Granulation and its importance in tablet manufacturing process

 

GRANULATION & IT’S IMPORTANCE IN TABLET MANUFACTURING PROCESS

Granulation process is an inevitable step in tablet manufacturing as it improves flow property and compressibility of powder mass intended for compression. Granulation prevents segregation of the constituents of the powder mix.

 Granulation is the process in which primary powder particles are made to adhere to form larger, multi particle entities called granules. Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm, depending on their subsequent use.

Granulation is so important in tablet manufacturing process because it

1. Improve fluidity

2. Degrease segregation of the powder components

3. Degrease dusting

4. Improve compressibility of the material

An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule, and segregation of the ingredients will not occur.

Types of granulation

There are two types of granulation technique

1.Dry granulation   2. Wet Granulation

Dry granulation

In dry granulation the primary powder particles are aggregated under high pressure. There are two main processes. Either a large tablet (known as a ‘slug’) is produced in a heavy-duty tabletting press (a process known as ‘slugging’) or the powder is squeezed between two rollers to produce a sheet of material (‘roller compaction’).

In both cases these intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size fraction. Dry granulation technique is applicable  for drugs which do not compress well after wet granulation, or those which are sensitive to moisture.

Wet granulation

Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry. Water is commonly used for economical and ecological reasons. Its disadvantages as a solvent are that it may adversely affect drug stability, causing hydrolysis of susceptible products, and it needs a longer drying time than do organic solvents. This increases the length of the process and again may affect stability because of the extended exposure to heat. The primary advantage of water is that it is non-flammable, which means that expensive safety precautions such as the use of flameproof equipment need not be taken. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required. In the traditional wet granulation method the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material, which can than be recycled. Variations of this traditional method depend on the equipment used, but the general principle of initial particle aggregation using a liquid remains in all of  the processes.

 Glossary of Terms

Compressibility – Compressibility is the ability of powder to decrease in volume under pressure.

Terminology and Definitions Related to Pharmaceutical Industry/Glossary of pharma related terms/Pharmaceutical Industry - Terms & Definitions

Pharmatreasures  glossary collection is one of the best available collection of pharmaceutical definitions, which covers terms related to production, quality control, quality assurance, regulatory affairs. Hope you all will enjoy and make use of this rare collection.This post is last updated on 8th March 2020.

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A

Accelerated testing: Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.

Acceptance criteria: Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures.

Accuracy: The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found. This is sometimes termed trueness.

Active Ingredient: An Active Pharmaceutical Ingredient (API) is the chemical substance contained in a pharmaceutical dosage form, which is responsible for its therapeutic effect.

Active Substance Master File (ASMF)/Drug Master File (DMF): Is a document containing complete information on an Active Pharmaceutical Ingredient (API) or finished drug dosage form. It is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) and US-Drug Master file (US-DMF) in Europe and United States respectively.

Adverse  Reaction (Adverse Drug Reaction, ADR): An adverse drug reaction is a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function. (WHO, 1972).  An adverse drug reaction, contrary to an adverse event, is characterized by the suspicion of a causal relationship between the medicine and the occurrence, i.e. judged as being at least possibly related to treatment by the reporting or a reviewing health professional.

Aerobic Microorganism: A microorganism that utilizes oxygen as the final electron acceptor during metabolism: a microorganism that will grow primarily in the presence of Oxygen.

Aerosol: Air suspension of solid or liquid particles having a volume median diameter of less than 50 µm. The small size of the droplets or particles allows entry to the body via the respiratory tract and readily contaminates clothing, skin and eyes

Agglomeration: Adherence of particles in to a larger mass due to moisture, static charge or chemical or mechanical binding.

Aggregation: Accumulation or collection of particles in to larger units.

ALCOA: Acronym referring to Attributable, Legible, Contemporaneous, Original and Accurate.

ALCOA +: Acronym referring to Attributable, Legible, Contemporaneous, Original and Accurate ‘plus’ Complete, Consistent, Enduring, and Available.

Amorphous: Solid substances that are not crystals.

Analgesic: A medication that reduces or eliminates pain.

Angle of repose: Angle of repose is the greatest angle form the horizontal that a heap of material will remain stationary.

Analytical Procedure: The analytical procedure refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test. This may include but is not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation, etc.

Anemometer: Anemometer is an instrument used to measure air flow velocity.

Antacid: An agent that counteracts or neutralizes acidity.

Antiemetics: Drugs used to treat nausea & Vomiting.

Anti flatulent: Any agent that reduces intestinal gas.

Antineoplastics: Drugs used to treat cancer.

Antimicrobial Resistance: Antimicrobial resistance corresponds to the emergence and spread of microbes that are resistant to cheap and effective first-choice, or "first-line" antimicrobial drugs. The bacterial infections which contribute most to human disease are also those in which emerging and microbial resistance is most evident: diarrheal diseases, respiratory tract infections, meningitis, sexually transmitted infections, and hospital-acquired infections. Some important examples include penicillin-resistant Streptococcus pneumonia, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, multi-resistant salmonellae, and multi-resistant Mycobacterium tuberculosis. The development of resistance to drugs commonly used to treat malaria is of particular concern, as is the emerging resistance to anti-HIV drugs.

Antipyretic: A medication that reduces body temperature or pain.

Anaerobic Organism: A microorganism that does not utilize oxygen as the final electron acceptor during metabolism:microorganism that will grow only in the absence of Oxygen.

Analyte: Substance for which analysis is being performed.

Annual Product Quality Review (APQR): APQR is overall review of the product manufactured during the whole calendar year , for all the parameters including critical parameters and trend of the batches .

1. ANDA: An application to market a generic drug in the USA. The application does not contain extensive preclinical (pharmacology & toxicology) or clinical data. Instead an ANDA for a typical tablet or capsule relies on therapeutic equivalence to the innovator product (or reference listed product), together with an extensive CMC section.

Aseptic Filling: The part of aseptic processing where a pre sterilized product is filled and / or packed in to sterile containers and closed.

Aseptic Processing: Handling sterile materials in a controlled environment, in which the air supply, facility, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels.

Aseptic Process Simulation: A means for establishing the capability of an aseptic process as performed using a growth medium. Note: Aseptic processing simulations are understood to be synonymous with media fills, process simulations, simulated product fills, broth trials, broth fills etc.

At-rest: Condition where the installation is complete with equipment installed and operating in a manner agreed upon by the customer and supplier, but with no personnel present.

Audit trail: Audit trail means a secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record. For example, the audit trail for a high performance liquid chromatography (HPLC) run should include the user name, date/time of the run, the integration parameters used, and details of a reprocessing, if any. Documentation should include change justification for the reprocessing.

B

BAN Book: The British Approved Names (BAN) book is the official dictionary of drugs names for regulatory use in the UK. The BAN book is published by British Pharmacopoeia publication every 5 years and supplements are published annually.

Bar code: A way of labelling a product with a description and batch information using a series of lines of various thickness that is read by a scanner.

Batch (or Lot): A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits.  In the case of continuous production, a batch may correspond to a defined fraction of the production.  The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.

BET: A toxin that forms an integral part of the cell wall of certain bacteria and is only released upon destruction of the bacterial cell. Endotoxins are less potent and less specific than most exotoxins and do not form toxoids. Also called intracellular toxin.

Binder: An excipient used to increase powder cohesiveness, which increases the bonding strength of the final product. In wet granulation, they help to form agglomerates.

Binding: Difficulty in ejection of tablets from a die after compression. Binding is evident as excessive ejection force, and it can sometimes be heard as a “sqeaking” noise during tableting. In extreme cases binding can result in tablet lamination. Increase in the amount of lubricant (magnesium stearate or talc) is a potential solution, as is proper maintenance and polishing of the dies. If this is not feasible then coated or tapered dies are available that can reduce the friction during ejection.

Bioavailability: A measure of the fraction of a drug that enters the systemic blood circulation after oral administration. The usual measure is the ratio of the AUC of two different formulations of the same drug, corrected for dose.

Bioburden: The level and type (e.g. objectionable or not) of micro-organisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected.

Bioequivalence: A high degree of similarity in the bioavailabilities of two pharmaceutical products (of the same galenic form) from the same molar dose, that are unlikely to produce clinically relevant differences in therapeutic effects, or adverse effects, or both

Biologicals: Products which cannot be tested adequately by chemical means such as vaccines.

