Pharmaceutical cold chain and novel technological tools: a systematic review

<jats:p>The pharmaceutical cold chain (PCC) deals with specific logistics operational require-ments related to product quality, safety, and regulations that make the supply chain management process complex. Also, the pharma industry market growth increases the awareness, in terms of good's temperature monitoring and controlling, of the storage and transportation processes across the network. This study provides a novel approach to PCC, based on a systematic literature review with an extensive analysis of the main aspects that influence the supply chain processes. The major findings highlight the recently worldwide research progress on the PCC subjects related, the challenges involving the PCC and its associated technological advances based on three attributes (product characteristics, vehicle capabilities, and logistics service provider’s expertise) and, finally, the impact of technologies and its potential utilization to im-prove the decision-making process on integrated cold chain operations.  </jats:p>

section_content: INTRODUCTION [1] [2] [3] [4] [5] Many dosage forms formulated today are complex system containing many other components along with the active pharmaceutical ingredient (API); these compounds are generally added along with the active pharmaceutical ingredients in order to  Protect, support or enhance stability of the formulation:-Most of the times it is observed that the active pharmaceutical ingredient in its pure form does not retain its stability for long which results in its denaturation, or sticking to the container wall thus rendering it unfit, hence in order to stabilize the API excipients are added which aid in maintaining the stability of the product and ensures that API retains its stability for a considerable period of time thus improving the shelf life of dosage formulation.  Bulk up the formulation in case of potent drug for assisting in formulation of an accurate dosage form.  Improve patient acceptance.  Help improve bioavailability of active drug:

-Excipients usually help in improving the bioavailability of the active pharmaceutical ingredient for e. g. In many cases an active substance (such as aspirin) is not absorbed easily by human body in such cases the active ingredient is dissolved in or mixed with an excipient which may either act as solvent or assist in absorption of the drug in human body.  Enhance overall safety and effectiveness of the formulation during its storage and use. These components are generally termed as excipients and according to the international pharmaceutical excipient council, Excipient is defined as "Any substance other than active drug or pro-drug that is included in the manufacturing process or is contained in finished pharmaceutical dosage forms". The US pharmacopoeia-National formulary (USP-NF) categorizes excipients according to the functions they perform in the formulations e. g. Binders, disintegrants etc. Excipients can be classified on the basis of their origin, use in dosage form, and functions they perform as follows 1. Excipient based on their origin 5 Animal source: -Lactose, Gelatin, Stearic acid, Bees wax, Honey, Musk, Lanolin etc. 

Excipient selection 14 :-Excipients can be considered as indispensible component of medicinal products and in most of the formulations they are present in greater proportion with regards to active pharmaceutical ingredient, as it forms the bulk of the formulation it is always necessary to select an excipient which satisfies the ideal properties for a particular excipient. Excipient selection generally focuses on the desirable characteristics of excipients such as functionality, material consistency, regulatory acceptance, cost, availability, and sources. Material properties like micromeritics, chemical thermal rheological, mechanical etc also play an important role in development of drug formulation. Formulators must also consider physicochemical properties, stability and compatibility issue, pharmacokinetic attributes, permeation characteristics, segmental absorption behavior, drug delivery platform, intellectual property issues etc while selecting an excipient for formulation development, this may help in determining the absorption challenges and desired delivery platform for active pharmaceutical ingredients. The concept of quality by design (QbD) helps in understanding excipients normal variability and its potential impact on the processes of formulation development can be achieved. 

Excipient compatibility tests allows us to determine drug excipient interactions which can be either avoided or can be modified to utilize in an efficient manner which helps in minimizing the risk associated with the excipients. Excipient selection also depends on various routes of administrations. Excipient selection must be done on the basis of characteristics an excipient offers. 

The ideal characteristics of an excipient are given as under:-An excipient must be:- Chemically stable  Non reactive  Low equipment and process sensitive  Inert to human body  Non toxic  Acceptable with regards to organoleptic characteristics  Economical  Having efficiency in regards with the intended use. Excipients even though considered inert substance, have the tendency to react with drug components, other excipients, and also the packaging system. Excipients may also contain various impurities which may result in decomposition of the active pharmaceutical ingredients in the formulation thus altering the shelf life of the formulation. In case of NSAID's premature breakdown of enteric coat may cause side effects like gastric bleeding. 

