Xylopia is a full-service Dosage Form Research company that develops generic pharmaceutical drugs for USA and European markets.

I learned the process of oral solid dosage development. I worked with multiple departments from formulation development, process development, analytical method development and validation, drug packaging, drug stability, quality assurance, and regulatory affairs. I began my internship with project management that involved coordination with drug substance vendors and drug product manufacturing sites.

I worked on three products. It was named as Product A, Product B and Product C (Due to confidentiality issues, I cannot mention the real molecule names)

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• Generic Drug and Development Process

Pg 5 • Active Pharmaceutical Ingredient

Pg 6 • Excipients

Pg 7 • Impurities

Pg 8 • Dosage Forms

Pg 9 • Product Development Cycle

Pg 10 • Product Identification and Project Management

Pg 11 • Sourcing, evaluation and testing

Pg 12 • Innovator product testing and characterization

Pg 13 to 27

• Manufacturing Process

Pg 28-30

• Analytical Development and Evaluation

Pg 31 • Packaging

Pg 32 • Quality Assurance

Pg 33 • Regulatory Affairs

Pg 34 • Generic Drug safety

Pg 36 • Glossary

IND

EX

Pg 3-4

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Generic Drug

Contain the same API as the innovator drug

Be identical in strength, dosage form, and route of administration to RLD

Have the same use indications as RLD (Reference Listed Drug)

Be bioequivalent to RLD

Meet the same batch requirements for identity, strength, purity and quality

Be manufactured under the same strict standards of FDA’s GMP regulations required for innovator products

Generic Drug Development Process

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Project Identification

API Sourcing

Ref. Product Evaluation

Analytical Development

Formulation Development

Packaging Development

Prototyping Formulation

Pilot BE Study Final Formulation

Scale Up Batch

Pivotal Batch Production

Pivotal BE Study

Stability Data. BE Study Report

Data Compilation

ANDA Submission

API are an organic compounds that have unique chemical structure intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient). This compound is used in a finished pharmaceutical product (FPP), intended to have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.

Example: Chemical structure of Metformin and Mirabegron

Active Pharmaceutical Ingredient (API)

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• Pharmaceutical excipients are substances that are included in a drug not for their direct therapeutic action, but to aid the manufacturing process.

• Purposes served by excipients: – to protect, support or enhance stability, or for bioavailability or patient acceptability– Provide bulk to the formulation – Facilitate drug absorption or solubility and other pharmacokinetic considerations. – Aid in handling of “API” in the manufacturing process – Provide stability and prevent from denaturation– Assist in flowability

• A list of pharmaceutical excipients used in pharmaceutical preparations usually: are Fillers. Binders. Disintegrants. Coatings. Antiadherent. Lubricants. Glidants. Preservatives. Antioxidants. Flavoring Agents. Sweeting Agents. Coloring Agents. Solvent & Co-solvent. Viscosity imparting Agents. Diluents.

• The real importance of ensuring an excipient’s quality and performance are often underestimated. In reality, the functionality of the excipient can help determine whether or not a drug succeeds or fails. The possible consequences of not choosing the best excipient for formulation are manufacturing complications, compromised stability, poor bioavailability of the API, unintended side-effects, and even serious adverse reaction or death of the patient . So to avoid these undesirable outcomes it is very important to select the right excipient and in accurate proportions for the formulation that guarantee its quality.

Excipient

• In the pharmaceutical world, an impurity is considered as any other organic or inorganic material, besides the drug substance, or ingredients, arise out of synthesis or unwanted chemicals that remains with API’s and excipients.

• The presence of these unwanted chemicals, even in small amount, may influence the efficacy and safety of the pharmaceutical products.

• These impurities may arise during manufacturing process as by products and/or storage, and/or organic or inorganic liquids used during the manufacturing process.

• Various regulatory authorities such as USFDA and Canadian Drug and Health Agency are emphasizing on the purity requirements and the identification of impurities in Active Pharmaceutical Ingredient’s (API’s).

• Evaluating of impurities is done by variety of Chromatographic and Spectroscopic techniques. At Xylopia the Conventional Liquid Chromatography that I worked on was the HPLC which was used in field of impurity profiling.

Impurities

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• There are various types of drug dosage forms such as solid, oral solutions, suspensions, and emulsions.

• The dosage forms are the means by which drug molecules are delivered to sites of action in the body.

• Determines the root of administration. And the root of administration is the path by which a drug is taken into the body.

• There are various dosage forms such as oral, topical, rectal, vaginal, parenteral, inhaled, opthalmic, and otic.

