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///Strategy

///Literature search


Upon request following literature search can be availed:

  • Background information from subject encyclopedia or a handbook.
  • Pubmed / medline data base search.
  • International Pharmaceutical Abstracts Database.
  • Formal reports of Scientific and Clinical findings from standard journals of repute pertaining to Pharmaceutics, Pharmaceutical Technology, Drug Delivery, Biotechnology, Medicinal Chemistry, Natural Products and Trends in Pharmacology.
  • Economic evaluations of healthcare interventions.
  • Updates on Pharmaceutical substances and Dosage forms, excipients and Delivery, OTC Drugs, Combination Products, Drugs currently available.
  • More relevant information to practising Pharmacists.
  • Information of prescription drugs, dosing information, pharmacokinetics, cautions and clinical applications. Information on some investigational and non-prescription drugs may also be searched including herbal medicines.
  • Summary on drug formulations, patents and exclusivity information.
  • Information on parenteral drug stability and compatibility and on parenteral nutrition.
  • Information related to prescription and non-prescription products, product suppliers, route of administration strength and quantity, average wholesale price and direct price.
  • Information on compounded preparations to meet the needs of individual patients.
  • Information related to veterinary products and paediatric drug formulations.
  • Source, chemical composition, pharmacology, biological activity, uses and commercial preparations of natural ingredients.
  • Information on Alternative and complementary medicine or therapies which include Foods, Herbs and supplements’ comparative effectiveness.
  • Genomics and proteomics.
  • Information about drug interactions,side effects and adverse drug reactions,food-medication interactions, drug induced diseases, prevention, detection and management.
  • Information regarding pharmaco-genetics.
  • Information related to innovations in product and process development and manufacturing methodology for pharmaceutical products.

///Pre-formulation studies


It is a combined study which includes physicochemical properties of a new drug candidate that could affect the drug performance and the development of a dosage form. This may provide important insight for formulation design and development. The following parameters will be studied:

  • Drug Solubility:- intrinsic solubility, pKa, Partition Coefficient.
  • Rate of Dissolution.
  • Stability studies.

Basic knowledge can be gained from literature search about

  • Properties Of Drug
  • Potency Of Drug
  • Potency Relative to Competitive Products and the Dosage Form.
  • Search Regarding Stability and Date about Its Degradation.
  • Proposed Route Of Drug Administration
  • Formulation Approaches
  • Bioavailability And Pharmacokinetics Of Chemically Related Drugs.
  • Approaches Towards Molecular Modifications.
  • Solid State Compatibility.
  • Thermal Analysis.
  • Absorbance Spectra.
  • Physicochemical Properties.
  • Other Studies Such As Plasma Protein Binding, Ionization Constant.
  • Hygroscopy
  • Crystallanity And Polymorphism.
  • Particle Characterization.
  • Powder Flow Properties
  • Compression properties
  • Solution Stability.
  • Organoleptic properties.

///Physiochemical characterization


It is a part of pre-formulation study but we emphasize on physico-chemical characterization of drugs and excipients and thus predict the formulation design and come to a solution

///Appropriate Excipient selection


Appropriate excipients selection: Liquid dosage forms (oral)(a) Solutions (b) Suspension (c) Elixirs (d) Concentrates. -Better compliance in case of pediatric and geriatric patients. - No dissolution time -Faster absorption through stomach/intestine - Achievement of peak plasma rapidly. Various excipients employed in theseformulation are: vehicles, solubilizers, viscosity builders, preservatives, sweetness, colors and flavors, antioxidants. Challenges such as stability of drug solubility of drug at required level and an acceptable taste can be achieved with proper and judicious use of these excipients. Drugs physicochemical characterization such as solubility, pH stability, pKa values of reactive functional groups is essential in order to choose the proper excipients.

Aqueous: water, hydro-alcoholic, polyhydric alcohols, buffers. Oily: Vegetable oils, mineral oils, organic oily base or emulsified bases.

Solubilizers: Wetting agents, and surfactants, tweens, spans, poloxamers.

pH modifiers: buffering agents

Suspending agents and viscosity modifiers: sodium alginate, methyl cellulose, HPMC, Na-CMC, MCC, tragacanth, xanthum gums, bentonite, guar gum, colloidal silicone dioxide.

