Saturday, June 28, 2014

Effect of seasonality on chemical composition and antibacterial and anticandida activities of Argentine propolis. Design of a topical formulation.

The effect of seasonality on Argentine propolis collected during one year on its phenolic and flavonoid content and on the growth of Gram-positive and Gram-negative antibiotic resistant bacteria and Candida species was evaluated. Extracts of propolis samples collected in the summer and spring showed higher phenolic and flavonoid contents than the samples collected in other seasons (5.86 to 6.06 mg GAE/mL and 3.77 to 4.23 mg QE/mL, respectively). The propolis collected in summer and autumn showed higher antibacterial activity (30 microg/mL) than the other samples (MIC values between 30 and 120 microg/mL). No antibacterial activity was detected against Gram-negative bacteria. Also, these extracts were able to inhibit the development of five Candida species, with MFC values of 15-120 microg/mL. Pharmaceutical formulations containing the more active propolis extract were prepared. The hydrogel of acrylic acid polymer containing summer propolis extract as an antimicrobial agent showed microbiological, physical and functional stability during storage for 180 days. The pharmaceutical preparation, as well as the propolis extracts, was active against Candida sp. and antibiotic-multi-resistant Gram-positive bacteria. These results reveal that propolis samples collected by scraping in four seasons, especially in summer in Calingasta, San Juan, Argentina, can be used to obtain tinctures and hydrogels with antibacterial and antimycotic potential for topical use.
sla MI1, Dantur Y, Salas A, Danert C, Zampini C, Arias M, Ordóñez R, Maldonado L, Bedascarrasbure E, Nieva Moreno MI.

Design and quality control of a pharmaceutical formulation containing natural products with antibacterial, antifungal and antioxidant properties.

Ordoñez AA1, Ordoñez RM, Zampini IC, Isla MI.
The aims of the present study were to determine the antibacterial and antifungal activity as well as mutagenicity of Sechium edule fluid extract and to obtain a pharmaceutical formulation with them. The extract exhibited antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Serratia marcescens, Morganella morganii, Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Candida spp. and Aspergillus spp. isolated from clinical samples from two hospitals of Tucuman, Argentina. Non-toxicity and mutagenicity on both Salmonella typhimurium TA98 and TA 100 strains until 100 microg/plate were observed. A hydrogel with carbopol acrylic acid polymer containing S. edule fluid extract as antibacterial, antimycotic and antioxidant agent was obtained. Microbiological, physical and functional stability of pharmaceutical formulation conserved at room temperature for 1 year were determined. Addition of antioxidant preservatives to store the pharmaceutical formulation was not necessary. The semisolid system showed antimicrobial activity against all gram positive and gram negative bacteria and fungi assayed. The minimal inhibitory concentration (MIC) values ranged from 20 to 800 microg/mL. Its activity was compared with a pharmaceutical formulation containing commercial antibiotic and antifungal. A pseudoplastic behavior and positive thixotropy were observed. Our current finding shows an antimicrobial activity of hydrogel containing S. edule extract on a large range of gram negative and gram positive multi-resistant bacteria and fungi. This topical formulation may be used as antimycotic and as antibacterial in cutaneous infections.

WHO Comments Signal Support For Compulsory Licensing In Pharma


Magazine Article | November 27, 2013



By Gail Dutton, contributing editor
The NIH recently made an unprecedented decision in granting the Lacks family some say in how the cervical cancer cells from the late Henrietta Lacks — the famed HeLa cell line — are used. A few months earlier, in May, controversy over ownership of a sample of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) erupted into a public spat involving the government of Saudi Arabia and Erasmus Medical Center in the Netherlands. In commenting, the WHO Director-General, Margaret Chan, demanded that labs not be allowed to profit from their work.
The underlying issue in both situations is the right to profit from scientific discovery. The ramifications of these incidents may affect not only the use of biological samples but also countries’ decisions to use compulsory licenses.
Developing World Unreceptive to Pharma Patents
The WHO appears suspicious of profitbased businesses. As Chan said in her WHO speech in May, “Many of the risk factors for noncommunicable diseases are amplified by the products and practices of large and economically powerful forces. Market power readily translates into political power. When public health policies cross purposes with vested economic interests, we will face opposition, well-orchestrated opposition, and very well-funded opposition.”
India, with a strong generic pharmaceutical industry, is particularly receptive to the notion of constrained patentability for pharmaceutical products. Earlier in 2013, India’s health ministry committee urged the government to exercise its compulsory licensing rights for Herceptin (trastuzumab). The Indian biopharmaceutical firm Biocon expects to complete Phase 3 trials of a biosimilar for trastuzumab this fiscal year, and Dr. Reddy’s Laboratories and Intas Pharmaceuticals indicate they may begin clinical trials soon. One year earlier, in March 2012, India exercised a compulsory license for Nexavar (sorafenib) by Bayer, which was subsequently produced by the Indian firm NatcoPharma.
When Roche relinquished its patent battles in India in August 2013, it cited India’s intellectual property environment as a key factor in that decision. Indian generics firms may see a boost from tight patent requirements and the exercise of compulsory licensing, but the results are chilling for innovators operating in India.
India’s success in exercising march-in rights has been noted by other nations. South Africa has an active campaign, spearheaded by the Treatment Action Campaign (TAC) and Médecins Sans Frontières (MSF), to remodel its patent laws after the Indian laws. In an August memorandum to the South Africa Department of Technology and Industry (DTI), TAC and MSF charged the lack of competitive markets in emerging regions enabled pharmaceutical companies to charge unaffordable prices that make life-saving medicines inaccessible.
“Although other BRICS [Brazil, Russia, India, China, and South Africa] countries like India and Brazil have utilized these pro-public health safeguards, South Africa is lagging behind and has not amended its patent law to incorporate or implement TRIPS [Trade Related Aspects of Intellectual Property Rights] flexibilities,” the TAC and MSF memo pointed out. It advocated a stringent patent examination process that “only grants patents on new drugs. If fewer secondary patents are granted, then more generic versions of medicines will be able to enter the market upon the expiry of compound patents, which will in turn drive down prices. Furthermore, when patents result in medicines being priced out of reach, actions that mitigate high prices, such as compulsory licensing, must be practically feasible to implement.” It called on DTI to “broaden the grounds and facilitate the procedures for issuing compulsory licenses.” Similar laws are enacted in China and are being planned in Argentina and the Philippines.
W. Murray Spruill, Ph.D., co-leader of Alston & Bird’s intellectual property patent proup and the leader of the law firm’s biotechnology, chemical, and pharmaceutical team, suggests these reactions are unrelated to Chan’s statements at the WHO meeting and that the willingness to exercise compulsory licensing rights in the United States is unlikely to change. “There was a lot of talk about compulsory licensing during the anthrax scare several years ago, but no compulsory license was granted in the U.S.,” Spruill says. “I don’t think it will be affected now.”
To exercise compulsory licensing in the U.S., the government must show that the company is not using the patent, the company is failing to meet a public demand, or the invention was funded partially by the government. The WHO agreement on TRIPS, in contrast, includes all patents.
The exercise of compulsory licensing in the EU is similar to that of the U.S. However, recent legislation allows a Europewide health emergency to be announced, with provisions to facilitate ordering vaccines for member states. Although the legislation does not address compulsory licensing, it does broaden the geographic scope of any actions. The EU Parliament says that, “Access to vaccines will be fairer, as they will be purchased at advantageous prices.”
Sample Ownership is Debated
Upstream from the patent issue lies the question of sample ownership. As Deborah Lacks, Henrietta Lacks’ daughter, says in The Immortal Life of Henrietta Lacks, “If our mother cells done so much for medicine, how come her family can’t afford to see no doctors? … People got rich off my mother … now we don’t get a dime. I used to get so mad about that …”
The issue with the MERS-CoV is only slightly different. Microbiologist Ali Mohamed Zaki, who uncovered the virus, says the Saudi Ministry of Health tested the sample for swine flu, then ceased testing. Zaki then sent a sample to virologist Ron Fouchier at the Erasmus Medical Center in the Netherlands for identification. The Saudi Ministry of Health says the sample left the country without permission, and disputes Zaki’s version of events. But, as Nobel Laureate Sir Richard Roberts, Ph.D., chief scientific officer of New England BioLabs, asserts, “It’s ridiculous to ban anybody from getting involved to help solve a disease.”
Saudi Arabia also claims viral identification was delayed three months because Erasmus Medical Center filed for a patent on the use of the virus’ DNA sequence and host receptor data. Other researchers point out that the virus sample is freely available and, in fact, has been analyzed by labs in many different countries. At that point, the WHO’s Chan entered the fray, forcefully telling meeting delegates that countries must not allow commercial labs to profit from MERS-CoV.
Yet, as Tilde Carlow, Ph.D., head of the division of parasitology at NEB, points out, “There must be some profit to drive R&D in our field. The consequence from not deriving profit could be really serious. There is an urgent need for new antibiotics, but because of the potential for meager profits, many companies aren’t interested.” Carlow predicts there will be a growing number of neglected diseases because of an inability to make a profit, thus hampering knowledge creation.
For-profit organizations aren’t necessarily getting involved in orphan diseases to make a profit, Roberts adds. “Some companies, like ours, have no desire to benefit financially, but instead want to solve a third-world disease.” For example, NEB became involved in lymphatic filariasis research some 30 years ago, before the WHO launched its own initiative in 2000. “Researchers at New England BioLabs are not interested in the commercial value of this research. We basically give away all the rights to anything we find here. We file patents, but do not charge licensing fees.”
Sample Sharing Guidelines Vary
The MERS-CoV flap illustrates confusion regarding the international rules for sharing samples, despite the pandemic influenza preparedness (PIP) framework the WHO developed to govern sample sharing. Under that framework, virus strains may be shared internationally with private companies as well as with public concerns. Countries sharing the virus receive equal access to the resulting treatments or diagnostics.
The guidelines for sample transfer and ownership vary, to some extent, by sample type. Within the Ocean Genome Legacy, which Roberts chairs, “There, the suppliers of the samples own the rights. With humans, however, it’s difficult to know who is the correct owner.” But, he points out, “Unless a researcher is there to isolate and characterize a sample, ownership doesn’t mean much.”
The question that remains is whether or how Saudi Arabia should benefit from the MERS-CoV. Nothing prevents it from developing diagnostic tests or therapeutics, either alone or in concert with other partners.
In the end, the spats regarding ownership of the MERS-CoV sample and the involvement of the Lacks family in determining who may use the HeLa cell line may be merely sideshows to a greater issue: the stance taken by the WHO and its perception of for-profit corporations. With the WHO’s tacit blessing, developing nations become more likely to tighten their patent laws and to exercise their compulsory licensing rights when they determine that medicines are unaffordable.