Biological Indicator (BI): A population of microorganisms inoculated onto a suitable medium (e.g., solution, container or closure) and placed within appropriate sterilizer load locations to determine the sterilization cycle efficacy of a physical or chemical process. The challenge microorganism is selected based upon its resistance to the given process. Incoming lot D-value and microbiological count define the quality of the BI.

Biopharmaceutical Classification System (BCS): A system of classification of drugs based on their solubility and their permeability through the gut wall. The system was introduced by Professor Gordon Amidon in 1995. A soluble drug is one whose highest dose is soluble in 250ml or less of aqueous media over the pH range 1 to 7,5. A permeable drug is one that is more than 90% absorbed from the human gut. Permeability may be determined using in vitro model systems. The BCS classes are Class 1: high solubility & high permeability. Class 2 = low solubility & high permeability. Class 3 = High solubility & low permeability. Class 4 = low solubility & low permeability.

Biosimilar: Biosimilar is a version of an already registered biological medicine that has a demonstrable similarity in physicochemical, biological and immunological characteristics, efficacy and safety, based on comprehensive comparability studies.

Biowaiver: An exemption from the need to perform a clinical bioequivalence study under certain circumstances. Biowaivers are possible in the USA, in Europe and in Japan, but the requirements for achieving a biowaiver differ in these countries. In the USA and Europe the biowaiver is potentially available for rapidly dissolving formulations of BCS class 1 drugs.

Blending: Process of mixing the ingredients together to form a uniform mixture. Blending in solid dose manufacturing has two objectives; 1) To achieve blend uniformity and 2) to distribute the lubricant.

Blister: A cavity formed in film or foil by heat and or chemical means.

Blister Pack: A package that comprises one or more blisters filled with tablets or capsules and sealed with film or foil lid stock.

Blow Fill Seal (BFS): Blow-fill-seal (BFS) technology is an automated process by which containers are formed, filled, and sealed in a continuous operation. This manufacturing technology includes economies in container closure processing and reduced human intervention and is often used for filling and packaging ophthalmics, respiratory care products, and, less frequently, injectables.

BNF: British National Formulary. This is a list of medicines used in the UK compiled by the British Medical Association and the Royal Pharmaceutical Society.

Boroscope: An instrument used to view unseen places such as internal weld finishes in an enclosed pipe work system.

Body: the lower part of a  two piece capsule. It is slightly smaller in diameter and longer than cap.

Body fold: An imperfection in the capsule body caused by depositing material on it during filling.

Bolar exception (provision): Many countries use this provision of the TRIPS Agreement to advance science and technology. They allow researchers to use a patented invention for research, in order to understand the invention more fully. In addition, some countries allow manufacturers of generic drugs to use the patented invention to obtain marketing approval (for example from public health authorities) without the patent owner’s permission and before the patent protection expires. The generic producers can then market their versions as soon as the patent expires. This provision is sometimes called the “regulatory exception” or “Bolar” provision.

BOM: Bill of Materials - is the term used to describe the raw materials and packaging materials and their quantities needed to manufacture a final product.

Bovine: Originating from cattle, used to describe gelatine made from cattle products.

Bovine Spongiform Encephalopathy: A disease of cattle (often called 'mad cow disease') caused by an agent that is neither a bacterium nor a virus.BSE is a fatal neurodegenerative disease which affects mainly the brain and spinal chord.

Bowie Dick Test: A test which used to detect air leaks and inadequate air removal in pre-vacuum type sterilizers.

Bracketing: The design of a stability schedule such that only samples on the extremes of certain design factors, e.g., strength, package size, are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells). Bracketing can be applied to different container sizes or different fills in the same container closure system.

Brand Name Drug: A brand name drug is a drug marketed under a proprietary,trade mark protected name.

Bronchodilators: Drugs that open up the bronchial tubes within the lungs when the tubes have become narrowed by muscle spasm. Bronchodilators  ease breathing in diseases such as asthma.

Brittleness: The extent to which a material will break without undergoing significant elastic or plastic deformation.

Bubble Point Test: Bubble point is a practical non destructive test used for confirming the integrity of sterilizing membrane filters and filter systems.

Bulk Density: The mass per unit volume of a material under specified conditions of pressure.

Bulk Product : Any product which has completed all processing stages up to, but not including, final packaging.

Bursting strength: Pressure at which a film or sheet (of paper or plastic, for example) will burst. Used as a measure of resistance to rupture, burst strength depends largely on the tensile strength and extensibility of the material.

C

Calibration: The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements.

Cap: The upper part of a two piece capsule. It is slightly larger in diameter and shorter than the body.

CAPA (corrective and preventive action): A systematic approach that includes actions needed to correct (correction), avoid recurrence (corrective action) and eliminate the cause of potential nonconforming product and other quality problems (preventive action).

Caplet: A tablet  shaped like a capsule to ease swallowing.

Capping: A fault in tablet making. In capping the top of the tablet separates from the rest of the tablet. Capping may be apparent as the tablet is ejected from the die, or occur at some subsequent stage in tablet processing, for example during coating or friability testing, or at any other time when the tablet is stressed. Capping is usually explained in terms of air entrapment in a tablet or in terms or stress relaxation during decompression. The cures include increasing the compression dwell time (slowing the machine or adding precompression), decreasing the compaction force applied or increasing the binding within the tablet. Fractures that occur between the tablet cup and the band due to poor particle adhesion, over compression and or insufficient air release during compaction.

Carcinogen: Agent (chemical, physical, or biological) that is capable of increasing the incidence of malignant neoplasms, thus causing cancer.

CBE (CBE & CBE 30 day Supplement): Change-Being-Effected Supplement (CBE) - A submission to an approved application reporting changes that FDA has identified as having moderate potential to adversely affect the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product. A CBE supplement must be received by FDA before or concurrently with distribution of the product made using the change. Change-Being-Effected-in-30-Days Supplement (CBE-30) - A submission to an approved application reporting changes that FDA has identified as having moderate potential to adversely affect the identity, strength, quality, purity, or  potency of a product as they may relate to the safety or effectiveness of the product. A CBE- 30 supplement must be received by FDA at least 30 days before distribution of the product made using the change.

CBER: Center for Biologics Evaluation and Research.

CDER: Center for Drug Evaluation and Research. The Center for Drug Evaluation and Research (CDER) performs an essential public health task by making sure that safe and effective drugs are available to improve the health of people in the United States. As part of the U.S. Food and Drug Administration (FDA), CDER regulates over-the-counter and prescription drugs, including biological therapeutics and generic drugs.

Centralized Authorization Procedure (CAP): A regulatory approval procedure within the European Union (EU). Under the centralized procedure, companies submit a single marketing authorization application to the European Medicines Agency. Once granted by the European Commission, a centralized (or 'Community') marketing authorization is valid in all European Union (EU) and EEA-EFTA states (Iceland, Liechtenstein and Norway).

CEP: CEP stands for Certification of suitability of European Pharmacopoeia monographs. COS (“Certificate of Suitability”) means the same and, even if often used, is not the official acronym.

CGMP: Current Good Manufacturing Practices.

Change Control: Change control is a procedure that ensures changes are implemented in a controlled and coordinated manner. A change control system provides checks and balances in the quality system by tracking, reviewing and approving the changes.

Change Management: A systematic approach to proposing, evaluating, approving, implementing and reviewing changes

Change Over: The process of changing production from one product to another. This often includes clearing the production area of supplies and components, changing size – specific machine parts, and cleaning the production area and equipment to eliminate cross contamination.

Chemistry, manufacturing and controls (CMC): The section of an ANDA or NDA where all the data on synthetic chemistry, impurities, formulation, manufacturing, packaging, specifications, analytical methods and stability are submitted.

Child Resistant Packaging: Child resistant packaging is a special type of packaging used to reduce the risk of children ingesting dangerous items. This is often accomplished by the use of a special safety cap.

Chipping: ‘Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations.

Classified Area: An area in which the environment is of specified  particulate and microbial quality. These areas are monitored  to ensure that microbial articulate qualities are maintained. The four types of classified area’s are as  defined in European Good Manufacturing Practices. Grade A: The local zone for high  risk operations. Grade B: In the case of aseptic preparation and filling, the  Background environment for Grade A areas. Grade C: Clean, controlled, support areas for carrying out less critical stages of manufacturing. Grade D: Clean, controlled, support areas for carrying out less critical stages of manufacturing.