Oral Topical Rectal Vaginal Parental Inhaled Ophthal Otic

Dosage Forms

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Literature Search

Sourcing Raw

Material

Testing materials

Innovator Product testing

Manufacturingprocess

Analytical Evaluation

Process Optimization

Scale up Batch

Bio Study ANDA Submission

Product Development Cycle

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Identifying the product:• Literature Research – using various search guides such as Office of Generic Drugs (OGD),

Electronic Data Base (articles and publication on test methods, Dissolution synthesis procedures, drug impurities, pharmacokinetics and dynamics), US Pharmacopia (USP), The Center for Drug Evaluation and Research (CDER).

• Evaluation of Biostudy parameters and Dissolution methods.• Patent evaluation.

Project Management: • Coordinate with various departments to provide for a seamless development of generic drugs.• Type of drug to be developed based on cost, requirement and profitability.• Sourcing various ingredients such as API, excipient, reference product, and packaging.• Coordinate with the analytical, formulation, and packaging teams for material.• After formation of a prototype, it is tested on healthy humans at a clinical research organization.

(third party service provider).• The results of these test are evaluated by formulation department for any improvement or

changes required.• Coordinate with manufacturing plant to transfer the development technology and manufacture

large batches.

Product Identification and Project Management Literature Search

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Sourcing material: • Identifying right source for raw materials such as API, excipients, bulk drugs and

other chemicals.• Samples are acquired with the certificate of analysis and specifications.

Evaluation:• Drug Master File (DMF) availability.• Compliance with USP.• Impurity profile and stability.

Testing materials• Testing conducted by analytical lab with in-house methods and/or suppliers test

methods.

Sourcing, evaluation and testingRawMaterials

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• Evaluating physical parameters such as tablet shape, color, punching, embossing, pack sizes, and more.

• Testing weight, thickness, hardness and more.• Evaluating innovator formula ingredients by analytical testing.• Observing particle size and crystallization.• Dissolution profile.• Evaluating of Biostudy parameters.

Innovator product testing and characterization InnovatorProduct

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Manufacturing Processes

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• Preformulation involves the characterization of a drug's physicochemical properties in order to choose what other ingredients (excipients) should be used in the drug product.

• Pre-formulation also includes drug – excipients compatibility study.• Drug-excipient compatibility is performed by preparing binary mixer of the API and

excipient in known ratio.• This mixture is stored for 1 month at room conditions of 25°C with 60% humidity. To

accelerate this process the mixture is stored at 40°C with 75% humidity. • This data is captured in PDR and submitted with ANDA to the FDA.

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• There are wet and dry granulation processes• At Xylopia there are two machines for wet granulation: Rapid Mixer Granulator (RMG) and Fluid Bed Processor.• For dry granulation they have machine called Roll Compactor• For Product A I used RMG machine. It is a commonly used process to improve flowability and compressibility.• RMG has two blades: impeller, used for mixing and chopper, used for cutting down• Then the API, disintegrant and diluent was added to the RMG• I started the impellor to mix for 600 seconds. • Then I added the binder solution (Polyvinylpyrrolidone (PVP) in water) into the RMG for 120 seconds. • Then we started the kneading process in which the

impeller and the chopper were put on a faster speed. The RMG was operated for another 120 seconds.

• After checking the material I had to re-run the RMG foranother 60 seconds.

• After the granules were formed, I discharged the material.

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Fluid bed processor is used to produce free flowing granules. It is a machine in which simultaneous granulation and drying takes place. There are two modes in the fluid bed processor: top spray in which binder sprays from top and Bottom spray in which binder sprays from the bottom. In the fluid bed processor there are filters on the top to prevent the material from over running and hence only air is released. Process for Product B: Used top spray • The API is co-sifted with lactose as the diluent. We put this in the

fluid bed processor.• Initially I do not spray the binder solution. The binder solution is ethyl

cellulose dissolved in IPA and water mixture. • the materials are pre mixed for 10 minutes in FBP at low air flow. • Then I started spraying binder solution at constant flow rate.• After approximately 45 minutes, the formation of granules were observed.• As the process continued, I increased the air blower velocity because

the material was getting heavier due to addition of binder solution. Therefore it had to be fluidized with greater air velocity.

• After the binder solution finished, I stopped the spray and continued drying process.

• Then I collected a small amount of material for sampling. • I checked the moisture content in a halogen moisture analyzer.• I needed 5% or less moisture . I got satisfactory results. So I stopped

the machine and then collected the material.• Then I sifted the material through a sieve to get uniform granules.