Prevention Instead of Decontamination

The highest possible quality of an end product, in compliance with requirements and regulations, can be attained only if quality assurance is not merely limited to final product testing. Rather, the entire manufacturing process, besides incoming quality control of the raw materials used, needs to be continuously monitored.

In the pharmaceutical industry, risk analysis of individual manufacturing steps is performed and the results of this analysis are used to define in-process quality control tests. Such QC tests permit timely detection of inconsistencies or non-conforming items and, in particular, increases in the bioburden as they occur in manufacture so that corrective action can be promptly initiated. Even though the risk of contamination has been considerably reduced by GMP-compliant production, decontamination, and sterilization of the end products, as well as by strict hygiene standards, quality control of the final product continues to be of prime importance.

Microbial enumeration

Quantitative analysis of microorganisms involves counting the colony-forming units (CFU), hence the term “microbial enumeration.” This number can be expressed either as the total viable number of CFUs in general or of certain product-relevant species of microorganisms. This is why microbial limit tests are performed on various products from different sectors, including the pharmaceutical, beverage, and waste water industries, to ensure that defined limits are not exceeded. The accuracy and reliability of microbial limit test results are essential as they serve as the basis for the release of products, whether potable water or pharmaceuticals, and the impact of undetected pathogens can be potentially devastating on the health of consumers.

Membrane filtration

For microbial enumeration, membrane filtration continues to be the method of choice for reliable quantification of microorganisms in liquid samples. The principle of this method is based on the concentration of organisms—which are filtered out from relatively large sample volumes—on the surface of a membrane filter and their subsequent cultivation by incubating the filter with the retained microbes on a culture medium.

Unlike direct incubation of a sample, membrane filtration offers the advantage that large sample volumes can be tested without individual microorganisms going undetected. In addition, inhibitors, such as antibiotics or preservatives, can be removed by rinsing the membrane with buffer so that microbial growth is not suppressed.

Microbiological tests in the pharmaceutical industry

From a microbiological viewpoint, pharmaceuticals can be subdivided into two categories: non-sterile and sterile products. For both categories, the potential risk resulting from microorganisms and their toxins on patients’ health must be eliminated or at least mitigated. At the same time, the quality and effectiveness of such pharmaceuticals must be retained.

Products defined as sterile, such as eye drops, physiological saline, antibiotics, etc., need to be tested for sterility (USP Chapter 71 and EP, Chapter 2.6.1) in order to be verified as such. Unlike sterile products, non-sterile end products are tested for their number of viable microbes according to the microbial limit test (USP Chapter 61 and EP Chapter 2.6.12). Furthermore, in the pharmaceutical industry, in-process microbiological quality control tests are carried out on raw materials, mostly water, as well as bioburden analysis during manufacture.

Critical steps in microbial enumeration

The classic equipment setup for performing membrane filtration consists of a vacuum pump, a multi-branch vacuum manifold, membrane filters, reusable funnel-type filter holders or single-use filtration units, culture media, and tweezers.

In this method, the filter support of a reusable filter holder is sterilized by flaming, and a membrane filter is subsequently placed on this support. Then the funnel is attached to the support and a sample is poured into this funnel. Filtration begins when the tap on the vacuum source is opened. At the end of filtration, tweezers are used to remove the membrane filter and transfer it to an agar culture medium.

The culture medium is incubated for a defined time at a predetermined temperature inside an incubator. At the end of incubation, evaluation is done by enumerating the individual CFUs and comparing their count with the permissible microbial limits for each particular sample.

Flaming or disinfecting the filter support poses an added risk of contamination due to the inherent inaccuracy in performing these sterilization procedures. In particular, maintaining the required time of contact with the flame or disinfectant, the choice of disinfectant (not just a bactericide, but a sporicide) and regular changing of the disinfectant are all critical factors in determining whether sterilization is 100% effective. Besides representing a health hazard for lab personnel, flaming also poses the risk that not all areas contaminated by microbes are exposed to the hottest point of the flame long enough in order to kill off these organisms.

Minimization of secondary contamination

A single-use filter unit does not require any decontamination, provided that a single-use filter base is used. As a result, the only especially critical step that remains is transferring the membrane filter to an agar medium, which increases the risk of secondary contamination and can lead to false-positive results. The reason lies in the use of tweezers to transfer the membrane. Although these tweezers are also flamed, i.e., sterilized, they can potentially carry over exogenous microbes when used to grasp the membrane.

Single-use filter units increase the safety and efficiency of microbiological quality control by eliminating the need for disinfection or flaming of the filter support, as well as for using tweezers to transfer a membrane to a culture medium. A system comprised of single-use filter units and agar media dishes can increase efficiency and reliable results.  

The filter unit in this type of system is a sterile, ready-to-use combination of a funnel, a filter base, and a gridded membrane filter. This filter unit is connected to a stainless steel multi-branch manifold in order to directly filter a sample. Afterwards, the filter unit is easy to remove from the manifold and eliminates the critical step of decontaminating the stainless steel base of a reusable filter holder.

Agar media dishes are used for microbial limit testing. They are pre-filled with different types of agar medium, sterile-packaged and, when together with a single-use filter, are ready to use immediately. In combination with a single-use filter unit, these media dishes feature an active lid that permits touch-free transfer of a membrane onto agar, without using any tweezers. This active lid lifts the membrane filter from the base of the filter unit so the filter can be safely transferred onto the pre-filled agar dish. Once the medium dish is closed, the membrane is ready to incubate.

Solution for safe membrane transfer

The combination of agar media dishes and filter units represents a new membrane transfer and agar concept. As just a few steps are all it takes to proceed from sampling to incubation, a single-use system of agar media dishes and filter units accelerates workflows, making them cost-efficient. At the same time, touch-free membrane transfer enables even more reliable results to be obtained in analysis, while reducing secondary contamination to an absolute minimum.