Clastogen: Agent causing chromosome breakage and (or) consequent gain, loss, or rearrangement of pieces of chromosomes.

Clean area (clean room):An area (or room) with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area.

Clean Hold Time: The time from the end of a cleaning process until the equipment is used again.

Clean in place (CIP): A method of cleansing all contaminants from the interior surfaces of process equipment without dissembling it.

Cleaning Validation: A process giving evidence that the cleaning operation can consistently meet predetermined standards.

Climatic zones: The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions. This is based on the concept described by W. Grimm (Drugs Made in Germany, 28:196-202, 1985 and 29:39-47, 1986).

Clinical Trial (Clinical Study): A clinical trial is any systematic study on pharmaceutical products in human subjects, whether in patients or other volunteers, in order to discover or verify the effects of, and/or identify any adverse reaction to, investigational products, and/or to study the absorption, distribution, metabolism and excretion of the products with the object of ascertaining their efficacy and safety. Clinical trials are generally divided into Phases I-IV. It is not possible to draw clear distinctions between these phases, and different opinions about details and methodology do exist. However, the individual phases, based on their purposes as related to the clinical development of pharmaceutical products, can be briefly defined as follows:  Phase I- These are the first trials of a new active ingredient or new formulations in humans, often carried out in healthy volunteers. Their purpose is to make a preliminary evaluation of safety, and an initial pharmacokinetic/ pharmacodynamic profile of the active ingredient. Phase II- The purpose of these therapeutic pilot studies is to determine activity and to assess the short-term safety of the active ingredient in patients suffering from a disease or condition for which it is intended. The trials are preformed in a limited number of subjects and are often, at a later stage, of a comparative (e.g. placebo-controlled) design. This phase is also concerned with the determination of appropriate dose ranges/ regimens and (if possible) the clarification of dose-response relationships in order to provide an optimal background for the design of extensive therapeutic trials. Phase III- This phase involves trials in large (and possibly varied) patient groups for the purpose of determining the short- and long-term safety-efficacy balance of formulation(s) of the active ingredient, and assessing its overall and relative therapeutic value. The pattern and profile of any frequent adverse reactions must be investigated, and special features of the product must be explored (e.g. clinically relevant drug interactions, factors leading to differences in effect, such as age). The trials should preferably be randomized double-blind, but other designs may be acceptable, e.g. long-term safety studies. In general, the conditions under which the trials are conducted should be as close as possible to the normal conditions of use. Phase IV- In this phase studies are performed after the pharmaceutical product has been marketed. They are based on the product characteristics on which the marketing authorization was granted and normally take the form of post-marketing surveillance, and assessment of therapeutic value or treatment strategies. Although methods may differ, the same scientific and ethical standards should apply to Phase IV studies as are applied in premarketing studies. After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc., are normally regarded as trials of new pharmaceutical products.

Closed Joined Length: The length of a hard elatine capsule after it has been filled and completely closed by a capsule filling machine. Most capsules have a lock that makes than difficult to open after they have been closed to this length.

Coating: The process of applying a coat to a tablet or other dosage form. Coatings are applied for a number of reasons from aesthetic (colour, identification and ease of handling or swallowing) to highly functional (delayed and modified release). Aesthetic coatings are typically based on low viscosity grades of HPMC or PVA, whereas functional coatings are typically based on methacrylic acid copolymers or cellulose derivatives such as ethylcellulose.

Code of federal regulations (CFR): CFR is the codification of the general and permanent rules and regulations.CFR can be called as administrative law and is published by federal government of united states.

Cold Forming: Cold forming is a technique that does not involve any application of heat. Unlike the thermoforming method that uses clear PVC, this technique uses thin sheets of laminate film that contain aluminum. In order to create packaging out of these sheets, a blister machine will typically use a stamp to force it into a form. The aluminum-based film will tend to stretch and retain the shape after the stamp has been removed. This type of blister pack is typically used to contain pharmaceuticals, since the aluminum-based film tends to prevent moisture from entering the packaging.

Colony Forming unit (CFU): A microbiological term which describes the formation of a single macroscopic colony after introduction of one (or more)  microorganism(s) to microbiological growth media. One colony forming unit is expressed as 1 CFU.

Conductivity: Conductivity is the ability of a material to pass an electric current. Since the charge on ions in solution facilitates the conductance of electrical current, the conductivity of the solution is proportional to its ion concentration.

Container closure system: The sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system.

Combination product: A drug product which contains more than one drug substance.

Committee for Medicinal Products for Human Use (CHMP): The CHMP is responsible for preparing the European Medicine Agency's opinions on all questions concerning medicinal products for human use and plays a vital role in the marketing procedures for medicines in the European Union: In the 'Community' or 'centralized' procedure, the CHMP is responsible for conducting the initial assessment of medicinal products for which a Community-wide marketing authorization is sought. The CHMP is also responsible for several post-authorization and maintenance activities, including the assessment of any modifications or extensions ('variations') to the existing marketing authorization.

Complete Response Letter: A written communication to an applicant or DMF holder from FDA usually describing all of the deficiencies that agency has identified in an abbreviated application (including pending amendments) or a DMF that must be satisfactorily addressed before an ANDA can be approved. Complete response letters will reflect a complete review and will require a complete response from applicant to restart the review clock.

Compounding: A process in which a bulk drug substance is combined with one or more excipients and/or another bulk substance to produce a bulk product.

Compression: The process of reducing the bulk volume of a material by applying external force.

Compression Mix: The powder processed into tablets on a tablet machine. A compression mix may be made by wet granulation, dry granulation, simple blending or any other suitable technique.

Concurrent Validation: Validation carried out during routine production of products intended for sale.

Contamination: The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging or repackaging, storage or transport.

Controlled Correspondence: FDA’s office of Generic Drugs provides assistance to pharmaceutical firms and related industry regarding a variety of questions posed as “Controlled documents”

Counterfeit Medical Product: The term counterfeit medical product describes a product with a false representation of its identity and/or Source. This applies to the product, its container or other packaging or labeling information. Counterfeiting can apply to both branded and generic products. Counterfeits may include products with correct ingredients/components, with wrong ingredients/components, without active ingredients, with incorrect amounts of active ingredients, or with fake packaging. Violations or disputes concerning patents must not be confused with counterfeiting of medical products. Medical products (whether generic or branded) that are not authorized for marketing in a given country but authorized elsewhere are not considered counterfeit. Substandard batches of or quality defects or non-compliance with Good Manufacturing Practices/Good Distribution Practices (GMP/GDP) in legitimate medical products must not be confused with counterfeiting.

Computer Systems Validation: (CSV) Confirmation by examination and provision of objective evidence that computer system specifications conform to user needs and intended uses, and that all requirements can be consistently fulfilled.

CRO: Contract Research Organization

Critical Area: Area where sterilized products  or containers/closures  are exposed to the environment (i.e aseptic preparation and filling).

Critical Process Parameter (CPP): A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Cross-Contamination: Contamination of a material or product with another material or product.

Concurrent Validation: Validation carried out during routine production of products intended for sale.

Corrective Action: Action to eliminate the cause of a detected non-conformity or other undesirable situation. NOTE: Corrective action is taken to prevent recurrence whereas preventive action is taken to prevent occurrence. (ISO 9000:2005)

COS: A certificate provided to the manufacturer by the European Directorate for the Quality of Medicines & HealthCare to certify that the relevant monograph in the European Pharmacopoeia adequately controls the substance as manufactured by the company at the time the certificate was granted.

CTD: A harmonised layout for the structure and content of application dossiers applicable to the USA, the European Union and Japan. The CTD has 5 modules of which module 3 (Quality) contains the chemical and pharmaceutical section of the dossier.

D

D Value: Decimal reduction value (for biological indicators). The time in minutes required to secure inactivation of 90% (one log) of the test organisms under stated exposure conditions.

Data Exclusivity: Data exclusivity is the protection of an originator pharmaceutical company’s data preventing other parties from using these data far a commercial purpose. Concretely, this protection prevents generic product manufacturers form proceeding to clinical trials and health authorities from evaluating generic product market authorization applications during this period. In the European Union, this period was harmonized to eight years in 2004.

Data governance: The arrangements to ensure that data, irrespective of the format in which they are generated, are recorded, processed, retained and used to ensure the record throughout the data life cycle.

Data life cycle: All phases of the process by which data are created, recorded, processed, modified, transmitted, reviewed, reported, used, approved, archived and restored until destruction.