2) Interactions due to adjunct therapy: -Tetracycline antibiotics form complexes with calcium and magnesium ions which are quite common excipients in various formulations which may be administered along with tetracycline as adjunct therapy the complex so formed is not absorbed from the G. I. T. g. Package -Excipient interactions [28] [29] [30] [31] :-Packaging of pharmaceuticals is a vital part of the processing steps of product formulation, hence in pharmaceutical industry its essential that package selected adequately preserves the integrity of products, the selection of package therefore begins with a determination of products physical and chemical characteristics, its protective needs, and its marketing requirements. The package thus selected should be inert in nature, should protect the product from external environmental conditions, etc. 

Usually the packaging material used is glass; plastic, metal, rubber closures etc, these containers and closures react to certain extent with the drug product as well as with the excipient and give deleterious effects thus altering the product stability. Such interactions generally cause loss of product quality. These interactions are listed in the following table no 8:-

section_content: Excipient quality plays a vital role in assuring safety, quality and efficacy of dosage forms. Standardization of excipient usually assures the customers and manufacturers that the excipient quality will meet the international market, therefore the rules for regulation of bulk excipients are stringent and whenever a new excipient is to be introduced it is necessary for the applicant to submit safety and quality data and for an approved excipient the applicant has to provide literature reference data. The various reasons for which excipients must be standardized are:-To assure the customer that the excipients used are safe and will not alter the formulation and cause undesirable effects.  To assure the manufacture that he is using a standard quality material for formulating his dosage form and  To reduce resources to host frequent customer audits and assure excipient GMP audit is conducted against appropriate GMP conformance expectations. The standard chosen as framework for quality management system is ISO 9001. The Iso certification has the advantage of assuring the customers that excipient manufactueres quality management system has been verified independently. GMPpractise for excipients assures product integrity, avoid product contamination etc. IPEC is an international industry association which is formed with the main objective of development and harmonization of international excipient standard and development of newer excipients. It deals with three kinds of stakeholder groups viz; suppliers, users and regulatory authorities. It is necessary to obtain sufficient data about the excipient and the manufacturer or distributer, usually to get such information and information of the excipient in detail the users and customers send questionnaires to the supplier, the questionnaire consists of large amount of queries which becomes very difficult to resolve and address every individual as lot of time and money is wasted during this process, hence in order to minimize this stressful process IPEC has put forward an standardized excipient package that comprises of  Product regulatory database  Site quality overview and  Site and supply chain security overview. This information is useful in responding to the questionnaires and other requests in a simplified and standard process which is very effective in saving time. This information helps both users and suppliers to manage the information in a systematic and efficient manner. 

 Product regulatory database: -this document has been formed with the main objective of providing information about important physical properties, manufacturing and regulatory information specific to excipients to the user which facilitates the use of excipients in drug formulations. The various sections included are  General product information:-this includes information like product identification, product code/name, scope of document, and any other information that is necessary,  Manufacturing, packaging, release and supplier information:-this section describes the information regarding excipient manufacturing site and the information related with it, for e. g. :manufacturing processing, packaging, product release warehousing, laboratory site etc, distribution channels, GMP or GDP compliance statements, equipment information etc.  Physicochemical information:-this section deals with the information related to the physical and chemical characteristics of the product for e. g. :-CAS number, information about the origin of excipients, their synonyms, its morphological characteristics, processes applied during manufacturing, mixed excipient information and the country of its origin if applicable.  Regulatory information:-this section describes the regulatory status of an excipient, it includes information like compendia compliance (e. customer and supplier about the quality of excipient and may also give assurance that this process will continue to provide excipients of good and standard quality. 

Excipient stability testing 33 The main objective behind the compatibility testing is to find out most appropriate Excipients(s) for the particular API in dosage form under consideration and also those Excipients(s) that should be avoided for particular API. Excipients are derived from various sources such as natural and synthetic origins. Natural sources of excipients are usually contaminated with microorganisms and certain impurities that may render the formulation incompatible and cannot be used, thus in order to avoid any incompatibilities in formulation the excipients must be tested for their stability. 