Three Consecutive Batches for Validation in Pharmaceuticals


This is common concept to validate three consecutive batches in pharmaceuticals. In process validation initial three batches are taken for validation. This is a basic question that concentrates everyone’s mind that why three batches are taken for validation?
Process Validation Stages
Neither FDA nor any other regulation specifies the maximum number of batches to be considered as validation. The manufacturers have to choose the number of batches to be validate in this regard. The number of batches to be taken under validation depends upon the risk involved in the process of manufacturing. The less knowledge about the process requires the more statistical data to confirm the consistent performance. Consideration of validation batches fewer than three will require more statistical and scientific data to prove the consistency of process to meet quality standards.
FDA’s “Guidance for Industry on Process Validation: General Principles and Practices” provides the guideline for process validation, no longer consider the traditional three batch validation appropriate but also does not prescribe the number of batches to validate or suggests any other method to determine it.

Related: Guidance for Industry on Process Validation: General Principles and Practice
Generally it is considered if we get the desired quality in first batch, it is accidental, second batch quality is regulator and quality in third batch is Validation. When two batches are taken as validation the data will not be sufficient for evaluation and to prove reproducibility because statistical evaluation cannot be done on two points, it needs minimum three points because two points always draw a straight line. Therefore, minimum three consecutive batches are evaluated for validation of manufacturing process and cleaning procedures. More than three batches may be taken in validation but it involves the cost and time and the companies don’t want to do so.

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Friday, June 27, 2014

Contamination Control

It’s only natural that contamination control in today’s world of critical environments is in a constant state of evolution. After all, the complexities of facilities and processes flow from the increasing intricacies of end products. And throughout the continued development of environmental monitoring programs, it pays dividends to recognize that what works today may not be the best solution for the future.

Wet wiping is a cornerstone of contamination control. A liquid’s ability to penetrate and sanitize the nooks and crannies of a surface—coupled with a process-appropriate sorptive material for absorption—will remain crucial to critical environments across industries.

Alcohol is a lasting standard for wet wiping. While it doesn’t have the broadest kill spectrum or the highest surface penetration, it is a gentle yet effective sanitizer and reliable dissolver of ionic compounds and common organics. Alcohol also evaporates cleanly enough to be used as a residue remover for many other cleaning chemicals. Pairing alcohol—often in a 70% IPA/30% USP purified DI water mixture—with a knitted polyester or polyester-cellulose wipe has been a reliable choice for wide-ranging critical cleaning applications.

It’s necessary to consider that the process you designed two years ago may not be effective two years from now. If this transpires, will your current supplier be able to meet unanticipated process needs? While it’s important to recognize the potential costs of product evaluation and risks associated with changing suppliers, assessing your supplier’s innovative and evolving capabilities is an equally important consideration.

Thursday, June 26, 2014

Pharmaceutical Industry Undergoing Transformation

  • Although the pharmaceutical industry’s investment in R&D has doubled in the past decade, fewer than half as many new products actually make it to market. Consequently, the business model of creating a handful of blockbuster drugs and marketing them to providers is no longer sustainable. As the industry responds to this new imperative, it will see more changes by 2020 than it has in a generation.
    Change is necessary because more of the same won’t work. Blockbuster drugs are coming off patent, fewer new products are in the pipeline because of a lack of fundamental innovation, sales and marketing expenses are increasing, regulatory costs are growing, and there has been a dramatic loss of trust in the industry. As a result, returns on pharmaceutical stocks have lagged behind those of other industries—during the past six years, the Dow Jones World Index rose 34.9% while the FTSE Global Pharmaceuticals Index rose just 1.3%. The pharmaceutical industry is relatively weak financially and cannot respond simply by throwing more money at the challenges it faces.
    However, the industry’s future is brighter than it seems because estimates indicate that the worldwide pharmaceutical market will more than double by 2020 to $1.3 trillion in annual sales. Demand will come partly from an older, larger, and more sedentary population, especially from new markets in developing countries.
    In addition, the incidence of some existing diseases are increasing, partly because of climate change, which is expanding the geographic range of tropical and semitropical infectious diseases. Chronic respiratory illnesses are increasing as well, as new factories and auto travel worsen air pollution in developing countries. Also, new diseases, many of them resistant to existing therapies, are emerging.
    As the pharmaceutical industry seeks to address challenges and make the most of strategic opportunities, it will see 10 transformational challenges by 2020:
  • Transformations

    1. The industry’s reliance on the blockbuster model will decrease. Rather than relying primarily on a handful of blockbuster drugs, the industry will shift to developing a wider range of medicines. Sales and marketing also will change, as today’s enormous sales forces are replaced by smaller teams that will negotiate prices based on proven benefits and sell related services that may add more value than the medicines themselves.
    2. The pharmaceutical industry will become increasingly bifurcated, with some companies becoming niche players, developing fewer, more targeted drugs; others will go the generic route, focusing on volume and sales for revenue. Companies can succeed on either path but will have to choose which way to go.
    3. Real results will be crucial to product success. Products will have to produce value, and companies will profit from innovation, not by replicating existing therapies. As a result, greater focus will be placed on obtaining results supported by measurable data.
    4. There will be a new focus on patient compliance. Patients often do not take their medications as prescribed or fail to take them entirely. Pharmaceutical companies will develop new, personalized compliance-monitoring technologies and techniques to ensure that patients take their medicine, improving results and safety while potentially generating more than $30 billion annually in new sales.
    5. Prevention will become as important as treatment. “A penny of prevention is worth a pound of cure” takes on added meaning when billions of dollars are at stake. The pharmaceutical industry has long been focused on treatment of disease but it will be far more cost-effective to prevent disease than to cure it, and this will be a driver of innovation. With consumers increasingly focused on healthcare costs, pharmaceutical companies will also begin supporting wellness programs, compliance monitoring, and increased vaccination.
    6. Technology will transform R&D. New molecular technologies will help realize the promise of genomic research, and the growing sophistication of medical devices, often in combination with drugs, will improve therapeutic effectiveness while cutting risk.
    7. The clinical trials process will become more flexible. Today’s all-or-nothing regulatory approval process will shift to a more progressive system of in-life testing and “live licenses,” which will be based on a drug’s performance over time, with greater collaboration and data-sharing between pharmaceutical companies and regulators. This will also depend on the arrival of pervasive computing to the home and the ability to monitor patients remotely.
    8. The regulatory process will go global. As international markets become more important, pharmaceutical companies will spur a drive for greater cooperation among national regulators to get lifesaving products to market faster and reduce regulatory compliance costs.
    9. Supply chains will become revenue generators. Applying just-in-time manufacturing and delivery systems used in other industries, pharmaceutical companies will develop products on a made-to-order basis, creating new channels to market products.
    10. Wholesalers will give way to direct-to-consumer distribution. As the over-the-counter product market grows and new technologies enable direct-to-consumer distribution, reliance on wholesalers will diminish with more prescriptions fulfilled automatically.
  • Success in the Future

    Like other sectors of healthcare, the pharmaceutical industry will see enormous changes that will render many of today’s practices, standards, and operations unrecognizable by 2020. The long-term success of today’s industry leaders is by no means guaranteed but instead will be determined by their ability to adapt to new realities. The winners will be those companies that have the vision, flexibility, and courage to begin making changes now.
    Pharmaceutical companies can prosper through adaptation—investing in research to produce products that yield results at realistic prices, collaborating with stakeholders here and abroad, and providing consumers with services that add value. The stakes and the risks are high but so are the potential rewards.