Data integrity: Refers to the completeness, consistency, and accuracy of data. Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA). Data integrity is critical throughout the CGMP data life cycle, including in the creation, modification, processing, maintenance, archival, retrieval, transmission, and disposition of data after the record’s retention period ends. System design and controls should enable easy detection of errors, omissions, and aberrant results throughout the data’s life cycle.

Decongestants: Drugs that reduce swelling of the mucous membranes that line the nose by contracting blood vessels thus relieving nasal stuffiness.

Deduster: A piece of equipment that removes flashing and dust from solid dosage forms. It is often combined  with a metal detector and installed at the outlet of a tablet press or capsule filler.

Degradation Product: An impurity resulting from a chemical change in the drug substance brought about over time and/or by the action of e.g., light, temperature, pH, water, or by reaction with an excipient and/or the immediate container/closure system. Also called decomposition product.

Delayed Release: A drug product (typically oral) that is not intended to release the drug substance immediately after ingestion. The delay is commonly related to change of pH in the gastrointestinal tract (“enteric coating”) or less commonly may relate to a specific time after ingestion when the drug is released. Enteric coating is achieved by coating with polymers that are poorly soluble in low pH media (for example gastric fluid), but are soluble in media with pH values typically found lower in the intestine. Methacrylic acid copolymers are very commonly used for delayed release coatings as they can be supplied in grades that dissolve at different pH values.

Desiccant: A highly hygroscopic substance used to absorb moisture in bottles,vials,blisters and other packing.

Design qualification (DQ):The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.

Depyrogenation: A process used to destroy or remove pyrogens.

Detection Limit: The  detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.

Deviation: Departure from an approved instruction or established standard.

Die: A circular machine tool with a central cavity in which powders or granular solids are compacted in to tablet between the upper and lower punches of a tablet press.

Diluent: A component of a tablet or capsule, usually present to add bulk to the dosage form. The most commonly used diluents include lactose, microcrystalline cellulose and native or pregelatinised starches. Dibasic calcium phosphate and mannitol are also used.

DIRA: Data Integrity Risk Assessment

Direct Compression: A means of producing a tablet without granulation. The active ingredient is blended with excipients, typically at least a filler-binder, a disintegrant and a lubricant and then the blend is compressed on a tablet machine. The filler-binders are usually special grades of excipients (for example spray dried lactose) exhibiting good flow and compaction properties to enable the DC process.

Dirty Hold time: The time from the end of product manufacturing until the beginning of the cleaning process.

Disintegrant: An excipient that facilitates the disintegration of a tablet or other dosage form in contact with water or gastro-intestinal fluid. Traditionally starch was used, but in general today’s formulations utilise a so called superdisintegrant such as croscarmellose sodium or sodium starch glycolate. Superdisintegrants are typically cross-linked hydrophilic polymers that strongly attract water. The presence of the cross links allows swelling, but prevents dissolution of the polymer and generation of high viscosity gels.

Disintegration: The process by which a solid oral dosage form breaks up in water when measured in a standard apparatus.

Dissolution: The process by which drug dissolves out of a dosage form and is made available for absorption from the gastro-intestinal tract. In vitro measurements are made in a range of apparatus types. The requirements for different types of dosage forms are given in each pharmacopoeia.

Diuretics: Drugs that increase the quantity of urine produced by kidney.

Dosage form: A pharmaceutical product type (e.g., tablet, capsule, solution, cream) that contains a drug substance generally, but not necessarily, in association with excipients.

DOP Test: Dioctyl Phthalate test is a test which used to check the HEPA filter integrity.

Drug master file (DMF): A DMF is a means of providing data on a processing facility, drug substance, packaging material or excipient confidentially to FDA. The data in a DMF can be accessed by FDA in support of an NDA upon provision of a letter of access (a letter from the DMF holder to the NDA applicant authorising FDA to access the DMF during their review of a particular NDA). In Europe there is no DMF system for excipients and in Japan there is a recently introduced system.

Drug product: The dosage form in the final immediate packaging intended for marketing.

Drug substance: The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.

Dry granulation: A means of granulation (size enlargement) of a powder using a compaction step followed by milling. The most common means of dry granulation in pharmaceutical industry is roller compaction, although the older process of slugging is still sometimes used. Anhydrous lactose is the most suitable form of lactose for these processes because it tends to retain compactability after the dry granulation process.

E

eCTD: The electronic Common Technical Document (eCTD) is an interface for the transfer of regulatory information. eCTD is the preferred format for submitting applications to CDER. It provides support for all application types, including: • Investigational New Drug Application (IND) • New Drug Application (NDA) • Biologics License Application (BLA) • Abbreviated New Drug Application (ANDA) • Drug Master File (DMF)

eCTD Triangle: The eCTD is commonly represented as a triangle that has five modules: 1. Administrative Information and Prescribing Information 2. Common Technical Document Summaries 3. Quality 4. Nonclinical Study Reports 5. Clinical Study Reports

EDQM: European Directorate for the Quality of Medicines & HealthCare.

EMA: European Medicines Agency. The European Medicines Agency is a decentralised agency of the European Union, located in Amsterdam. The Agency is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union.

Embryotoxicity: Production by a substance of toxic effects in progeny in the first period of pregnancy between conception and the foetal stage.

Enantiomeric Impurity:  A compound with the same molecular formula as the drug substance that differs in the spatial arrangement of atoms within the molecule and is a non-superimposable mirror image.

Endotoxin: A pyrogen (eg:lipopolysaccharide) derived from the cell wall of gram negative bacteria. Endotoxin can lead to reactions in patients receiving injections ranging from fever to death.

Enteric Coat: A delayed release coating, usually designed to delay release of the drug from the dosage form until it has reached an area of the gastro-intestinal tract of a specified pH. Methacrylic acid copolymers are very commonly used.

Equipment Train: The sequence of equipment through which a product is produced or processed.

Environmental monitoring Program: Defined documented program which describes the routine particulate and microbiological monitoring of processing and manufacturing areas.

Excipient: A component of a drug product other than the API, that is intentionally added to the dosage form to enable processing into patient friendly medicines, to control the rate at which the API dissolves from the dosage form, to aid drug stability and other reasons. For solid oral dosage forms, main classes of excipients include diluents or filler-binders, disintegrants, glidants, lubricants, coating materials, and stabilising agents.

Exotoxin: An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell.

Expectorant: Drugs that stimulate the flow of saliva and promotes coughing to eliminate phlegm from the respiratory tract.

Expiration date: The date placed on the container label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf life specification if stored under defined conditions, and after which it must not be used

Extended Release:  A form of modified release dosage form in which the dissolution rate of the drug from a medicine is controlled over an extended period of time, usually to reduce the frequency at which a patient has to take the medicine. A number of means of effecting extended release are possible, the most common being barrier coating (with for example acrylate polymers), inclusion of hydrogel polymers (for example hydroxypropyl methyl cellulose) and construction of osmotic pumps.

Extractable: Extractables are chemical entities, both organic and inorganic, that will extract from components of a container closure system or device into solvents under controlled conditions.

F

Factory Acceptance Test (FAT): Factory acceptance test is test conducted at the vendors premises, to verify that the equipment/system operates according to the specifications.

Facility Establishment Identifier (FEI): The FEI number is a unique identifier assigned by the FDA to identify firms associated with FDA regulated products.

Fetotoxicity: Production by a substance of toxic effects in progeny in the second period of pregnancy between foetal stage and delivery.

Finished product: Finished product is a product that has undergone all stages of production, including packaging in its final container and labelling.

First-pass effect: Biotransformation and, in some cases, elimination of a substance in the liver after absorption from the intestine and before it reaches the systemic circulation.

Fixed Dose Combination(FDC): Fixed Dose Combinations (FDCs) refer to products containing two or more active ingredients used for a particular indication(s).

Flashing: Small  extrusions that appear around tablet periphery where the band meets the cups. It usually flakes off during handling, dedusting or coating.

Fluid-bed dryer (FBD): A device that dries powder using mechanical force and/or airflow to evaluate and aerate it, increasing interstitial particle spacing   and driving off moisture.

Fluid bed granulation: The process of spraying   solution onto aerated powders to form granules.

Foil: Thin-gauge aluminium, usually 20 to 25 microns thick, that can be used as blister material,push-through lidstock,or backing when combined with film or paper.