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• I added the material that I granulated into RMG. • This container was fitted onto the machine . • Hot air passed from the bottom.• After 5 minutes I measured the moisture content of the material by putting it in the

moisture analyzer. • The moisture content in the material was 6.5%. The requirement is less than 7%. • Therefore there was no further drying required.

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During the drug manufacturing process, milling is often required in order to reduce the average particle size in drug powder.

There many types of milling process. I worked on three types: The comminuting mill (Cadmill), Ball Mill and Conical Milling (Comill).

The Cadmill device has knives which cut down the material till it passes through particular sized sieve. I used 3mm sieve for Product C. The Cadmill has three speeds. The knives in the Cadmill are sharp on one side and flat on the other side, as in the picture. When sharp edge cuts the particles it is called ‘knives forward’. When the flat part crushes the particles it is called ‘impact forward’. The rotation is reversible. For Product C, I used knives forward.

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A Ball Mill is a typical type of fine grinder. A slightly inclined or horizontal rotating cylinder is partially filled with balls, usually stone or metal, which grinds material to the necessary fineness by friction and impact with the tumbling balls. The ball milling is done to cut down particle size, and that increases solubility.

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A Conical Mill used to reduce the size of material in a uniform manner. The Conical Mill varies in diameter from where the feed enters to where the product exits. The Conical Mill operates by having the product being fed into the mill by gravity or vacuum.

For Product A I used 1.5mm mill screen

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• Blending is a process which mixes the API and excipients to ensure there is ahomogeneous blend of the all ingredients for subsequent manufacturing process.

• Blending is a process that can be carried out numerous times within a manufacturingprocess when new excipients need to be added to the blend.

• I put the sized granules of product A into the blender and added , diluent, disintegrate and lubricant to the product and then began the blending process for approximately 15 minutes.

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• There compression machines are used to produce the tablets from the blend.• The machine consists of a die, which is a disc shape with a hole cut through its centre, to fill the

material in exact amounts.• The machine has a hopper to input material.• It also has a feed frame that is used to collect material and allow exact amounts to pass into the die. It

also scraps excess material from the die.• The powder is compressed in the centre of the die by two hardened steel punches • The turret is the rotating part that holds

the dies’ and punches. • Tooling is the term for the upper punch,

lower punch and die. • There are a few types of tooling such as:-B type tooling for lower weight-D type tooling for more than 500mg weight-BB type tooling between two above

• There is a precompression roller and main compression roller to press the punches.

• There is a weight adjustment knob to fill exact weight in die and a hardness adjustment knob to acquire the accurate hardness.

22Animation file from the Wikimedia Commons

• I began the process by transferring the material into the hopper. • The die got filled with material stored in the feed frame and access

material was discarded by the scraper.• As the die moves, the punches get pushed towards the hole of the die

by pre-compression roller. This is done essentially to remove the air gaps between the material.

• Then the die and punches moves towards to the main compression roller.• The upper and lower punches gets pushed by the main compression

rollers downwards and upwards respectively to produce the final tablet.This tablet exits the machine.

• I checked the weight of the tablet. It was suppose to be 200mg. But it came out to be 314mg. and I checked the hardness in the hardness tester which came to be 4 kp.

• So I decreased the mass by altering the weight adjustment knob to get closer to 200 mg. and increased the hardness by altering the hardness adjustment knob to get to 9 kp.

• After a few trials and errors I got the desired weight and hardness.

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Bilayered Compression:

• The bilayered compression is different from the single layer machine.

• The compression of two different blend into a single tablet.• First I used only first material and did the initiate compression

process• This is done to achieve proper parameters of weight and hardness

for the first layer.• The hardness should be low for just the first layer alone for the

second layer to stick on it. If the hardness is high, than the second layer won’t stick.

• After satisfying parameters were achieved , we added the second layer into the machine.

• Then we started bilayered compression. • And while checking the parameters for the final product an

earthquake took place (April 25,2015).• I had to abort the process.

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• Tablet coatings are polymer and polysaccharide based and strong enough to survive the handling of the tablet, must not make tablets stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets.

• Coatings are necessary for tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to swallow.

• Tablet coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation.

• Coatings also enhance brand recognition.• Protecting drug from the gastric environment. • Coating modifies release rate of the drug in the body. • Coating contains polymer which adhere. • There are 3 parts

-polymer for film formation-solvent to prepare solution for uniform dispersion-plasticizer to give flexibility to film and to bed temperature during coating process.