Recent trends and future of pharmaceutical packaging technology


Nityanand Zadbuke, Sadhana Shahi, Bhushan Gulecha, Abhay Padalkar,

Abstract

The pharmaceutical packaging market is constantly advancing and has experienced annual growth of at least five percent per annum in the past few years. The market is now reckoned to be worth over $20 billion a year. As with most other packaged goods, pharmaceuticals need reliable and speedy packaging solutions that deliver a combination of product protection, quality, tamper evidence, patient comfort and security needs. Constant innovations in the pharmaceuticals themselves such as, blow fill seal (BFS) vials, anti-counterfeit measures, plasma impulse chemical vapor deposition (PICVD) coating technology, snap off ampoules, unit dose vials, two-in-one prefilled vial design, prefilled syringes and child-resistant packs have a direct impact on the packaging. The review details several of the recent pharmaceutical packaging trends that are impacting packaging industry, and offers some predictions for the future.
KEY WORDS: Pharmaceutical packaging, packaging materials, recent trends, future
Packaging is defined as the collection of different components which surround the pharmaceutical product from the time of production until its use. Packaging pharmaceutical products is a broad, encompassing, and multi-faceted task. Packaging is responsible for providing life-saving drugs, medical devices, medical treatments, and new products like medical nutritionals (nutraceuticals) in every imaginable dosage form to deliver every type of supplement, poultice, liquid, solid, powder, suspension, or drop to people the world over. It is transparent to the end user when done well and is open to criticism from all quarters when done poorly.[1,2]
Distribution of products is now more global than ever. Mass customization of packaging to permit its use in multiple markets is a topic that needs exposition and discussion. Environmental issues, including sustainability, will always be a subjective dimension to any packaging design.
Packaging is an emerging science, an emerging engineering discipline, and a success contributor to pharmaceutical industries.
Packaging can reside, or report through research and development (R and D), engineering, operations, purchasing, marketing, or the general administrative department of a company. For the majority of products produced in pharmaceutical industries it is probably the single largest aggregate purchase made by a company of materials critical to the protection, distribution, and sale of the product.

Functions of Pharmaceutical Packaging

  1. Containment - The containment of the product is the most fundamental function of packaging for medicinal products. The design of high-quality packaging must take into account both the needs of the product and of the manufacturing and distribution system. This requires the packaging: not to leak, nor allow diffusion and permeation of the product, to be strong enough to hold the contents when subjected to normal handling and not to be altered by the ingredients of the formulation in its final dosage form.[3]
  2. Protection - The packaging must protect the product against all adverse external influences that may affect its quality or potency, such as light, moisture, oxygen, biological contamination, mechanical damage and counterfeiting/adulteration.
  3. Presentation and information - Packaging is also an essential source of information on medicinal products. Such information is provided by labels and package inserts for patients.
  4. Identification - The printed packs or its ancillary printed components serves the functions of providing both identity and information.
  5. Convenience - The convenience is associated with product use or administration e.g., a unit dose eye drop which both eliminates the need for preservative and reduces risks associated with cross infection, by administering only a single dose.

Categories of Pharmaceutical Packaging Materials

  1. Primary packaging system is the material that first envelops the product and holds it i.e., those package components and subcomponents that actually come in contact with the product, or those that may have a direct effect on the product shelf life e.g., ampoules and vials, prefilled syringes, IV containers, etc.
  2. Secondary packaging system is outside the primary packaging and used to group primary packages together e.g., cartons, boxes, shipping containers, injection trays, etc.
  3. Tertiary packaging system is used for bulk handling and shipping e.g., barrel, container, edge protectors, etc.

Materials used for Pharmaceutical Packaging

Traditionally, the majority of medicines (51%) have been taken orally by tablets or capsules, which are either packed in blister packs (very common in Europe and Asia) or fed into plastic pharmaceutical bottles (especially in the USA). Powders, pastilles and liquids also make up part of the oral medicine intake. However, other methods for taking medicines are now being more widely used. These include parentral or intravenous (29%), inhalation (17%), and transdermal (3%) methods.
These changes have made a big impact on the packaging industry and there is an increasing need to provide tailored, individual packaging solutions, which guarantee the effectiveness of medicines.[4]
The present review article details several key trends that are impacting packaging industry, and offers some predictions for the future packaging encompassing solid oral dosage forms and injectables.

Recent Packaging Technologies

Blow-fill-seal technology

Aseptic blow-fill-seal (BFS) technology is the process by which plastic containers are formed, filled with sterile filtered product and sealed in an uninterrupted sequence of operations within the controlled sterile environment of a single machine.[5,6]
The blow-fill-seal process is a robust, advanced aseptic processing technology, recognized by worldwide regulatory authorities for its inherent operational advantages over conventional aseptic production. Blow-fill-seal systems offer a unique combination of flexibility in packaging design, low operating cost and a high degree of sterility assurance. The machines require a minimum number of operating personnel and have a relatively small space requirement.
A variety of polymers may be used in the process, low and high-density polyethylene and polypropylene being the most popular. The innate ability to form the container/closure during the actual aseptic packaging process allows for custom design of the container to meet the specific needs of the application. This flexibility not only improves container ease of use, but provides a means of interfacing with many of today's emerging drug delivery technologies, most notably in the field of respiratory therapy.

Blow-fill-seal process

Container moulding

Thermoplastic is continuously extruded in a tubular shape [Figure 1a]. When the tube reaches the correct length, the mold closes and the parison is cut [Figure 1b]. The bottom of the parison is pinched closed and the top is held in place with a set of holding jaws. The mold is then transferred to a position under the filling station.
Figure 1
Blow-Fill-Seal process

Container filling

The nozzle assembly lowers into the parison until the nozzles form a seal with the neck of the mold [Figure 1c]. Container formation is completed by applying a vacuum on the mold-side of the container and blowing sterile filtered air into the interior of the container. The patented electronic fill system delivers a precise dosage of product into the container. The nozzles then retract into their original position.

Container sealing

Following completion of the filling process, the top of the container remains semi-molten. Separate seal molds close to form the top and hermetically seal the container [Figure 1d]. The mold opens and the container is then conveyed out of the machine [Figure 1e].
The cycle is then repeated to produce another filled container. The filled containers are tested and checked to ensure that they meet the very strict specifications laid down for such products.
The duration of the complete cycle is between 10-18 seconds, depending on the container design and the amount of liquid to be filled.

Advantages of BFS Technology

BFS technology offers considerable advantages over conventional aseptic filling of preformed (plastic or other) containers, which are described as follows:
  1. BFS technology reduces personnel intervention making it a more robust method for the aseptic preparation of sterile pharmaceuticals.
  2. There is no need to purchase and stock a range of prefabricated containers and their closures. Bulk containers of plastic are required.
  3. Cleaning and sterilization of prefabricated containers and closures is not required. A clean, sterile container is made within the BFS machine as it is required for filling.
  4. The cost of material transport, storage and inventory control is reduced.
  5. Validation requirements are reduced.
  6. The technology allows the design of high-quality, custom-designed containers with tamper-evident closures in a variety of shapes and sizes.
  7. There is a large choice of neck and opening device shapes.
  8. A single compact BFS machine takes the place of several conventional machines, saving floor space. In addition, zones for transport to successive filling and closing procedures are not required because these operations all take place in the BFS machine itself.
  9. The operation of BFS machines is less labor intensive than conventional aseptic filling.
  10. The code numbers and variable data such as batch number and expiry date can be molded into the container itself rather than being added at a subsequent stage.
  11. The process lends itself to the production of single dose containers and therefore preservatives are not necessary as they are with multi-dose containers.
Blow-fill-seal technology has gained much market focus in recent years due to the increased focus on biologics, proteins and other complex solutions. These important products often cannot withstand exposure to high temperatures for extended periods of time without degradation of their active components. Conventional terminal sterilization, therefore, is not an acceptable method to produce a ‘sterile’ product. Bulk sterilization, sterilization by gamma irradiation or filter sterilization followed by direct packaging utilizing the blow-fill-seal process are often used successfully for these types of products.

Anti-Counterfeit Packaging Technologies

Counterfeiting means producing products and packaging similar to the originals and selling the fake as authentic products. Counterfeit is a problem of product security, with reference to packaging is not a problem in isolation; it is the part along with:
Duplication - i.e., copying labels, packaging, products, instructions and usage information,
Substitution - placing inferior products in authentic or reused packaging,
Tampering - by altering packages/labels and using spiked, pilfered, or stolen goods in place as real,
Returns and Warranty frauds they are addressed as Brand Theft.

Anti-Counterfeiting Technology Solutions

The current numbers of anti-counterfeiting solutions are many and new options are introduced in the market with some variations. An attempt is made to explain the technologies for easy understanding on product packaging.