Forced Degradation : Forced degradation testing studies are those undertaken to degrade the sample deliberately.  These studies, which may be undertaken in the development phase normally on the drug substances, are used to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation.

Form FDA 483: A form of observations usually produced after an FDA inspection of a drug development or drug manufacturing facility. Only significant deviations from cGMP are listed and thus 483 observations are only negative.

Formulation: An ingredient or mixture of specific ingredients; that is, drug substances and excipients in specific amounts, defining a given product.

Friabilty: A measure of the resistance to abrasion and breakage of tablets during a standardised test involving tumbling tablets in a rotating drum. Details of the equipment and test protocol are found in all main pharmacopoeia. A limit of not more than 1% weight loss is generally taken to be a satisfactory measure of friability.

G

GAMP: Good Automated Manufacturing Practice.

Gavage: Administration of materials directly into the stomach by oesophageal intubation.

GCP: Good Clinical Practice.

GDP: Good Distribution Practice. That part of quality assurance which ensures that products are consistently stored, transported and handled under suitable conditions.

GDUFA: Generic Drug User Fee Amendments(Introduced by USFDA).The Generic Drug User Fee Act is a law designed to speed access to safe and effective generic drugs to the public, and reduce costs to industry.

Generally regarded as safe (GRAS): Phrase used to describe the USFDA philosophy that justifies approval of food additives that may not meet the usual test criteria for safety but have been used extensively and have not demonstrated that they cause any harm to consumers.

Generic Drug: A drug for which the patents protecting the originator product have expired (or may be challenged). Generic products are pharmaceutically equivalent to a reference listed drug (same drug substance, same route of administration, same dosage form and same strengths) and are also therapeutically equivalent (typically bioequivalent for oral solid dosage forms).

Genetically modified organism (GMO): A genetically Modified Organism is an organism that has been modified by gene technology; or an organism that has inherited particular traits from an organism (the initial organism), being traits that occurred in the initial organism because of gene technology; or anything declared by the regulations to be a genetically modified organism, or that belongs to a class of things declared by the regulations to be genetically modified organisms.

Genotoxic: Capable of causing a change to the structure of the genome.

GLP: Good Laboratory Practice.

Glidants: Glidants are  execipients used to promote powder flow by reducing inter particle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction (ex: talc).

GLP: Good Laboratory Practices.

GMP: Good Manufacturing Practice. This is a recognised standard for pharmaceutical processing and manufacture ensuring medicinal products are consistently produced and controlled.

Gowning Qualification: Program which establishes,both initially and on periodical basis,the capability of an individual to done the complete sterile gown in aseptic manner.

Generic Product Identifier (GPI): Generic Product Identifier (GPI) is a 14 character hierarchical classification system which identifies drugs from their primary therapeutic use down to the unique interchangeable product regardless of manufacturer or package size. The code consists of seven subsets, each providing increasingly more specific information about a drug available with a prescription in the US market.

Granulation: Granulation is the process in which primary powder particles are made to adhere to form larger, multi particle entities called granules. Granulation process is an inevitable step in tablet manufacturing as it improves flow property and compressibility of powder mass intended for compression.

Growth Promotion Test: Test performed to demonstrate the ability of the microbial media to support microbial growth.

GxP: General abbreviation for Good Practice standards. Good ‘X’ Practice where ‘X’ is used as a collective term for GDP – Good Distribution Practice, GCP – Good Clinical practice, GLP – Good Laboratory Practice GMP – Good Manufacturing Practice GPvP – Good Pharmacovigilance Practice.

H

Hatch-Waxman Act: Also known as the Drug Price Competition and Patent Term Restoration Act (1984). Among other provisions, created an abbreviated pathway for FDA approval of generic drug products, statutory exclusivity provisions for new and patented drug products, and a 180-day exclusivity period for ANDA filers that challenge patents listed in the Orange Book.

HEPA Filter: High efficiency particulate air filter with minimum 0.3 micron particle retaining efficiency of 99.97%.

Hygroscopicity: A material’s ability to absorb moisture from its surroundings.

Hypersensitivity: state in which an individual reacts with allergic effects following exposure to a certain substance (allergen) after having been exposed previously to the same substance.

HMI: Human to Machine Interface. Generic expression for the device providing the platform to operate the GUI software.

I

ICH: International Council for Harmonization.

IND: Investigational New Drug.

International Non-Proprietary Name (INN): INN is a unique name that is globally recognized and is public property. Since its inception, the aim of the INN system has been to provide health professionals with a unique and universally available designated name to identify each pharmaceutical substance. The existence of an international nomenclature for pharmaceutical substances, in the form of INN, is important for the clear identification, safe prescription and dispensing of medicines to patients, and for communication and exchange of information among health professionals and scientists worldwide. As unique names, INNs have to be distinctive in sound and spelling, and should not be liable to confusion with other names in common use. To make INN universally available they are formally placed by WHO in the public domain, hence their designation as "non-proprietary". They can be used without any restriction whatsoever to identify pharmaceutical substances. Another important feature of the INN system is that the names of pharmacologically-related substances demonstrate their relationship by using a common "stem". By the use of common stems the medical practitioner, the pharmacist, or anyone dealing with pharmaceutical products can recognize that the substance belongs to a group of substances having similar pharmacological activity. Non-proprietary names are intended for use in pharmacopoeias, labeling, product information, advertising and other promotional material, medicine regulation and scientific literature, and as a basis for product names, e.g. for generics. Their use is normally required by national or, as in the case of the European Community, by international legislation. As a result of ongoing collaboration, national names such as British Approved Names (BAN), Dénominations Communes Françaises (DCF), Japanese Adopted Names (JAN) and United States Adopted Names (USAN) are nowadays, with rare exceptions, identical to the INN. To avoid confusion, which could jeopardize the safety of patients, trade-marks cannot be derived from INN and, in particular, must not include their common stems.

Immediate (primary) pack: Is that constituent of the packaging that is in direct contact with the drug substance or drug product, and includes any appropriate label.

Impermeable containers: Containers that provide a permanent barrier to the passage of gases or solvents, e.g., sealed labelling tubes for semi-solids, sealed glass ampoules for solutions.

Immediate Release: Allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug.

Impurity:  Any component of the new drug substance that is not the chemical entity defined as the new drug substance.

Intermediate precision: Intermediate precision expresses within-laboratories variations: different days, different analysts, different equipment, etc.

Intermediate Product: Partially processed product that must undergo further manufacturing steps before it becomes bulk product.

Intermediate testing: Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C.

International Organization Of Standardisation (ISO): ISO (International Organization for Standardization) is the world's largest developer and publisher of International Standards. ISO is a network of the national standards institutes of 159 countries, one member per country, with a Central Secretariat in Geneva, Switzerland, that coordinates the system. ISO is a non-governmental organization that forms a bridge between the public and private sectors. On the one hand, many of its member institutes are part of the governmental structure of their countries, or are mandated by their government. On the other hand, other members have their roots uniquely in the private sector, having been set up by national partnerships of industry associations. Therefore, ISO enables a consensus to be reached on solutions that meet both the requirements of business and the broader needs of society.

In-process tests: Tests which may be performed during the manufacture of either the drug substance or drug product, rather than as part of the formal battery of tests which are conducted prior to release.

Installation Qualification (IQ): The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.

Intervention: Aseptic manipulations or activity performed by a personnel that occurs within the critical area.

Investigation new drug application (INDA): It is an application which is filed with FDA to get approval for legally testing an experimental drug on human subjects in the USA.

In vitro:  In glass, as in a test tube. An in vitro test is one that is done in glass or plastic vessels in the laboratory. In vitro is the opposite of in vivo.

In vivo: In the living organism. For example, an experiment that is done in vivo is done in the body of a living organism.In vivo is the opposite of in vivo.

L

Lamination: The presence of weak planes in a compressed tablet normal to the direction of compaction. On subsequent handling or processing it is possible for the tablet to separate into layers along these weak planes. Lamination may have the same causes as capping, or it may also be a result of under lubrication of the tablet compression mix.

Laxatives: Laxatives (purgatives, aperients) are foods, compounds and/or drugs that facilitate or increase bowel movements. They are most often used to treat constipation.

LD50: The dose of a material which results in 50% mortality in an animal test.

Leachable: Leachables are chemical entities, both organic and inorganic, that migrate from components of a container closure system or device into a drug product over the course of its shelf-life.

Lethal dose (LD): Amount of a substance or physical agent (e.g., radiation) that causes death when taken into the body.

