatives.


NGCs are parenteral antibiotics that are administered every 8 hours to adult patients with a creatinine clearance >50 mL/min.6,7 Dosing for each antibiotic is the same for the 2 approved indications. Ceftazidime/avibactam 2.5 g (2 g/0.5 g) should be infused during a 2-hour period, whereas ceftolozane/tazobactam 1.5 g (1 g/0.5 g) only requires a 1-hour infusion. The dose of ceftolozane/tazobactam is reduced with declining kidney function (creatinine clearance ≤50 mL/min), but the 8-hour frequency is unchanged. In contrast, decreased dosing and extended interval frequency are required for ceftazidime/avibactam when the creatinine clearance is ≤50 mL/min.

The duration of therapy differs between the 2 agents and by indication. A cUTI should be treated for at least 7 dayswith either NGC, although it may require up to 14 days with ceftazidime/avibactam.6,7 Patients with a cIAI should receive ceftolozane/tazobactam for 4 to 14 days or ceftazidime/ avibactam for 5 to 14 days. When used to treat cIAI, intravenous metronidazole 500 mg every 8 hours also should be administered.


To the author’s knowledge, no head-to-head studies between the 2 NGCs have been conducted. The approvals of both NGCs for cIAIs were based on the results of similar large clinical trials of hospitalized patients in which the NGC plus metronidazole was compared with meropenem.6,7

Ceftolozane/tazobactam was evaluated in a multinational noninferiority study of 979 patients that assessed clinical response, defined as complete resolution or significant improvement in signs and symptoms of the infection 24 to 32 days after the first dose of the study drug.6 Ceftolozane/ tazobactam plus metronidazole was shown to be noninferior to meropenem in clinical response (83% vs 87.3%; observed difference, −4.3% [95% CI, −9.2% to 0.7%]). A subanalysis of Escherichia coli and K pneumoniae isolates used genotypic testing to identify ESβL groups in 9% of isolates, with clinical cure rates being similar between the groups.

Ceftazidime/avibactam also was evaluated in a multinational noninferiority study in combination with metronidazole compared with meropenem alone.7 The study enrolled 1058 patients to evaluate clinical cure, which had the same definition as previously noted for clinical response, but was evaluated at 28 to 35 days after enrollment. Ceftazidime/avibactam plus metronidazole also was shown to be noninferior to meropenem alone (81.6% vs 85.1%; observed difference, −3.5% [95% CI, −8.6% to 1.6%]). A subanalysis of genotypic testing for ESβLs also was conducted, with cure rates continuing to be similar between the 2 groups.

Ceftolozane/tazobactam was approved by the FDA for the treatment of cUTIs based on a multinational study of 1068 patients that compared cephalosporin with levofloxacin for 7 days.8 The primary endpoint was complete resolution or marked improvement of clinical symptoms and microbiological eradication at 7 days after the last dose of the medication. Ceftolozane/tazobactam was shown to have better efficacy compared with levofloxacin (76.9% vs 68.4%; observed difference, 8.5% [95% CI, 2.3%-14.6%]), but 26.5% of patients had isolates that were resistant to levofloxacin. Among the patients with levofloxacin-sensitive organisms, efficacy was similar between the 2 antibiotics (82.6% vs 79.7%; no 95% CI provided).

The approval of ceftazidime/avibactam for cUTIs was granted predominantly based on the results of previous studies on the efficacy and safety of ceftazidime alone forcUTIs7; the contribution of avibactam to the efficacy of the medication was supported by in vitro and animal studies.7 Ceftazidime/avibactam was compared with imipenem-cilastatin in a phase 2 randomized multicenter study of hospitalized patients with cUTIs caused by Gram-negative organisms. 9 The cure’s effectiveness was evaluated in 62 patients who were microbiologically evaluable 5 to 9 days after therapy, with a favorable microbiologic response similar between the groups (70.4% vs 71.4%; observed difference, −1.1% [95% CI, −27.2% to 25%]).