1. Overt (visible) features

Overt features are intended to enable end users to verify the authenticity of a pack. Such features will normally be prominently visible, and difficult or expensive to reproduce. They also require utmost security in supply, handling and disposal procedures to avoid unauthorized diversion. They are designed to be applied in such a way that they cannot be reused or removed without being defaced or causing damage to the pack for this reason an overt device might be incorporated within a tamper evident feature for added security.

Tamper evident packaging systems

Some packages are inherently tamper proof, like a tin can hermetically sealed, an aseptically packed multilayer carton or a vacuum or the retort pack. The tamper evident packaging systems are:

a) Film wrappers

A transparent film with a distinctive design is wrapped securely around a product or product container. The film must be cut or torn to open the container and remove the product. Substrates options include ultra destructible films, voidable films that provides image when removed. e.g., Solvent sensitive papers.

b) Shrink seals and bands

Bands or wrappers with a distinctive design are shrunk by heat or drying to seal the cap and container union. The seal must be cut or torn to remove the product.

c) Breakable caps

Such caps break when an attempt is made to open it. These caps provide external tamper evidence and can also be combined with the internal seals thereby providing double security.

d) Sealed tubes

The mouth of the tube is sealed, and the seal must be punctured to obtain the product.

2. Covert (hidden) features

The purpose of a covert feature is to enable the brand owner to identify counterfeited product. The general public will not be aware of its presence nor have the means to verify it. A covert feature should not be easy to detect or copy without specialist knowledge, and their details must be controlled on a “need to know” basis. If compromised or publicized, most covert features will lose some if not all of their security value [Figure 2].
Figure 2
Encrypted text visible under special light as a covert feature

3. RFID

Radio frequency identification (RFID) is hardly a new concept. For some, RFID is already a mainstream technology-it is used every day to pay tolls, secure building access, catch shop lifters etc., It allows the identification of objects through a wireless communications in a fixed frequency band. Three essential components in any RFID system are: the tag, the reader and the software. The tag is an integrated circuit containing a unique tracking identifier, called an electronic product code (EPC), which is transmitted via E.M. waves in the radio spectrum. The reader captures the transmitted signal and provides the network connectivity between tag data and the system software. The software can be tailor made for the purpose of anti-counterfeiting. For their track and trace usage, RFID tags are used [Figure 3].
Figure 3
RFID tags

a) Passive tag

When RFID tag is within the interrogation zone of the reader (i.e., interrogator) equipment; sufficient power is extracted from the interrogator to power up the tag or circuit, or a special reflective material. It then responds by transmitting data back to the interrogator.

b) Active tag

Such tags incorporate a battery to increase range for collating data, tag to tag communication, etc., But these are much more expensive.

c) Semi-active tag

In these tags batteries are used to back up the memory and data, but not to boost the range. With some active RFID tags, the batteries are only used when interrogated or when sending a homing pulse at fixed intervals to reduce cost and size.

4. Packaging designs: Materials/Substrates and other design options

a) Substrates

There are variety of substrates used in the design of packages with intent to provide counterfeit and tamper evident features starting from litho paper, polystyrenes, destructive vinyl's, acetate films synthetic paper and coatings etc., There are many ways of incorporating covert markers within a substrate, such as visible or UV fluorescing fibers, or chemical reagents in carton board or paper. Watermarks can be embedded in leaflet paper, or metallic threads interwoven in the base material, possibly including an overt optically variable devices (OVD) feature. These require a dedicated supply source and large volume production, which, if affordable, results in a very effective option. Micro-encapsulated distinctive odors can be applied as an additive to an ink or coating to provide a novel covert or semi-overt feature, as well as sound chips creates special opportunities in the design.

b) Packaging designs

Packaging designs like sealed cartons, aerosol containers have inherent strength against counterfeiting

c) Sealing systems

Special caps such as the outer tamper evident system or the foil seal as an internal tamper evident feature are commonly used for pharmaceutical products. Sealing options are lever-lidded tins, secure packaging tapes, lined cartons and tear tapes/bands.

5. Security labels

Tamper evident and security labels play an important role in providing some relief to the consumers against fakes. In self adhesive labels the substrate mostly performs as a complimentary interaction of the substrate and the pressure sensitive adhesive. While passive security labels have been extensively used, today one can find a greater application of functional labels such as printing plus anti-theft. Some label options are:

a) Paper labels with security cuts

The substrate used for these labels is ordinary coated/uncoated paper. The security features are built in by the label printer at the converting stage. With the help of a special cutting die, the face material is given cuts at various angles so that by any ways one tries to remove these labels the paper will tear off. A general purpose permanent adhesive works fine with such labels. Care is taken to ensure that the adhesive will adhere well and firmly to the surface on which the label has to be applied.

b) Destructible labels

Needs a special substrate designed for the purpose. Most of the high-end applications use a specially made cellulose acetate film. The film is very intricately designed so that it has adequate strength to undergo conversion into label stocks in roll form. It is available both in clear and opaque formats and further converted into labels using aggressive pressure sensitive adhesives. The labels can be automatically dispensed on automatic label dispensers and when attempted to be removed, break-up into very small fragmented pieces. The cost effective vinyl have replaced acetate film. A combination of various synthetic polymers can be used to impart low inherent strength to the substrate.

c) Void labels and tapes

The most important of the tamper evident security labels and have text built into them. When as a self adhesive label they are removed, they exhibit the word VOID both in the removed film and the adhesive layer left behind. These substrates gain importance as there can be customization built into the labels produced with it. One can use polyester or biaxially-oriented polypropylene (BOPP) as face materials. Variety of colors, even metallization is possible. The text VOID could be replaced by the customers brand, emblem or a message, which would normally be invisible till the label is opened. Due to the versatility of things that can be done with the product, these label substrates have found widespread usage worldwide. The substrates can even be designed to work as tapes for the final outer corrugated cartons to prevent pilferage.

d) Self destructing paper label

The labels are very similar to destructible labels as mentioned earlier. In this case, the substrate used is of very weak strength paper of low grammage. The paper is also heavily loaded with fillers creating a weak and brittle paper. Labels made from such papers fragment into pieces when attempted to be removed. However, converting it is a very tricky issue when using these substrates due to the lack of strength. The papers are very difficult to source since most of the paper mills are trying to develop papers with very high strength.

e) Holographic labels

The labels form a very large and important part of the security label market and are an ideal choice for product authentication. The holographic foil that is an optically variable device is largely made using a polyester film base. The optical interaction of the holographic image and the human eye makes it ideal for brand promotion and security. These products reveal the holographic image when tilted in light. The image so revealed can be customized to the need of the brand owners to make the maximum impact. The hologram production involves development of complex origination process and a lot of innovation to make it difficult for counterfeiters to duplicate. Many holograms are designed such that besides offering brand authentication they also have tamper evident properties. The top polyester layer has a special coating that if the hologram is attempted to be removed, the top layer peels off leaving the hologram behind on the product [Figure 4].
Figure 4
Holographic labels

f) Multi layered labels

The face stock of the labels is laminates of different substrates depending on the requirement of the security label, which can be film to a film or film to paper or other coatings. The layers are designed such that on separation they either exhibit tamper evidence by way of a one layer getting fiber tear or by complete separation and exhibiting a design or message. The various layers are bonded together by adhesive or heat seal coatings depending on the requirement of the design of the label. The segment of substrates can be vast and can be designed to the requirements of the user and offering variants as per the imagination of the designer or producer.

g) Transfer labels

The substrate consists of either polyester or BOPP. The film has a release coat over which the matter is printed and then adhesive coated. Such labels when applied and peeled off, the clear top layer comes off leaving the printed matter behind. This can also be designed such that some printing is subsurface and remains behind and some printed matter is on the top and comes off with the top layer.

h) UV fibers in paper

Here the substrate is paper and the security is built in at the paper mill during the paper making process. UV light sensitive fibers are incorporated into the pulp and evenly distributed in the paper. When labels made from such paper are exposed to UV light, the fibers glow indicating the genuineness of the labels. The volumes required for these substrates have to be large enough to allow the paper mill to produce a batch full of pulp that would eventually be converted into paper for security labels. The color of the fibers can be selected as per the wish or need.

i) Security threads

Thin micronic threads are introduced in the substrates either at the label stock making stage or they are separately built into two layers of paper laminated together. The threads can also be sensitive to UV light which will glow under UV light. e.g., currency notes.

j) Water mark

The mark that can be seen as an image in the paper when held against the light. The mark scan can also be built into the paper at the paper making stage in a paper mill. The volume has to be large enough to justify incorporating the markings in the paper making process. However, some converters do print these with inks where security requirements are not of a very strict nature.