Lidstock: Material used to seal blisters to prevent or minimize moisture and/or gas permeation.

Line Clearence: Line clearance includes a careful examination of the area and equipment before batch to batch or product to product change over to avoid cross contamination.

Linearity: The linearity of an analytical procedure is its ability (within a given range)  to obtain test results which are directly  proportional to the concentration (amount) of analyte in the sample.

Long term testing: Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labelling.

Lowest-effective dose (LED): Lowest dose of a chemical inducing a specified effect in a specified fraction of exposed individuals.

Lowest-observed-adverse-effect level (LOAEL): Lowest concentration or amount of a substance (dose), found by experiment or observation, that causes an adverse effect on morphology,functional capacity, growth, development, or life span of a target organism distinguishable from normal (control) organisms of the same species and strain under defined conditions of exposure.

Lowest-observed-effect level (LOEL): Lowest concentration or amount of a substance (dose), found by experiment or observation, that causes any alteration in morphology, functional capacity, growth, development, or life span of target organisms distinguishable from normal (control) organisms of the same species and strain under the same defined conditions of exposure.

Lubricant: An excipient that is used in tablet and capsule formulations to allow ejection of the compressed tablet from the die, or the capsule plug from the dosator. Lubricants also act as anti-adherents to prevent sticking of the tablet to the tablet punches during compression. By far the most commonly used lubricant is magnesium stearate, although less hydrophobic materials such as sodium stearyl fumarate are now available. Other lubricants include calcium stearate and mixtures of talc and stearic acid. Options to minimise the need for tablet lubrication include the use of coated punches in compression and tablet machine developments that add very small quantities of lubricants directly to the punches during tableting.

Lyophilization: A process by which material is rapidly frozen and dehydrated under high vacuum.

M

MA: Marketing Authorisation. This is the European licensing system for medicines that replaced the Product Licence (PL) system.

Marketing authorisation application (MAA): Is an application (to the relevant authority ; typically the UK’s MHRA or the European Commission’s Committee for Medicinal Products for Human Use (CHMP) to market a drug or medicine. The U.S. Food and Drug Administration equivalent of  Marketing authorisation application (MAA) is a New Drug Application (NDA).

MAH: Marketing Authorisation Holder.

Marketing Pack: Marketing pack is the combination of immediate pack and other secondary packaging such as a carton.

Mass balance: The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error.

Material safety data sheet (MSDS): Compilation of information required under the U.S. OSHA Hazard Communication Standard on the identity of hazardous substances, health and physical hazards, exposure limits, and precautions.

Matrixing: The design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same container closure system, and, possibly in some cases, different container closure systems.

Maximum permissible daily dose (MPDD): Maximum daily dose of substance whose penetration into a human body during a lifetime will not cause diseases or health hazards that can be detected by current investigation methods and will not adversely affect future generations.

Maximum tolerable dose (MTD): Highest amount of a substance that, when introduced into the body, does not kill test animals (denoted by LD0).

Maximum tolerable exposure level (MTEL): Maximum amount (dose) or concentration of a substance to which an organism can be exposed without leading to an adverse effect after prolonged exposure time.

Maximum tolerated dose (MTD): High dose used in chronic toxicity testing that is expected on the basis of an adequate sub chronic study to produce limited toxicity when administered for the duration of the test period.

Mean kinetic temperature: A single derived temperature that, if maintained over a defined period of time, affords the same thermal challenge to a drug substance or drug product as would be experienced over a range of both higher and lower temperatures for an equivalent defined period. The mean kinetic temperature is higher than the arithmetic mean temperature and takes into account the Arrhenius equation. When establishing the mean kinetic temperature for a defined period, the formula of J. D. Haynes (J. Pharm. Sci., 60:927-929, 1971) can be used.

Media Fill: A “media fill” (sometimes known as a “process simulation”) is the performance of an aseptic manufacturing procedure using a sterile microbiological growth medium in place of the drug solution. Microbiological growth medium is used in place of the drug solution during media fills to test whether the aseptic procedures are adequate to prevent contamination during actual drug production. A media fill is one part of the validation of an aseptic manufacturing process.

Median lethal dose (LD50): Statistically derived median dose of a chemical or physical agent (radiation) expected to kill 50% of organisms in a given population under a defined set of conditions.

Medication Guide: A medication guide contains information for patients on how to safely use a drug product.

Metadata: Metadata are data that describe the attributes of other data and provide context and meaning  and form an integral part of original records. An audit trail record is an example of metadata.

MHRA: Medicines and Healthcare Products Regulatory Agency.

Milling: The process of de-agglomerating or reducing the particle size of powders manually or by machine.

Modified Release: Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products.

Moisture vapour transmission rate (MVTR): The amount of humidity that passes through packaging film or foil over a unit of time and under specific environmental conditions.

Mottling: ‘Mottling’ is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface.

Mutagenicity: ability of a physical, chemical, or biological agent to induce (or generate) heritable changes (mutations) in the genotype in a cell as a consequence of alterations or loss of genes or chromosomes (or parts thereof).

N

New Drug Application (NDA): The process by which a pharmaceutical company requests permission to manufacture and sell a new drug in the USA. The NDA differs from the ANDA in that it contains extensive data on safety and efficacy of the proposed new drug.

National Formulary: Published by the U.S. Pharmacopoeia (USP), a private nonprofit organization, the National Formulary is the official compendium of standards for drugs, excipients, dietary supplements, and vitamins and minerals. The USPNF defines standards of strength, quality, purity, identity, packaging, labeling, and storage, and describes and defines the appropriate tests, assays, and analytical methods that are used to measure strength, purity, and so forth.

NDC: National Drug Code. A numeric code that uniquely identifies drug products. The code includes three segments that identify the labeler, the product, and the packaging.

No-effect level (NEL): Maximum dose (of a substance) that produces no detectable changes under defined conditions of exposure.

New molecular entity: An active pharmaceutical substance not previously contained in any drug product registered with the national or regional authority concerned.  A new salt, ester, or non-covalent-bond derivative of an approved drug substance is considered a new molecular entity for the purpose of stability testing under this guidance.

No-observed-effect level (NOEL): Greatest concentration or amount of a substance, found by experiment or observation, that causes no alterations of morphology, functional capacity, growth, development, or life span of target organisms distinguishable from those observed in normal (control) organisms of the same species and strain under the same defined conditions of exposure.

No-observed-adverse-effect level (NOAEL): Greatest concentration or amount of a substance, found by experiment or observation, which causes no detectable adverse alteration of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions of exposure.

Non Condensable Gas: Gases which cannot be liquefied by compressron under the range of conditions of temperature and pressure used during the operating cycle.

NRx: New Prescriptions.

Non viable: A term used in reference to particulates, which are not capable of living, growing or developing and functioning successfully –“unable to divide”

O

Operational Qualification (OQ):The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

Orally Disintegrating Tablet (ODI): An ODT is a dosage form designed to disintegrate or dissolve quickly in the mouth without the need for water and without chewing. In general the tablet should disintegrate within 30 seconds when tested using standard pharmacopoeial disintegration apparatus, or another correlated disintegration test method.

Orange Book: “The Orange Book" is actually the U.S. Food and Drug Administration's (FDA) official listing of Approved Drug Products with Therapeutic Equivalences. “Orange book” is published by the FDA's Centre for Drug Evaluation and Research (CDER).

Orange Guide: “Orange guide” is published by MHRA. Alternative title for the “Rules and Guidance for Pharmaceutical Manufacturers and Distributors” because of its orange cover. “Orange guide” contains the requirements of Good Manufacturing Practice (It contains EU guidance on good manufacturing and good distribution practice along with relevant information on EU and UK legislation).

Orphan Drugs: "Orphan drugs" are medicinal products intended for diagnosis, prevention or treatment of life-threatening or debilitating rare diseases. They are "orphans" because the pharmaceutical industry has little interest under normal market conditions in developing and marketing drugs intended for only a small number of patients suffering from very rare conditions.

Out of specification (OOS): Test result that does not comply with the pre-determined acceptance criteria (i.e. for example, filed applications, drug master files, approved marketing submissions, or official compendia or internal acceptance criteria).

Out of trend (OOT): Is generally a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study. However the trends of starting materials and in-process samples may also yield out of trend data.

Overage : Increased content of drug substance, usually due to loss of potency on storage.

Over Fill: Increased volume of drug product to account for loss during delivery.