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Process: Preparation of the fluid for coating• First made a mixture of isopropyl alcohol (IPA) [90%] and water [10%] for coating. • Then weighed 308g of IPA and 34g of water.• Then weighed the polymer. The plasticizer should be 10% to 30% of polymer. • Then mixed the IPA and polymer in a mixer and added plasticizer. • Then added ready mixture(brown color). • Then added water. Due to the addition of water the viscosity of the mixture

increased. • Then covered the beaker having the mixture being mixed with a foil to prevent

evaporation as the solvent (IPA) evaporates at room temp. • Then stirred it for around 15 minutes. • Then filtered the mixture to remove any lump and to get smooth dispersion. • The nozzle in the coating machine has a diameter of 1mm. (no 20), so there

should not be bigger particles then that. • So we passed the dispersion through ASTM no. 60 sieve. After this the dispesrion

is ready for coating.

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Process: Coating• First the tablets were kept in the machine to dry as they contain some

moisture from the air. After they were dried I measured the weight of some tablets. Took average weight.

• The tablets weighed had an average weight of 200.0006 mg. • After the coating the weight of the tablet should increase by around 3%.

So the weight after coating was around 206mg.• Then started the spray. It is pumped by a peristaltic pump.• Then took the recordings of process parameters such as inlet temp, outlet

temp, bed/product temp, spray rate, atomization air pressure and pan rpm.

• Checked the weight of the tablets few times to verify.• After the correct weight was gained I stopped the spraying and let the

tablets dry. • the tablets were evaluated for any physical defect.

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Analytical Development and Evaluation Analytical Evaluation

• Analytical chemistry supports pharmaceutical drug development by providing assurance of the quality, safety and efficacy of medicines.

• There are different types of chromatographic procedures such as HPLCs (high performance liquid chromatography), GC (gas chromatography), TLC (thin layered chromatography), IC (iron exchange chromatography) and gel chromatography.

• At Xylopia I worked on HPLC• The mobile phase ionizes the components of the drug solution to gain affinity to silica and the organic

phase eludes the material from the silica column.• HPLC contains silica column which helps distribute the different components of the drug according to the affinity

to the Silica

The HPLC has different parts: -The first part is the motor to suck in the phases. -The second part is the part in which all the different phases get mixed in proper proportions.-The third part has a chamber containing HPLC vials containing the drug solution which are extracted and sent to the next stage with the mixed phases.

-The next part contains the silica column which is where the drug components get separated. The –mixed mobile phase and organic phase also goes to the column.

-The last part is the UV detector which analyses and sends the reports to the computer. It shows absorbance in graph form.

• The mobile phase, organic phase, water and other substances are placed on the top of the HPLC.• On top of the HPLC there are ports. Our mobile phase went in port A, the organic phase in port B, water in port

C and methanol or acetonitrile in port D. Port C and D are used to clean the HPLC and column after use.

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Analytical Development and Evaluation Analytical Evaluation

Process:• Begin with Chromeleon software that runs the HPLC• Then begin purging process in the all the ports. This is done to clean all the tubes in the HPLC and to remove bubbles from the phases. If bubbles persistently appear then you need to sonicate the specific phase.

• Then inserted the vials containing the drug solution in the HPLC • Then designed the program of ‘sequence of events’ in the chromeleon software to run the HPLC• After the program completed, received different graphs which showed the amount of UV lightenergy the substance emitted.

• This is compared to the reference standard.

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Analytical Development and Evaluation Analytical Evaluation

UV Spectrophotometer:

• In chemistry, spectrophotometry is the quantitative measurement of the reflection or absorption properties of material.

• I was measuring the absorbance of Mirabergron solution. Overnight the six Mirabergron tablet was kept in a dissolution apparatus in the media (ph 6.8 phosphate buffer) for 12 hours. At specific time intervals the small portion of the media is sampled out for each tablet.

• Before operating the UV Spectrophotmeter we have to make a standard against which the samples made above are checked.

• Making the standard: We weighed 56.43mg of Mirabergron and put it in a 100 ml volumetric flask. Then added 5 ml of ethanol to dissolve the Mirabegron. Then added ph 6.8 phosphate buffer till the 100 ml mark is reached.

• Then used pipette to extract 5ml of the solution and put it in a 200 ml volumetric flask. Then added ph 6.8 phosphate buffer till the 200 ml mark is reached. The above process is done twice to give us two working standards. Two standards are made for assurance.

• Begin with UV Probe software that runs the UV Spectrophotometer. Designed the program file to begin running the machine.

• Cuvettes are the vials made of quartz in which the solution are kept for testing in the UV Spectrophotometer.• In one cuvette we put ph 6.8 phosphate buffer (blank) and all the solutions are measured in comparison to this

blank. Then the we begin the procedure to measure the absorbance of each solution in comparison to the blank. • Then the statistics were generated. • Then the calculation sheet was made in which these statistics were inputed. The purpose of this sheet is show

the RSD (Relative Standard Deviation). This is shared with the formulation dept. so that they can improve on the formulation of the drug.