6. Coding, printing and graphics

a) Coding and marking

For a long time, regulatory compliance drove the need for coding and marking on the packaged products starting with best before date. However, with an increasing awareness and greater printing and marking options like ink jet coding, laser coding and electrolytic etching for metal marking on can decide their use to evolve an overall anti-counterfeit feature. These provide the opportunities for online coding with flexibility, programmable options, time saving and low running costs. Depending on the exact requirements one can go for the touch dry contact coding, non contact coding or the permanent laser coding etc.
Traceability and counterfeiting measures can be improved by using a variable data on the labels i.e., to create unique marking of the packages, which can be made cost effective by using digital printing technology for producing on demand short run packed products.

b) Security graphics

Fine line color printing, similar to banknote printing, incorporating a range of overt and covert design elements such as guilloches, line modulation and line emboss. They may be used as background in a discrete zone such as an overprint area, or as complete pack graphics, and can be printed by normal offset lithography or for increased security by intaglio printing. Subtle use of pastel “spot” colors makes the design more difficult to scan and reproduce, and security is further enhanced by the incorporation of a range of covert design elements, such as micro-text and latent images.

7. Holograms

Holograms were used first for promotional purposes during 80's and exhibited a phenomenal growth by 1996. Probably the most familiar overt feature is the “dove” hologram which has been used to protect credit cards for many years. A hologram normally incorporates an image with some illusion of 3-dimensional construction, or of apparent depth and special separation. Holograms and similar optically variable devices (OVD) can be made more effective when incorporated in a tamper evident feature, or as an integral part of the primary pack (e.g., blister foil). They can be incorporated into tear bands in over wrap films, or as threads embedded into paper substrates and hence may be usefully employed on secondary/transport packs. Several processes can be used to incorporate holograms into packaging; flexible, folding cartons or bottles. Methods include pressure sensitive, shrink, or glue applied labels, hot stamping, web transfer and lamination. Essentially selection options for the hologram are the image and media. The right combination of the two components produces a successful anti-counterfeiting marking that meets the desired objective.

a) Image choices

In the form of Parallax, 3-D perception, switching images, animated images, dynamic color effects, micro text, fine line patterns, machine readable image, hidden image readable through special reader.

b) Media or the form of delivery

The choices available are tamper evident, frangible, paper labels, induction wads, shrink sleeves, hot stamping foils, aluminum foils, PVC films, hologram tape/thread.

c) Optically variable devices

Optically variable devices (OVDs) also include a wide range of alternative devices, similar to holograms, but often without any 3D component. Generally, they involve image flips or transitions, often including color transformations or monochromatic contrasts. Like holograms, they are generally made-up of a transparent film which serves as the image carrier, plus a reflective backing layer which is normally a very thin layer of aluminum. Other metals such as copper may be used to give a characteristic hue for specialist security applications. Extra security may be added by the process of partial de-metallization, whereby some of the reflective layer is chemically removed to give an intricate outline to the image, as can be seen on many banknotes. Alternatively, the reflective layer can be so thin as to be transparent, resulting in a clear film with more of a ghost reflective image visible under certain angles of viewing and illumination. DOVID's (differentially optically variable image devices) that cannot be copied by electronic means are being used in decorative packaging and brand enhancement with security. DOVID's are generated through micro embossing, dot matrix mastering, photo resist interference, lithography, electron beam lithography and classical holography.

d) Color shifting security inks and films

These can show positive changes in color according to the angle viewing angle, and can be effective either as an overt graphic element or by incorporation in a security seal. Color shifting pigments are finely ground metallic laminates which need to be laid down in a thick opaque film to achieve the optical effect, and are therefore better suited to printing techniques such as gravure and screen printing rather than lithographic printing. Their security value lies in the specificity and dynamics of the color change (e.g., from blue to gold), combined with the difficulty and expense involved in manufacture. They are only available from a limited number of pigment suppliers, via a few specialist ink manufacturers. Positive authentication may involve forensic (microscopic) examination and embedded taggants. Color shifting films have been used for security applications, involving multi-layer deposition of thin films to build up a structure with unique diffractive properties, and vibrant color transitions. They can be applied as security seals or tamper evident labels.

e) Sequential product numbering

Unique sequential numbering of each pack or label in a batch can make counterfeits easier to detect in the supply chain. If printed visibly, it provides a semi-overt means of authentication by reference to a secure database, because duplicates or invalid numbers will be rejected. The main disadvantages of sequential numbering are that the sequence is predictable and easily replicated, and end users require some means of access to the database. The more secure option is serialization by means of a pseudo-random non-repeating sequence, and is discussed in the track and trace section.

f) On-product marking

On-product marking technologies allow for special images or codes to be placed on conventional oral dosage forms. The overt technologies can be difficult to replicate and offer a security technology at the pill level. The added layer of security is effective even when products are separated from the original package.

g) Invisible printing

Using special inks, invisible markings can be printed on almost any substrate, and which only appear under certain conditions, such as via UV or IR illumination. They can be formulated to show different colors with illumination at different wavelengths.

h) Embedded image

An invisible image can be embedded within the pack graphics which can only be viewed using a special filter, and cannot be reproduced by normal scanning means. The effects can be quite dramatic, and yet well hidden.

i) Digital watermarks

Invisible data can be digitally encoded within graphics elements and verified by means of a reader and special software. The data can be captured using webcam, mobile phone or other scanning equipment, but the digital information is not visible to the human eye, and attempts to replicate it will be detected by virtue of the degradation of the embedded data.

j) Hidden marks and printing

Special marks and print may be applied in such a way that escapes attention and is not easy to copy. Their effectiveness relies on a combination of secrecy and subtlety.

k) Anti-copy or Anti-scan design

Fine line background patterns appear as uniform tones, but when scanned or copied reveal a latent image which was not previously visible. Commonly used on secure documents to prevent photocopying, they may be applied to product packaging as a background tint.

l) Laser coding

The application of batch variable details by lasers coding requires special and expensive equipment, and results in recognizable artifacts which may be difficult to simulate. Laser codes can be applied to cartons and labels, and plastic and metal components.

8. Forensic markers

There is a wide range of high-technology solutions which require laboratory testing or dedicated field test kits to scientifically prove authenticity. These are strictly a sub-set of covert technologies, but the difference lies in the scientific methodology required for authentication.

a) Chemical taggants

Trace chemicals which can only be detected by highly specific reagent systems, but not normally detectable by conventional analysis.

b) Biological taggants

A biological marker can be incorporated at extremely low levels (parts per million or lower) in product formulations or coatings, or invisibly applied to packaging components. At such low levels they are undetectable by normal analytical methods, and require highly specific “lock and key” reagent kits to authenticate.

c) DNA taggants

Highly specific DNA “lock and key” reagent systems can be applied to packaging by a variety of printing methods. They require a “mirror image” recombinant strand to effect the pairing, and this reaction is detectable by a dedicated device. Security is further assured by hiding the marker and reagent pair in a matrix of random DNA strands, but the test is tuned to work only with one recombinant pair.

d) Isotope ratios

Naturally occurring isotopes are highly characteristic of the source compound, and accurately be determined by laser fluorescence or magnetic resonance techniques. They can provide a “fingerprint” of one or more of the product constituents, or alternatively a specific marker added with its own unique signature. Detection requires highly specialist laboratory equipment.

e) Micro-taggants

Micro-taggants are microscopic particles containing coded information to uniquely identify each variant by examination under a microscope. It may take the form of alphanumeric data depicted on small flakes or threads, or fragments of multicolored multilayered laminates with a signature color combination. These can be embedded into adhesives, or directly applied to packaging components as spots or threads.

f) Nano-Printing

The technologies allow microscopic application onto individual tablets. UV inks allow invisible printing onto any substrate including glass vials and ampoules and provide an excellent security.