Over the counter drugs (OTC):  Over-the-counter medicines are medicines that can be sold from licensed dealers without professional supervision and without prescription. These medicines are suitable for self medication for minor disease and symptoms.

Oxygen transmission rate (OTR): The amount of oxygen that passes through packaging film or foil over a unit of time and under specific environmental conditions.

P

PAS: Prior Approval Suppliment

Paragraph 4 Filings: A type of ANDA submitted during the patent term of the originator product. The filing asserts that either the patents supporting the originator product are invalid or that they are not applicable to the product that is the subject of the ANDA.

Parametric Release: A sterility release system based upon effective control, monitoring, documentation, and batch records review of a validated sterilization process cycle in lieu of release procedures based upon end product sterility testing.

Performance Qualification (PQ): The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and  reproducibly, based on the approved process method and product specification.

Pharmacopoea: Pharmacopoeia is a book or encyclopedia of Drugs Standards, their formulas, Methods for making medicinal preparations and other related information's which is published under the jurisdiction of government body.

Pharmacodynamics: The study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of their actions and effects with their chemical structures.

Pharmacokinetics: The study of the movement of drugs in the body, including the processes of absorption, distribution, and localization in tissues.

Pharmacovigilance: Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.

PIC: Pharmaceutical Inspection Convention. An international organisation which mutually recognises inspection reports on manufacturers (excludes EC members).

PICS: Pharmaceutical Inspection Co-operation Scheme. The scheme’s goal is to improve cooperation between regulatory authorities and the pharmaceutical industry in the field of Good Manufacturing Practice.

Picking: A imperfection caused by powders sticking to a punch surface during tabletting.

Pilot scale batch: A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.

Pill Burden: Pill burden is a term that refers to the number of pills (tablets or capsules, the most common dosage forms) that a patient takes on a regular basis.

Placebo: A product which stimulates the marketable product but has no active ingredient present.

PLAIR: Pre Launch Activities Importation Requests. USFDA’s PLAIR program allows the foreign drug product manufacturer for the importation of an unapproved finished dosage form drug product (no more than 60 days prior to anticipated approval or goal date) in preparation for market launch. [Based on anticipated approval of a pending new drug application (NDA) or an abbreviated new drug application (ANDA)].

Polymorphic Forms:  Different crystalline forms of the same drug substance. These can include hydration products (also known as pseudo-polymorphs) and amorphous forms.

Potential Impurity:  An impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the new drug substance.

Precision: The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision may be considered at three levels:  repeatability, intermediate precision and reproducibility.Precision  should be investigated using homogeneous, authentic samples. However, if it is not possible to obtain a homogeneous sample it may be investigated using artificially prepared samples or a sample solution.The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements.

Preventive Action: Action to eliminate the cause of a potential non-conformity or other undesirable potential situation. NOTE: Preventive action is taken to prevent occurrence whereas corrective action is taken to prevent recurrence. (ISO 9000:2005)

Primary batch: A batch of a drug substance or drug product used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period or shelf life, respectively.  A primary batch of a drug substance should be at least a pilot scale batch.  For a drug product, two of the three batches should be at least pilot scale batch, and the third batch can be smaller if it is representative with regard to the critical manufacturing steps.  However, a primary batch may be a production batch.

Probiotics: Probiotics are live microorganisms or microbial mixtures administered to improve the patient's microbial balance, particularly the environment of the gastrointestinal tract and the vagina.Probiotics have demonstrated an ability to prevent and treat some infections.Probiotics can be bacteria,moulds or yeast.Commonly used bacterial strains are Lactobacillus & Bifidobacterium.Commonly used yeast strain is Saccharomyces boulardii.

Process Analytical technology (PAT):A system for designing,analyzing and controlling manufacturing through timely measurements critical quality and performance attributes of raw and inprocess materials and processes with the goal of ensuring final product quality.

Process-Related Impurities: Impurities that are derived from the manufacturing process.  They may be derived from cell substrates (e.g., host cell proteins, host cell DNA), cell culture (e.g., inducers, antibiotics, or media components), or downstream processing (e.g., processing reagents or column leachables).

Product-Related Impurities: Molecular variants of the desired product (e.g., precursors, certain degradation products arising during manufacture and/or storage) which do not have properties comparable to those of the desired product with respect to activity, efficacy, and safety.

Process Validation: The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.

Production batch: A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified in the application.

Pyrogen: Substance which induces febrile reactions in a patient.

Purple Book: A compendium identifying biological products, including any biosimilar and interchangeable biological products, licensed by the FDA under the Public Health Service Act. Comparable to the Orange Book.

Pure Steam: Steam whose condensate complies with the ompendia monograph, water for injection (WFI).

Q

Quality Assurance (QA): The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.

Quality by Design (QbD): A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

Qualification: Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results.  Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.

QP: Qualified Person. A QP must certify every batch of a medicine before release to the EU market. Article 51 of Directive 2001/83/EC defines the duties of the Qualified Person and more information can be found in the Orange Guide.

QRM: Quantitative Risk Management

Qualification Threshold: A limit above (>) which an impurity should be qualified.

Quality Manual: Document specifying the quality management system of an organisation. (ISO 9000:2005)

Quality Risk Management: A systematic process for the assessment, control, communication, and review of risks to the quality of the drug product across the product lifecycle.

Quality System: The sum of all aspects of a system that implements quality policy and ensures that quality objectives are met.

Quantitation Limit: The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.

Quarantine: The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.

R

Range: The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.

Rapporteur: A member of the Committee for Proprietary Medicinal Products who provides expert evaluation.

Raw data (source data): The original record (data) which can be described as the first-capture of information, whether  recorded on paper or electronically.

Raw Material: A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.

Recovery: The introduction of all or part of previous batches of the required quality into another batch at a defined stage of manufacture.

Reconcilation: Comparing the total number of an item accounted for against the number or quantity of the item at the beginning of the process to determine the difference (Comparison between the theoretical quantity and the actual quantity).

Reference Listed Drug (RLD): Reference listed product is an approved drug product to which new generic versions are compared to show that they are bioequivalent.

Reference Standard, Primary: A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity.  This standard can be: (1) obtained from an officially recognised source, or (2) prepared by independent synthesis, or (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material.

Reference Standard, Secondary: A substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.

REMS: Risk Evaluation and Mitigation Strategy. A post-approval monitoring program required by the USFDA for certain drugs.

Relative humidity : The ratio of the actual water vapour pressure of the air to the saturated water vapour pressure of the air at the same temperature expressed as a percentage. More simply put, it is the ratio of the mass of moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature.

Repeatability: Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision .

Reprocessing: Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process.  Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not reprocessing.

Reproducibility: Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).

Residual Solvent: Residual solvents in pharmaceuticals are organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.

Re-test date: The date after which samples of the drug substance should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product.

Re-test period: The period of time during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be re-tested for compliance with the specification and then used immediately. A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification.  For most biotechnological/biological substances known to be labile, it is more appropriate to establish a shelf life than a re-test period. The same may be true for certain antibiotics.

Retrospective Validation: Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data.

Revalidation: Repeated validation of an approved process to ensure continued compliance with established requirements.

Reworking: Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent).

Risk Assessment: A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.

Risk Management: The systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating, and reviewing risk

Robustness: The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.

Roller Compaction: A dry granulation process in which a powder blend is passed through rollers under pressure to form a ribbon. The ribbon is milled into granules, optionally blended with extra granular excipients and recompressed into tablets or filled into capsules.

RTR: Refuse to receive (Refuse to file an ANDA application) When an applicant submits an ANDA to USFDA, OGD (Office of Generic Drugs) first conducts a review to determine whether the application is sufficiently complete to permit a substantive review. OGD refers to this period as the filing review. The filing review takes approximately 60 days from the ANDA’s receipt date to complete it. If the submitted application is not complete or any deficiencies are identified, then "refuse to file letter" is issued by the OGD/CDER to the applicant.

S

Saturated steam: Steam whose temperature, at any given pressure, corresponds to that of the vaporisation curve of water.

Scale Up: The process of converting a small volume process to large -  volume production

Screening: The process of reducing agglomerates, sorting particles by size and removing oversized particles and contaminants using a woven metal screen or perforated plate.