IPEC with an objective to contribute to the development and harmonization of international excipient standards has laid certain guidelines for the stability testing of excipients. These guidelines provide an approach for excipient manufacturer to establish a stability study program for excipients, which will help in defining revalidation intervals or expiration date. The primary purpose of excipient stability study serves the purpose to retain its stability throught the manufacturing process, packaging upto the point at which the package is opened. The stability studies are designed on the basis of following factors like 1) utilization of historical data about a particular excipient and drawing conclusions about excipient stability. 

2) Conducting stability studies using excipients packed in commercial packaging placed in different warehouses where the temperature is monitored. 

3) Conducting studies using conditions and recommendations as in ICHQ 1A (R2):-These guidelines serve the purpose of stability testing which provides the evidence of the quality of drug products under influence of various climatic conditions. Choice of test conditions are based on the analytic effects of climatic conditions in three regions namely Europe, Japan and United states. Following procedures are followed in accordance to the guidelines:-1) Stress testing: -it helps to identify the degradation products within the formulations. Such testing's are carried in single batch where the effect of temperature is tested where the temperature is kept in increments of 10 0 c for e. g. 50 0 c, 60 0 c etc above which accelerated stability testing is performed. Humidity is maintained at around 75% RH or greater for the testing procedure. Photo stability testing forms an integral part of stress testing where the excipients are exposed to conditions as mentioned in ICHQ 1B. 2) Specifications:-specifications to analytical procedures are followed as per the guidelines mentioned in ICHQ 6A [9] and ICHQ 6B, and for degradation products as in ICHQ 3A. 

3) Testing frequency:-for long term storage conditions testing is carried out every three months over first year, every six months over second year, and annually thereafter. For accelerated stability studies testing carried out at 0 month, 3 month, and 6 month. Testing over period of 6 months is generally recommended. 1) Storage conditions:-excipients are tested for the storage conditions for its thermal stability, moisture sensitivity or solvent loss. 

The specifications for storage testing are given as under: (
section_name: Standardization of excipients 32

section_content: In 2007, the IPEC-Americas Safety Committee developed the IPEC New Excipient Safety Evaluation Procedure, which is an independent excipient review procedure. The procedure is intended to reduce costs stemming from unnecessary testing and the uncertainty related to using new excipients, thereby encouraging their use in drug development and boosting innovation in formulating drug products. In this procedure Excipients are evaluated for their safety using various in-vitro assay methods to screen for potential toxicity in this process the undesired toxicity producing material can be eliminated, this program is developed in different tiers of testing, where in first tier the compound is tested for its genotoxicity, cytotoxicity, metabolism and ability of compound to cross the biological membrane. This step may also include development of QSAR studies which can help predict the toxicity of compounds. In later cases the other steps can be followed, for eg testing for immunotoxicity Reviews are expected to last 1 to 3 months, depending on the quantity of information within (or absent from) the dossiers. In most cases, the cost will be based on not more than 50 hours of review time plus administrative overhead. The chairperson or a designee collates the comments of the committee members and drafts a report that is sent to each member for concurrence or further discussion. Once agreement is reached, the final report is sent to the excipient sponsor for review and comment. If the expert committee cannot agree on one or more points in the final report, the sponsor is told of the disagreements and the reasons for them. The sponsor may discuss the final report with the expert committee and request clarifications or explanations. Once everyone is satisfied, the chairperson signs the final report and sends it to the sponsor, who becomes its sole owner. The report will contain, at a minimum: 1. Discussion of chemical and toxicological data and human safety concerns based on intended use of the excipient; 2. Opinions on conformance with data needs according to the CDER Guidance; and 3. Identification of data gaps, if any, and points of reviewer disagreement that were not resolved and the reasons for them.
section_name: Excipient safety evaluation 34

section_content: Procedure provides an excellent method for independently evaluating the safety of new excipients, including co-processed mixtures of existing excipients, physical and chemical modification of existing excipients, higher use levels of existing excipients, and NCEs. The Excipient sponsor can use the NEEC's report to support the use of a new excipient in a drug development approval process. As new excipients emerge, it's important to recognize their potential use in various complex delivery systems, and the IPEC procedure helps do that. 35. 2) Formulation of chlorpromazine with polysorbate 80 and sodium lauryl sulphate decreased membrane permeability of drug. 