9. Mass encoding/trace and track technologies

These involve assigning a unique identity to each stock unit during manufacture, which then remains with it through the supply chain until its consumption. The identity will normally include details of the product name and strength, and the lot number and expiry date although in principle it may simply take the form of a unique pack coding which enables access to the same information held on a secure database. The latter solution overcomes some of the concerns about privacy where the encoded data can be read at a distance by radio equipment.
In itself the track and trace label may not be immune to copying or falsification, but its security is greatly enhanced by the inclusion of unique and apparently random serialization, or non-sequential numbering, ideally at individual item level. If the serialization was sequential, then the level of security would be very low as the sequence is predictable, whereas “random” serialization using a highly secure algorithm or method of encryption overcomes this. Individual packs may still be copied, but the database will identify duplicates or invalid serials, as well as those which have been cancelled or expired, or which appear in the wrong market, or with invalid product details.
Individual products are encoded in an overt manner either through a barcode or a human readable form. Coding therefore becomes the essence in design process. Encoded products need the support of software solutions that permit product tracking through the various nodes in the LSCM operations. Options adopted for encoding are:

a) Barcodes

Barcode is a series of parallel, adjacent bars and spaces used to encode the small string of data. 2-D codes are also available now with possibility to encode large amount of information that makes it an option for anti-counterfeiting. Bar-coding when used with GS-1 standards, permit universal and unique identification of goods, services, assets etc., A bar code reader (scanner) decodes the bar code using intensity of the light reflected. While package printing gives emphasis to product appeal and acceptance by the consumer, barcodes captures the specific information that may contain information related to track and trace traceability, inventory management, security, identification etc., Bar-coding provides the means for automatic data capture of information. When used with international numbering standards, it permits universal and unique identification and security of packaged products. Barcoding works essentially with the optically scanning devices e.g., for the UPC bar code scanners use a helium neon (red) laser emitting at 660 nanometers to determine the contrast between the reflected light from the dark bars and light spaces. For their use as a system they also need the decoders, software's for coding. Universally GS-1 barcodes provide an access that could operate with countries/users who are the members of GS-1. However, due to some specific reason many retail chains use their proprietary codes. Use of barcodes as anti counterfeit option is attempted, especially with the possibilities to go for 2-D codes [Figure 5].
Figure 5
2-D barcode

b) Digital mass serialization

The technology includes the generation of a random, pseudo random code in a sequential manner by the technology provider entered into their or the customers data base for later verification. These codes are provided to customers who in turn can apply them in different ways. These codes can be printed on the labels and then affixed on the product or can be used in a covert way on a pack. The authentication process involves matching the unique code on a product to those stored in the data base. If the code is present in the data base, then the then the product is authentic. This technology needs to be integrated with proper protocols and SOP's for its success with security features to its data base since it could be the weakest link in the technology.

c) Digital mass encryption

In all respects it is similar to the digital mass serialization (DMS) except for the way code is generated. In this process encrypted codes (defined) are produced by a cryptographic algorithm. The codes themselves do not carry or contain any product or logistical information. There is no need for maintaining a data base.

d) Auto identification systems

Smart packaging or auto identification systems are defined as small inexpensive label or tags that are attached onto primary packaging (e.g., treys, pouches bottles) or often onto secondary packaging (e.g., shipping containers) to facilitate communication through-out the supply chain for safety enhancements. Auto identification systems as per Ustandao are classified as optical character recognition (OCR), barcode system, chip cards, biometric systems and RFID as shown in Figure 6. Data carriers such as barcode labels and RFID tags are used to store and transmit data. Packaging indicators such as time temperature indicators, gas indicators, biosensors are used to monitor the external environment and whenever appropriate issue warnings.
Figure 6
Auto identification of tags and barcodes with scanners, readers and phone

Plasma Impulse Chemical Vapor Deposition

Plasma impulse chemical vapor deposition (PICVD) was developed by Schott more than 10 years ago. It was the first CVD - based coating technology for the mass production of optical coatings on glass components (cold light mirrors, infrared reflective coatings and others). During the last few years, a modified PICVD-process for the deposition of three different functional coatings on plastics has been developed. The functions- anti-reflective, anti-scratch and easy-to-clean layers- are provided by only one technology-PICVD. This is a major progress compared for instance to the standard production line of polymer based eyeglass lenses, which uses a PVD process for anti-reflective coating, dip coating for anti-scratch and plasma polymerization for easy-to-clean coatings. Moreover, the development was extended to different kinds of plastics including optical polymers like polymethylmethacrylate (PMMA) and polycarbonate (PC). The PICVD coating technologies were not capable of depositing durable functional coatings on PMMA with a sustained adhesion to the substrate. A completely new layer system on PMMA with an adapted adhesive layer has been developed for these coatings. Durability has been proven by passing different types of functionality tests like tape test, grid test, climate tests or temperature shock tests.[7]

Materials can be Coated Using Plasma Impulse Chemical Vapor Deposition

Although developed 20 years ago by Schott Glass, PICVD has been very successful in coating high volume glass products, such as pharmaceutical vials, ampoules, syringes. To expand the application areas of PICVD) into plastics Schott HiCotec was set up as a new division. Very quickly it succeeded in modifying the original PICVD process and applying bonded homogeneous coatings - in particular glass-like SiO2 and TiO2 oxide coatings to a broad range of plastics (e.g., PET, PMMA, PC, COC, PP and HDPE). The result is that plastic can now have all the positive properties of glass. In the case of plastic lenses and display covers it is now possible to produce anti-scratch and antireflective coatings, while in the case of plastics packaging, a PICVD coating creates a barrier against the passage of gas oxygen can no longer get in, and released carbon dioxide cannot get out. Consequently, the contents have a longer shelf life with no effect on their taste.[8]

Prefilled Syringes

The use of prefilled syringes is a modern way to apply parenteral drugs. With the achievements in science and technology in the past twenty years an increasing number of injectables apply prefilled syringes. The benefits compared with vial-disposable syringe concepts are obviously convenience and ease of handling, as well as advantages in safety and a reduction of drug overfill.
The currently existing market of prefilled syringes is in the range of US$1-2 billion. The growth rate is to be expected to remain at a high level of more than 10% annually.
In the future, the pharmaceutical and biotech industries will ask for prefillable drug delivery systems for valuable potent drugs. Particularly, for biologicals the parenteral application will remain the most important route of application. The worldwide prefilled market is estimated to be one billion units.[9]
Prefilled syringes in the US market have been growing at a rate of 20% per year for at least five years. Studies indicate that the majority of healthcare professionals are demanding the convenience and safety that prefilled syringes provide.[10]
The primary driving factors behind the growth of prefilled syringes includes:
  1. Ease of administration; more convenient for healthcare professionals and end users; easier for home use; easier in emergency situations.
  2. Reduction of medication errors, misidentification; better dose accuracy.
  3. Increased assurance of sterility.
  4. Better use of controlled drugs such as narcotics.
  5. Lower injection costs- less preparation, fewer materials, easy storage and disposal.
  6. Elimination of vial overfills for products transferred to syringes for direct injection or addition to primary diluents.
  7. Removal of preservatives (i.e., thimerosal) from vaccine formulations.
  8. Product differentiation.
Today, prefills can be introduced at any point during a product's lifecycle to make it more desirable. Switching from vials to prefilled syringes, syringes to a nasal spray or a self injection system, prefills can work easily for products in development and those already on the market. At the same time, drug delivery systems must evolve and adapt to meet tomorrow's demands.
BD Medical-Pharmaceutical Systems markets a broad range of customizable, prefilled solutions for parental drug delivery such as BD Hypak Physiolis™ glass prefilled syringe, BD Accuspray™, BD Sterifill TSCF™, BD Preventis™ [Figure 7].[11]
Figure 7
BD Hypak PhysiolisTM glass prefilled syringe (reproduced with permission from BD)