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PackagingPackaging

There are mainly four types of packaging executed at Xylopia.

Blister packs: are mainly of two types. Thermoform which is made of PVC (Polyvinyl Chloride) and PVDC (Polyvinylidene Chloride). Coldform which is made of OPA (Oriented Polyamide), aluminium and PVC.A blister is made of two parts: forming foil and a lidding foil.

HDPE bottles: High Density Polyethylene bottles. It can be round or rectangular. It has two types of closures. One is CRC (child resistant closure) and the other is NCRC (non-child resistant closure). CRC cap used for unit dose dispensed for patients. NCRC is used in hospital packs. There are three types of HDPE bottles: normal weight, heavy weight and ultraheavy weight. These are categorised according to product sensitivity.

PET bottles- polyethylene terephthalate bottles. It is used for liquid dosage form. For light sensitive material the PET bottle color is amber.

Glass bottles- they are used for suspensions.

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Quality Assurance

Functions of QA:• The main function of QA is to have control of quality. • SOP - Standard Operating Procedure. These are managed by QA• The QA gets MFC (master formula card). QA will review and approve these MFCs.• QA works with issuance, retrieval, and archival.• Guidelines are prepared by QA which is practiced by the whole premise.• If there is a change to be done then it is done by a controlled procedure. • It is called the change control system. • Deviations are temporary changes.• QA also looks after employee training.• For new instruments QA will do IQ(installation qualification), OQ(operational qualification)

and PQ(performance qualification). QA also compiles the documents required for technology transfer to manufacturing site.

• Water purity check and also area monitoring for the site(temp, and humidity) is done by QA.• STP( standard test procedure) is formed by respective department but it is reviewed by QA.• QA does internal audits at regular time periods.

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Regulatory Affairs

• Regulatory affairs include forming CTD (Common Technical Document) format for ANDA.• DMF Drug Master File) Drug Master File or DMF is a document prepared by a pharmaceutical

manufacturer and submitted solely at its discretion to the appropriate regulatory authority in the intended drug market. The document provides the regulatory authority with confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.

• One of the basic functions of the RA is to check whether the different files and processes are according to FDA requirements and submitting the file to FDA by filing for Abbreviated New Drug Application (ANDA).ANDA has 5 modules:

-Administrative information-Summary of ANDA-Chemistry manufacturing and control-Non clinical study(not applicable)-Clinical study( BA and BE)

• The label is made by RA. It is named according to the main substance. • The NDC(national drug code) is on the label for identification of developers.• The package insert is also handled by RA.• RA responds to FDA queries

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Thank you35

Glossary

API: Active Pharmaceutical IngredientExcipient: is a natural or synthetic substance formulated alongside the active ingredient of a medicationImpurities: are substances inside a confined amount of liquid, gas, or solid, which differ from the chemical composition of the material or compound.USFDA: The Consumer Protection Agency of the U.S. Government which monitors medical devices, foods, & drugs, USP: The U.S. Pharmacopeial Convention is a scientific non profit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed and consumed worldwide. USP’s drug standards are enforceable in the United States by the Food and Drug Administration, and these standards are used in more than 140 countries.FPP: Finished Pharmaceutical ProductOGD: The Office of Generic Drugs is responsible for providing regulatory oversight to expedite the availability of safe, effective, and high-quality generic drugs.CDER: The Center for Drug Evaluation and Research 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. It is part of USFDA.NDA: new drug applicationANDA: Abbreviated New Drug Application. Application for generic drugsDMF: Drug Master File is a document prepared by a pharmaceutical manufacturer and submitted solely at its discretion to the appropriate regulatory authority in the intended drug market.BABE: Bioavailability & BioequivalenceQA: Quality AssuranceRA: Regulatory AffairsHPLC: high performance liquid chromatographyCRO: Clinical Research OrganizationInnovator Drug: are brand-name drugs. These drugs are patented, which protects them from market competition because generic companies cannot replicate them while they remain under patent.Generic: is a drug defined as "a drug product that is comparable to a brand/reference listed drug product in dosage form, strength, quality and performance characteristics, and intended usHDPE: High Density Polyethylene bottles offer good strength and chemical resistance.SOP: Standard Operating Procedure.RLD: Reference Listed Drug is an FDA-approved drug product to which new generic versions are compared to show that they are bioequivalent.GMP: Good Manufacturing Practices are a set of internationally recognized standards which are applied to drug manufacturing to ensure drug quality and safety.