Ceftazidime/avibactam also was compared with doripenem in a postapproval phase 3 noninferiority study for 10 days (up to 14 days, if bacteremia was detected) in 1033 patients with cUTIs.10 Ceftazidime/avibactam was shown to be noninferior to doripenem in patient-reported symptomatic resolution at day 5 (70.2% vs 66.2%; observed difference, 4% [95% CI, −2.39% to 10.42%]) and combined symptomatic resolution and microbiological eradication at test of cure (71.2% vs 64.5%; observed difference, 6.7% [95% CI, 0.3%-13.12%]).


Adverse effects (AEs) with NGCs typically are mild, but there are several common and serious AEs worth noting. Both agents cause nausea and diarrhea in ≥5% of patients.6-10 Ceftazidime/avibactam also may cause constipation, diarrhea, abdominal pain, dizziness, or anxiety.7 Ceftazidime alone has been associated with more serious central nervous system (CNS) AEs, including seizures, encephalopathy, and coma.7 AEs with ceftolozane/tazobactam include headache and pyrexia.6 


Minimal drug–drug interactions have been observed with the NGCs. Both tazobactam and avibactam are substrates of organic anion transporter 1 (OAT1) and OAT3 kidney transporters.6,7 Probenecid, an inhibitor of these transporters, can prolong the half-life of the beta-lactamase inhibitors, and coadministration is not recommended. Cytochrome activity is not affected at clinically relevant blood concentrations, but at supratherapeutic blood concentrations, tazobactam may inhibit cytochrome P450 1A2 (CYP1A2), CYP2D6, and CYP3A4, and avibactam may induce CYP2E1.


Ceftolozane/tazobactam and ceftazidime/avibactam are less effective in patients with a baseline creatinine clearance of 30 to ≤50 mL/min.6,7 Creatinine clearance should be monitored daily in patients receiving these antibiotics, and alternative agents, if available, against the target organism should be considered in patients whose kidney function fallsconsistently within these parameters. Studies of both NGCs reported more AEs in geriatric patients.6,7 Clostridium difficile- associated diarrhea has been reported with both agents, with severity ranging from mild to fatal.6,7 Caution should be exercised when determining whether to use either antibiotic in a patient with a penicillin or other beta-lactamase allergy because of the risk of cross-reactivity.

Serious CNS reactions are known to occur with ceftazidime, especially in patients with decreased kidney function.7 Reactions include seizures, encephalopathy, coma, asterixis, myoclonia, and neuromuscular excitability. Ceftazidime/ avibactam should be avoided in patients with other risk factors for these CNS effects whenever possible. However, if the combination must be used in patients with a creatinine clearance ≤50 mL/min, then the dosage should be adjusted to lessen the risk of CNS reactions.7 

Both NGCs should be protected from exposure to light.6,7 Ceftazidime/avibactam can be stored at a controlled roomtemperature (77°F, with excursions 59°-86°F permitted).7 Once mixed in fluid, it is stable for 12 hours at temperatures ranging from 68° to 77°F and for 24 hours if refrigerated. Ceftolozane/tazobactam should be refrigerated until it is reconstituted. After dilution, ceftolozane/tazobactam can be stored at room temperature for a maximum of 24 hours or in the refrigerator for up to 7 days.6 

Marilyn Novell Bulloch, PharmD BCPS, is an associate clinical professor of pharmacy practice at the Auburn University School of Pharmacy and an adjunct assistant professor at the University of Alabama School of Medicine College of Community Health Sciences Department of Internal Medicine. She serves on multiple committees and in leadership positions for many local, state, and national pharmacy and interdisciplinary medical organizations.

Pharma Book by Mohan Patidar Unlocked pdf

Full 300 Pages Pharma Book by Mohan Patidar Unlocked pdf. Password protected copy viral on WhatsApp.

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New EU GMP Annex 16 - Certification by a Qualified Person and Batch Release

A new version of Annex 16: Certification by a Qualified Person and Batch Release has been published on EU Commission web page. Deadline for coming into operation is 15.April.2016.