Safety Ampoule Breaker

Ampoules are small glass vessels in which liquids for injections are hermetically sealed. They are opened by snapping off the glass top at the neck. The scoring at the neck does not always break where it is intended. This is due to the glass re-melding to some degree at the score line. When the cap is snapped off, glass chips can fly off and a jagged or sharp edge can cut the hands of the healthcare worker. Safer products exist removes the risk of broken glass cuts when breaking off the glass top.
SafeBreaK™ is a safety ampoule breaker [Figure 8] and it avoids dangerous glass filing required during breaking the ampoule. No gauze pads necessary to protect hands. SafeBreaK™ prevents cross contamination.
Figure 8
SafeBreaK™ for breaking pre-scored glass ampoules
Snapit® invented by a Registered Nurse in Rockhampton, QLD, Australia [Figure 9]. Most people who work with ampoules have suffered an injury from breaking an ampoule. Furthermore, the very sharp edge on both the ampoule and the ampoule lid when the neck of an ampoule is snapped off can cause serious cuts. Snapit® reduces the risk of sustaining a sharps injury by keeping hands out of harms away.[12]
Figure 9
Snapit® for open the ampoule (reproduced with permission from Quicksmart)

Snap Off Ampoules

Ampoules are small glass vessels in which liquids for injections are hermetically sealed. A typical pharmaceutical ampoule has a narrow neck between a cylindrical body and a conical tip.
Ampoule is a small, hermetically sealed glass or plastic container, e.g., one containing medication for parenteral administration. Snap off ampoule enables to break a piece from a whole ampoule.
Hisafe™ ampoules are manufactured with pre-fragilized systems like SafeCut™ OPC ampoules or SafeBreaK™ color ampoules for easy opening by doctors without cutter or filling. SafeCut™ ampoules open safely by using a predetermined breaking point to give a clean cut. SafeBreak™ ampoules come with color ring on its constriction which is used to open the ampoules easily by hand.[13]

Two-In-One Prefilled Vials

The innovative tamper-evident design of new EZ Fusion two-in-one prefilled vials enables consumers to easily determine authenticity of the product. Two-in-one prefilled vial consists of top and bottom chambers made of polypropylene, an insulating spacer, a stopper and tin cap [Figure 10]. Two-in-one vials enables consumers to easily determine authenticity of the product. There is less chance of contamination, and it provides a cost-effective solution versus traditional glass vials.
Figure 10
Two-in-one prefilled vials
Two-in-one vial is a multi-chamber dispenser, which provides a closure solution for filling and separately packing the medication and water for injection, or for the compound injection packaging in a sterile vial. The mixture forms with a simple twist after removing the safety ring and flip-flopping the insulation spacer, then gently shaking the vial prior to usage

Unit Dose Vials

A unit dose is the amount of a medication administered to a patient in a single dose. Unit-dose packaging is the packaging of a single dose in a non reusable container. It is increasingly used in hospitals, nursing homes, etc., Medications in unit-dose packaging are easily identifiable and can be returned to the pharmacy if the medication is discontinued.[15]
Twist-Tip™ unit-dose vial incorporates a plastic squeeze-bulb with an integral twist-off tab. Once opened, the vial's contents can be dispensed through the opening by squeezing or pouring.[16]
Twist-Tip™ units are manufactured and filled by modified blow-ill-seal technology [Figure 11].
Figure 11
Figure 11
Twist-Tip™ unit-dose vials (reproduced with permission from Unicep)
These unit dose vials are used in medical devices (in vitro diagnostics: buffers, reagents), oral health care (whitening gels, tooth conditioners, disinfectants, topical anesthetic, dental restorative materials, pharmaceuticals, ultrasonic cleanser concentrate), personal care products and cosmetics (shampoo, conditioner, lotions, skin creams) and veterinary (medicines, topical applications)

Child-Resistant Packaging

Child-resistant packaging (CRP) or C-R packaging is special packaging used to reduce the risk of children ingesting dangerous items. The CRP containers defy penetration by children but can be opened by adults. This is often accomplished by the use of a special safety cap with locking mechanism.[18]
The U.S. Consumer Product Safety Commission has stated in a press release that “There is no such thing as child-proof packaging. So you should not think of packaging as your primary line of defense. Rather, you should think of packaging, even child-resistant packaging, as your last line of defense.”
It is required by regulation for prescription drugs, over-the-counter medications, pesticides, and household chemicals. In some jurisdictions, unit packaging such as blister packs is also regulated for child safety.
In developed countries like UK, it has been made compulsory to pack drugs like Aspirin, Paracetamol, Elemental iron, Contraceptives and many other drugs to be packed in CRP.

Future of Pharmaceutical Packaging Technology

A changing pharmaceutical industry

Changes in pharmaceutical industry research and manufacturing technologies have driven significant developments in packaging and delivery systems. An increase in the number of large-molecule, biopharmaceutical drugs in development pipelines has led to an increase in the need for injectable packaging and administration systems. The old glass and elastomer closure systems may not provide the effective barrier properties needed for high-value, life saving therapies. Component manufacturers have responded with new materials and technologies that ensure extended drug-product shelf-life. Many new biotechnology-derived drug therapies are unstable in liquid form and therefore are introduced as lyophilized or dry powder dosage forms. Lyophilized drugs need special stoppers for optimal performance in lyophilization chambers. The stoppers must solve the problem of the stopper sticking to the lyophilization shelf after the cycle is completed. In addition, lyophilized drugs typically are reconstituted at the point of care, thus requiring patient-friendly administration systems.

The increase in self-administered therapies

Decades ago, healthcare revolved around hospital care. Today, healthcare often revolves around the home - a situation that has largely resulted from cost constraints and the introduction of maintenance-type drugs for treating chronic conditions such as arthritis, cancer, multiple sclerosis, and other diseases that require frequent medication. Many of these maintenance therapies are delivered by injection, spurring a need for patient-friendly administration systems. These systems must ensure the potency of the drug, be tamper-evident, help deter counterfeiting, promote compliance with a dosing regimen, ensure dosing accuracy, and be as safe, easy to use and painless as possible.
An outgrowth of these changes is the move from the typical vial and disposable syringe to the prefillable syringe. With prefillables, dosing accuracy is ensured but they present some challenges for the industry. A pharmaceutical company needs a prefillable system that protects the integrity of the packaged drug product over time and will function as represented over the full shelf life of the drug product. The response from component manufactures was to develop syringe plungers with barrier films that minimize the interaction between the packaged drug and the components. At the same time, the industry has developed elastomers for molded plungers that maintain functional properties such as seal integrity, and break-loose and extrusion forces.
When self-administered drugs are in lyophilized or dry powder form, manufacturers must find methods or packaging systems that help prevent accidental needle stick injuries, inaccurate dosing, and drug spray-back. Manufacturers familiar with the drug administration process must provide delivery systems that simplify drug reconstitution, especially for non-professional caregivers.

What's next?

Packaging and delivery systems as a differentiator for drug products will continue to become more important, especially in crowded therapeutic areas and for solving industry-wide problems such as drug-product counterfeiting. The market today is receptive to packaging systems that can provide track-and-trace capabilities and product authentication throughout the supply chain. Pharmaceutical seals are an ideal platform for these technologies. The wider use of technologies such as RFID tags embedded in the plastic button affixed to the seal, or ultraviolet inks applied to the seal, providing item-level security may be seen. The drive for cleanliness and purity will no doubt continue into the foreseeable future. With advances in material science, we can expect cleaner elastomeric formulations by utilizing BFS technology for manufacturing primary packaging and delivery-system components e.g., Respules™, Twist Tip™. The coatings with near-total barrier properties e.g., PICVD coatings may have a potential market.
Although predicting the future is problematic, but one prediction with confidence can be made: as pharmaceutical research continues to develop advanced, life-saving therapies, the systems used to package and administer those therapies will keep pace through advances in material science and innovative design.

Conclusion

In the era of globalization, it would be a challenge for the packaging industry, as the years ahead would witness the opening of the global channels, and to match the international standards and quality, it is necessary that packaging industry upgrades more in research to have a holistic approach to packaging that would go beyond functional aspect of packaging. Presently, very few pharmaceutical industries spend time and money on R and D in packaging. The conventional packages available do not serve the purpose of providing protection against counterfeiting and quality, and the industry seems to be sluggish in adopting the technical advances in the packaging, probably on account of the prohibitive cost factor. As packaging industry is directly or indirectly involved in the drug manufacturing process, it becomes ethically mandatory to understand and incorporate scientific methods in packaging. The pharmaceutical packaging trends are on the verge of innovative rapid growth provided the needs of the product, its security, cost and patient convenience is taken into consideration to build brand identity.

Footnotes

Source of Support: Nil
Conflict of Interest: None declared.

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