Preservatives: Phenol, chloro-cresol, alkyl esters of p-hydroxy benzoic acid, boric acid, sorbic acid and their respective salts, chlorobutanol, benzyl alcohol, beta-phenyl ethyl alcohol.

Stabilizers: alpha-tocopherol, acetate, ascorbic acid, BHT, monothioglycerol, sodium bisulfite, sodium sulfite, ascorbyl palmitate, cysteine, sodium thiosulfate, BHA, propyl gallate, sodium meta-bisufite, thiourea.

Excipients selection in solid oral dosage form

Excipients are considered as indispensable components of drug products. Mostly they remain in greater proportion in comparison to active pharmaceutical ingradien, as it forms the bulk of the formulation.
Excipients selection generally focused on the following desirable characteristics: Functionality, material consistency, regulatory acceptance cost, availability and sources. Material properties such as micomeritics, chemical, thermal, rheological, mechanical, etc. also play an important role in development of drug formulation.
Other factors such as physico-chemical properties, stability and compatibility, pharmacokinetic attributes, permeation characteristics, absorption behaviors,, drug delivery, intellectual property issues also matter while selecting an excipients.
The quality by design excipients help in studying excipients normal behaviours and their impact on the processes related with formulation development. Excipients stability test allows a formulator to determine drug-excipient interaction 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. Excipients selection also depends on the route of administration.
Excipients used in solid oral dosage forms: Diluent, binders, adhesive, lubricant, glidant, disintegrants, super disintegrants, coloring agents, flavors, sweeteners,, sorbents, wetting materials, plasticizer.
Excipients are also used in aerosol formulation are known as propellant. Excipients used in semi-solid dosage forms are structure forming excipients, preservatives, antioxidants, solubilizers, gelling agents, emollients, suppository bases.
Therefore it may be concluded that excipients are indispensable part of the drug products, must be evaluated for their expected performance, safety and stability. Excipients may interact with the drug , with other excipients and also with packaging material which render them harmful. Therefore their safety and stability are tested by subjecting them to extreme conditions of temperature and humidity. If stability testing data favor the use of excipients in the formulation, they are further tested for assuring safety for humans or animal use. Many new excipients are introduced in the market along with co-processing techniques. Therefore it is important to test their use in various complex delivery systems, and as per IPEC norms new excipients utilised for human use need to be investigated to a thorough safety assessment

///Stability testing and shelf life studies


The manufacturer of dosage forms must assure that the packed product will be stable for it's anticipated shelf life. For this he must accumulate valid data on the drug in it's commercial package. Stability data which include certain parameters (selected) together form the stability profile.

We shall investigate stability of your pharmaceutical product through various stages namely

  1. At pre-formulation stage
  2. at phase-2 clinical studies, the product is usually prepared for commercial use
  3. stability at phase-3 clinical studies, i.e. study of totally ready formulation for final approval
  4. stability studies in final container package along with closure
  5. assigning of an expiration period and date for the product.
Types of stability: to be investigated
  1. Chemical: to check chemical integrity and labeled potency
  2. Physical: to investigate appearance, palatibility, uniformity in content, dissolution and suspendibility
  3. Microbiological: sterility check. Presence of antimicrobial agents, if there any
The following information includes a variety of stability investigations on dosage forms as per FDA & ICH guidelines.
  1. Product storage requirements need to be established
  2. Submission of stability information for new drugs, biologics, new drug application and biological product license application.
  3. Preparation of experimental design, data analysis and documentation needed to meet regulatory requirements.
  4. Assessing the intrinsic photostability characteristics of new drug substances and drug products.
  5. Physical stability in case of tablets such as size, shape, weight, colour under normal handling and storage conditions throughout their shelf-life. In-vitro availability of active ingredient during storage. * Tablet hardness and friability test. * Uniformity of weight, order, texture, drug and moisture content, humidity effects.
  6. Stability study related to hard gelatin capsules, suspension, solution, emulsions, ointments, transdermal patches, metered dose inhalers
  7. Incompatibility studies include physicochemical stability of drug at the pre-formulation stage of development, binary mixture investigations
  8. Prediction of shelf-life of the drug product and temperature effects on product.