Adsorption:-Adsorption of drug by excipient can lead to reduced bioavailability as the drug is not available for dissolution. 

Adsorption of drug on excipient surface can assist in increasing surface area of drug available for dissolution which eventually increases bioavailability. 

Formulation of Indomethacin (NSAID) using kaolin as adsorbent increased its dissolution rate which leads to increase in bioavailability of drug.
section_name: The IPEC New Excipient Safety Evaluation

section_content: Conversion of a chemical into its optical or geometric isomer, having different pharmacological or toxicological activity. (here optically active substance looses its optical activity without change in chemical composition). biological activity of the formulations is hampered as for e. g. biological effect of a drug in dextro form can be less than that in laevo form. 

Adrenaline has optical 15-20 times greater biological activity then D -Adrenaline.
section_name: 3) Racemization

section_content: The polymorphic forms possess higher potential energy with respect to the thermodynamically stable or lowest energy forms. This potential energy is given out during mixing with the solvent, in some cases potential energy of compound is sufficient to exhibit an apparent solubility greater than more stable form which may eventually result into reversion of drug into less soluble form Amorphous forms of sodium and potassium Penicillin-G were unstable to dry heat, whereas crystalline forms were stable for several hours. 3) Leaching.
section_name: 4) Polymerization

section_content: 1) Dyes migrate into parentrals and cause toxic effects. 

2) Release of a constituent from plastic results in contamination. 

3) Leaching of antioxidants from polyolefinic plastics into oleginious containers anti-oxidants like Pentaerythrityl tetrakis (3, 5-di-tertbutyl-4-hydroxyphenyl) propionate (Irganox) and tris (2, 4-di-tertbutylphenyl) phosphate (Igrafos) showed release into oily vehicles which affects content quality.
section_name: Maillard reactions

section_content: Preservatives are sorbed into the containers leading to the loss of preservative activity. 

3) metals 1) corrosion 1) Tin tubes can be corroded by chlorides or acidic conditions. 2)Sodium lauryl suphates are mildly corrosive to steel, copper, brass, bronze, and aluminium

2) reactivity Aluminium reacts with fatty alcohol emulsions to form a white encrustation, unstable for mercury containing compounds.
section_name: 4) sorption

section_content: Antimicrobial preservatives like phenyl mercuric acetate are known to partition into rubber during storage reducing formulation concentration below effective antimicrobial levels 2 Water permeability Permeation of water through closures affects the overall stability of formulation.
section_name: 4) rubber 1) sorption

section_content: Presence of rubber closure extractives in the vial solutions could affect toxicity pyrogeneticity of injectable preparations, interaction with preservatives to cause inactivation or loss of stability and causes physical instability of preparation.
section_name: 3) Leaching

section_content: 1) Ethyl oleate dissolves certain types of rubber and causes others to swell. 2) When Isopropyl myristicate comes in contact with rubber there is drop in viscosity with concomitant swelling and partial dissolution of the rubber.
section_name: 4) dissolution

section_content: Excipients being an indispensible component of medicinal products, must be evaluated for their safety and stability. The various excipent interactions like drug-excipient interactions, excipient-excipient interactions and package-excipient interactions may render the excipient harmful for use in formulation. 

In order to avoid the use of incompatible excipients and to assure that that the excipients are safe and stable for use in the designing of the formulation, various stability testing procedures are carried out where the excipients are subjected to extreme conditions of temperature,humidity etc. if the stability testing data is in favor of the use of excipient in formulation the excipients are further tested for assuring safety, which is the most important feature of any formulation intended to be used in humans or animals. As new excipients emerge, it's important to recognize their potential use in various complex delivery systems, and the IPEC procedure subjects new excipients for potential use in humans to a thorough safety assessment. The safety assurance of excipients helps the formulator to design an effective and safe dosage form with the use of efficient and safe excipients. 

Thus for an excipient to be in a formulation it must be highly stable, safe and efficacious, and above all it must comply with the expected performance in the formulation.
section_name: CONCLUSION