Semi-permeable containers: Containers that allow the passage of solvent, usually water, while preventing solute loss.  The mechanism for solvent transport occurs by absorption into one container surface, diffusion through the bulk of the container material, and desorption from the other surface.  Transport is driven by a partial-pressure gradient.  Examples of semi-permeable containers include plastic bags and semi-rigid, low-density polyethylene (LDPE) pouches for large volume parenterals (LVPs), and LDPE ampoules, bottles, and vials.

Serialization: Serialization refers to a numerical system that assigns a unique number or identification code to each packaging unit. A serialization scheme is built around a code structure that typically identifies the manufacturer, the product type, and each specific item unit.

Shelf life (also referred to as expiration dating period): The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label.

Shingle: An effect caused by tablets stacking or backing up on the die table during the ejection instead of them pushing each other of the tablet press.

Site Acceptance Test (SAT): An Acceptance Test at the Customer's site, usually involving the Customer.

Slugging: A form of dry granulation, somewhat similar to roller compaction. In slugging however a powder blend is first compressed on a tablet machine and the resulting, usually large, tablets (slugs) are milled, optionally reblended with more excipients, and recompressed into tablets. Alternatively the milled slugs are sometimes filled into capsules.

Specification: A list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use. “Conformance to specifications” means that the drug substance and / or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities.

Specificity: Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s). This definition has the following implications: Identification: To ensure the identity of an analyte. Purity        Tests:   to ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e. related substances test, heavy metals, residual solvents content, etc.                  Assay (content or potency): to provide an exact result which allows an accurate statement  on the content or potency of the analyte in a sample

Specified Impurity:  An impurity that is individually listed and limited with a specific acceptance criterion in the new drug substance specification. A specified impurity can be either identified or unidentified.

Spore: A bacterial form highly resistant to adverse conditions.

Stability: Ability of a material to maintain a stated property value within specified limits for a specified period of time, when stored under specified conditions.

Standard operating procedure (SOP): An authorized written procedure, giving instructions for performing operations, not necessarily specific to a given product or material, but of a more general nature, (e.g. equipment operation, maintenance and cleaning, validation, cleaning of premises and environmental control, sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.

Starting Material:  A material used in the synthesis of a new drug substance that is incorporated as an element into the structure of an intermediate and/or of the new drug substance. Starting materials are normally commercially available and of defined chemical and physical properties and structure.

Sterile: Free of any viable organisms (Absence of life).

Sterility Assurance Level (SAL): Probability of a single viable microorganisms occurring in an item.

Sterilization: A process used to render a product free of viable organisms with a specified probability.

Sterilization in place (SIP): Sterilization in place or Steam in place (SIP) is a method used to clean or disinfect process equipment and piping without disassembly. The SIP process can be done manually or automated through the control system.

Sticking: Adhesion of a powder to the faces of a punch during tablet compaction. Causes are various and include low melting components in a compression mix, inadequate drying of a granulation, and inadequate lubrication of the compression mix. Additionally poor punch maintenance can contribute to sticking. The remedies are generally evident from the causes, but if low melting components cannot be excluded from a formulation then specially coated tablet punches may be a solution. Occasionally changes to the punch design (for example reducing the depth of concavity) may alleviate the problem.

Storage condition tolerances: The acceptable variations in temperature and relative humidity of storage facilities for formal stability studies. The equipment should be capable of controlling the storage condition within the ranges defined in this guideline. The actual temperature and humidity (when controlled) should be monitored during stability storage. Short term spikes due to opening of doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be addressed, and reported if judged to affect stability results. Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effect assessed.

Stress testing (drug substance): Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.

Stress testing (drug product): Studies undertaken to assess the effect of severe conditions on the drug product.  Such studies include photostability testing (see ICH Q1B) and specific testing on certain products, (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products).

Super heated steam: Steam whose temperature, at a given pressure, is higher than that indicated by the equilibration curve for the vaporization of water.

Supplement: A supplement is an application to allow a company to make changes in a product that already has an approved new drug application (NDA). CDER must approve all important NDA changes (in packaging or ingredients, for instance) to ensure the conditions originally set for the product are still met.

Surfactant: A substance that decreases the surface tension of a liquid.

Sustained release: A method of drug delivery by which API release occurs over an extended period after administration. The method reduces dosing frequency compared to a traditional method such as immediate release.

T

Therapeutic Equivalence (TE): Drugs classified by the FDA to be therapeutically equivalent can be substituted for one another. For example, generic drugs are typically given “AB” TE codes, which indicate substitutability with a reference product has been demonstrated through evidence supplied via the ANDA.

Tentative approval letter for an ANDA: A written communication to an applicant from FDA delaying the approval of an application or an abbreviated application by an effective date.   A tentative approval letter is issued to the applicant if the application is submitted for approval before the expiration of any patents or exclusivities granted to the original, brand-name product. The tentative approval letter delays final approval of the application until all patent or exclusivity issues have been resolved.

Teratogenicity: The occurrence of structural malformations in a developing foetus when a substance is administered during pregnancy.

Terminal sterilization: A process whereby product is sterilized with its sterile barrier system.

Thermoforming: Thermoforming is a technique that involves heating sheets of PVC prior to insertion into a blister machine. This is typically achieved by passing the sheets between upper and lower heating plates. When a sheet enters a thermoforming blister machine, it is soft and pliable and can be forced to take on the shape of a mold through the application of pressure. In some cases, a mechanical stamp will be used in addition to the application of pressure, particularly when the shape of the mold is difficult or complex.

Tincture: A medicine consisting of an extract in alcohol solution.

TOC: Total organic carbon (TOC) is the amount of carbon bound in an organic compound and is often used as a non-specific indicator of water quality or cleanliness of pharmaceutical manufacturing equipment.

Toxicity: An adverse event produced by a medicine that is detrimental to the subject’s health. The level of toxicity associated with a medicine varies with the condition for which the medicine is used.

Track & Trace: It is a system capable of uniquely identify a specific product within the complete supply chain in both the directions (manufacturer to end-user and vice versa).

Transmissible Spongiform Encephalopathy (TSE): TSE is a neurodegenerative disorder  caused by prions. Although these infections usually remain asymptomatic for years, the disease is always progressive and fatal once the clinical signs develop.

Twininng: The bonding of tablets with large, flat surfaces during the coating process.

U

Uniformity of dosage Forms: A measure of the degree of uniformity of the amount of active substance in individual dosage units (for example individual tablets or capsules). For uncoated tablets, film coated tablets and hard capsules containing at least 25mg of drug substance and the drug substance is at least 25% of the dosage form, then variation in weight may be used as a measure of uniformity. For other solid oral dosage forms then individual unit assays are necessary. Specific details are given in major pharmacopoeia.

Unidentified Impurity:  An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time).

Unspecified impurity: An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification.

Untitled letter: Untitled letter is issued by USFDA for violations that are not as significant as those that trigger warning letters.

User Requirement Specification (URS): A formal document that list out all requirements of buyer regarding the equipment to be purchased. It is sent to equipment manufacturer to make it as desired criteria.

V

Variation: An amendment to an existing product licence by a licence holder or the licensing authority

Validation: A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria.

Validation Master Plan(VMP):  Validation master plan is a high-level document which establishes an umbrella validation plan for the entire project, and is used as guidance by the project team for resource and technical planning

Viable: Capable of living

Viscosity: The measurement of a materials resistance to flow.

W

Warning Letter: The Warning Letter is a document that usually originates from the FDA-483 observations that have been linked to citations by one or more legal reviews within the Compliance and legal branch of the FDA. Warning letters are issued for violations of “regulatory significance”

Water for Injection (WFI): Water, which is intended for use in the preparations of parenteral  solutions.WFI is produced by distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms.

Wet Granulation: A means of granulation of powders using water or other liquid to agglomerate powders into granules, and drying the granules. The process fixes API and excipients into a granular form that helps to prevent segregation of the components, that aids flow of there powders, and allows the incorporation of binders to improve compactability. The granulation step and the drying step may be performed consecutively (typically using high shear granulation and fluid bed drying) or concurrently (typically using fluid bed granulation). Continuous wet granulation is increasingly being used to aid throughput in pharmaceutical processing factories.

WHO: World Health Organisation.

Y

Yield,  Expected: The quantity of material or the percentage of theoretical yield anticipated at any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing data.

Yield, Theoretical: The quantity that would be produced at any appropriate phase of production, based upon the quantity of material to be used, in the absence of any loss or error in actual production.

Z

Z- Value: The number of degrees of temperature change necessary to change the D-value by factor of 10.

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