/// Analysis of Dosage Forms


Analytical Testing is an important aspect rather more important than preparing a formulation. The design should fulfill the outcome of a product. A medicinal product in order to be released for clinical or commercial use and specification should b as per the compendia to ensure quality and efficacy of the medicinal product.

Since a pharmaceutical manufacturer is responsible for assuring the quality, identity, purity and strength of each batch of drug product manufactured, he has to ensure that batch conforms to specification when tested to the listed analytical methods, shall meet the acceptance criteria which in other words are known as quality standards.

Following tests may be performed: general quality attributes and product performance, for instance drug assay, viscosity microbial limits if desired by the manufacturer.

Universal tests of drug products, such as description, identification, assay and tests for presence of impurities may also be conducted. Analytical tests on sophisticated instruments like FTIR, UV, COMPATIBILITY WITH EXCIPIENTS, IMPURITIES, DEGRADATION PRODUCTS, MASS SPECTROSCOPY, HPLC, UHPLC, GC, LCMS ETC.

To determine the strength or content of the API in the dosage form a specific test is carried out which can give results in quantitative terms and if desired can detect chemical changes with respect to time.

ICH Guidelines Q6A defines an impurity in a drug product as any component that is not the API or an additive. They may be process impurities from the new drug substance synthesis, degradation product of API or both. This test may be a purity test and must be stability indicating. This may be performed as assay or can be developed differently for measuring low-level impurities.

The drug product assays can be performed to validate label claim of the product manufacturers.

Assay methods used are validated for SPECIFICITY, LINEARITY RANGE, ACCURACY, PRECISION, and ROBUSTNESS AND SAMPLE AND STANDARD STABILITY.

Product quality and performance tests for drug injection products are listed:
  • Identification
  • Assay
  • Impurities
  • pH
  • Particulate matter
  • Moisture content
  • Content uniformity
  • Endotoxin
  • Sterility
  • Reconstitution Time.
Oral Dosage forms:

Tests can be carried out on different types of oral dosage forms, such as, tablets, capsules, powders, granules, medicated gums, chewable tablets, lozenges, solutions, suspensions generally sold on prescription or as OTC products. Tests on oral tablet prescribes are as follows:
Appearance,
Identification
Assay
Impurities
Content uniformity
Dissolution
Moisture content
Tablet Breakin Force
Friability
Disintegration
X-Ray Diffraction
Microbial content

Micro-organisms presence or absence (specific) Tests on delayed release tablets, extended release tablets may also be carried out as per discretion of the manufacturer and his requirements.

Quality Assurance and Quality Control:

Our pursuit of quality approach is guidance through the application of quality systems including defect prevention and continuous improvement.

Our help shall be to those pharmaceutical manufacturers, both small and medium scale to educate and guide them about current Good Manufacturing Practices (cGMP) for finished dosage forms.

Our guidance will also include in operations like aseptic manufacturing, validation and stability testing as per 21CFR both for QC and QA departments of an industry to serve as the primary contact with regulatory agencies for product acceptance or rejection. SOPs shall be created accordingly. Internal standards should be adopted within the industry to meet quality requirements. Quality monitoring is another major function performed by QA team of the industry, so that standard manufacturing procedures are followed and are carried out by trained operators. This achieves compliance with regulatory bodies. Therefore prior to product failure a deficiency can be detected and necessary corrections are made.

Guidance about quality control begins with sampling and analytical testing of raw materials, investigation of packaging components including labeling. In-process testing such as environmental monitoring may also be guided. Evaluation of product stability may also be conducted. Often in-process action levels will be identified and set so that they will allow timely corrective action before out-of control situation occurs. Our Quality by design approach will identify parameters within which the process will perform satisfactorily.

We as part of quality control team will monitor environmental conditions under which parenteral and ophthalmic products must be produced in a controlled atmosphere. This is created to ensure their sterility. Monitoring and evaluation of environment in which liquids, tablets and capsules are manufactured may also be done which determines an acceptable level of particulates and microbial contaminants and control them to this level; thereby ensuring quality and stability of the final dosage forms.

Controls of packaging component specially which come in direct contact with a product is required. Rigid specifications are prescribed such as compatibility of the product with these materials, storage stability, leachability, and limits for extractives. Final product labeling must be 100% checked to ensure its correctness.

Quality must be developed into products, starting with R&D phases. Quality by Design (described by ICHQ8 (R2) guidance for industry) is of most importance in the development of product and processes. We have established product quality criteria and write detailed specification for dosage form manufactured. We can design facilities for construction of suitable plants to provide stable environment for protecting integrity of products. We may supervise selection of proper equipments. We shall be happy to train your personnel properly so that their job performance is equipped to satisfactory levels. We can carry out training programs for your team.

Document such as those found in the product development phase, those associated with actual manufacturing and testing of individual batches shall be developed in the form of

  • Research & Development reports
  • Technology Transfer reports
  • Non-clinical and Clinical study reports
  • Validation records.

There are unique quality checks on the products obtained in the field of pharmaceutical biotechnology due to complex physical and chemical nature of protein products. Therefore all phases like early R&D, synthesis, product scale-up and commercial manufacture is associated with rigid quality specifications. There is a big difference between biologics and chemical drug products. They may be macromolecules frequently thermo labile, consisting of complex mixtures of proteins with other molecules and lastly are highly susceptible to microbial contamination.

The attributes possessed by them shall be investigated, they are: sterility, absence of pyrogens unwanted organisms by products and degradation by-products. cGMP requirements prevail here also. Their full characterization includes their physical and chemical stability.

///Packaging and Storage


The food, drug and cosmetic act states that having adequate information related to packing materials is mandatory.

Packaging materials may be of any of the following types:

  • Glass
  • High density polyethylene(HDPE) resin
  • Metal

Components of packaging are
ampules, vials, bottles.
Container liners and tube liners.
Closure
  • Screw Caps
  • Stoppers

Closure liners
Stopper over seals
Container inner seals.
Administration ports in large volume parentrals.
Administration accessories and container labels.

Two types if components:
  1. Primary packaging component-is in direct contact with the dosage form
  2. A secondary packaging component is not and will not be in direct contact with the dosage form

A container closure system together contain and protect the dosage form. This is also formed as a packaging system (21 CFR 600.3). This is also refers to associate components such as dosing caps, droppers and spoons and external packaging systems such as cartons and shrink wrap.

Quality of the above mentioned articles refers to physical, chemical, microbiological, biological, bioavailability and stability attributes that a drug product should maintain if it is to be deemed suitable for therapeutic or diagnostic use. As per cGMP, CPSC and USP requirements on containers and closures (21 CFR,210,211) Degree of concern associated with the route of administration is as per the following

Highest High Medium Low
Inhalation Sterile powders
Aerosols powders for injection
Solution Inhalation Inhalation powders
Injections
Injectable suspensions
High Ophthalmic solutions and suspension
Transdermal ointments and patches
Nasal aerosols and sprays
Low Topical solution Topical powders and oral powders Oral tablets and oral hard and soft gelatin capsules
Topical and sublingual aerosols
Oral solutions and suspensions

Following checks may be made for the purpose of investigations of suitability in case of containers:

  • Protection from the exposure to light.
  • Protection form loss of solvent.
  • Protection from exposure to reactive gases.
  • Protection from absorption of water vapor.
  • Protection from microbial contamination.
  • Compatibility-means packaging components do not interact with drug products. Examples include absorption, adsorption or degradation of the active drug substances induced by a chemical entity leached from packaging components, reduction in the concentration of excipients due to above mentioned factors, precipitation, changes in drug product pH, discoloration of either drug product or the packaging components increase in the brittleness of the components.

Therefore any change noted during the stability studies may be due to interaction between the dosage form and a packing component.

Safety: Packaging components should not leach harmful un indesirable amounts of substances to which a patient will be exposed when being treated with the drug product. Following studies need to be undertaken to check the safety (1) Extraction study (2) A toxicological evaluation of extractives (3) Absence of adverse reactions.

Performance (for assembled packaging system) - Functionality and or drug delivery QC involves tests and acceptance criteria, dimensional drawing, performance criteria, consistency monitoring.


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