Intro to the profession test 2

what is the Primary processing stage:

synthesis and manufacturing at

industrial scale of active ingredient.

what is the Secondary processing stage

conversion of the active ingredients into pharmaceutical medicines. (Formulation science)

➢ Solid dosage forms: tablet, capsule, sachet,...

➢ Semi-solid dosage forms: cream, ointment, gel, suppository,...

➢ Liquid dosage forms: syrup, emulsion, suspension,...

➢ Patch and other dosage forms

what is the definition of an API

Active Pharmaceutical Ingredient is a chemical substance that interact with a living system and

produces a biological response

What are Excipients

Excipients are safe chemical substances that have been incorporated into

the drug product in order to:

➢ Facilitate the manufacturing of the drug product

➢ To protect, support, or enhance stability, bioavailability, or patient acceptability

➢ To assist in product identification

➢ Provide taste masking and palatability enhancement

➢ Control drug release rate

What is drug product?

A drug product consist of a mixture of API and Excipients combined in a

delivery system (i.e. Tablet, capsule, solution,...).

➢ The success of a drug product lies in its ability to deliver the whole dose of

API at a certain rate in a certain environment in the body.

➢ Example of drug product

➢ Tylenol

➢ Advil

Manufacturing process of drug products

Manufacturing process of drug product involves a series of important steps

including:

➢ Product design and feasibility study

➢ Pre-formulation and formulation

➢ Scale-up and commercial batch manufacturing

➢ Packaging

➢ Quality control testing

➢ Storage

➢ The whole development manufacturing process is said to be complete

when all these steps are completed successfully.

what are the goals in product development goals

• bioavalability ideas at least 30% of target profile

• stability idealy 2years +

• ease of administration

• manufacturability

  • scalable

  • reproducible

  • cost effective

what are the invivo dissolution absorption

• dosage form

• disintergration

• granules

• deaggregration

• fine particles

• dissolution in the gut lumen

  • transportation into the blood in the papilla

what effects in vivo disolution and absorptiom

• characteristics of the API solubility

  • absorption depends on the release rate of the drug substance

what is the test to evaluate in vitro bioavalibility

• dissolution test

• USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm.

• Dissolution media (900 ml):

• Simulated gastric fluid (SIF) 0.1 N HCl

• Simulated intestinal fluid (SIF) pH 6.8 or 7.5 (i.e. phosphate buffer).

• Temperature 37  2oC

what is the BCS classification

based on solubility and permeability

1=solubility is high premability high

2=sol=low perm=high

3=sol=high perm=low

4=sol=low perm=low

what are the conditions for highly soluble drug

< 250 ml water over

a pH range of 1 to 7.5.

what are the conditions for a drug to be highly permeable

> 90% of an administered dose mass-balance or in comparison to an

intravenous reference dose.

a drug is considered repidly disolving when

more than 85% of the labeled amount of the drug substance disolves in 30 mins using a USP apparatus I or II of less than 900 mL buffer colution

what are the components of solid dosage form development

• excepients

• API

  • process

what are the partd of the piolt scale 1

After promising formulation and stability data, first step in evaluating

manufacturability.

➢ Large enough to challenge process parameters such as Mixing and

lubrication time, press speed, hardness etc..

➢ Tablets produced at this scale can be used for clinical studies (phase 1).

what is the approved protocall before starting up

➢ Objective

➢ Scope

➢ Responsibilities

➢ Formulation

➢ Equipment

➢ Critical process parameters

➢ Sampling, testing and acceptance criteria

➢ Approved report incorporating results

what are the needs for scale reproducibility

Confirmation of parameters established during scale-up.

➢ The drug product will be tested for stability to support the clinical study.

➢ Quality Assurance involved in later stages for approval of established

tentative finished products specifications to be used for clinical studies

manufacturing.

➢ Parameters conformed will be used in the manufacturing of clinical batch.

what needs to be done for pivotal scale 1

Scale to up to one tenth of the commercial scale.

➢ If the commercial batch size is 1 million tablets, the pivotal scale will be one tenth of

1 million = 100, 000 tablets

➢ Protocol and Report approved by QA usually.

➢ Same or more challenges as Pilot scale.

➢ Parameters established to be used for

clinical (phase III) trials manufacturing (CTM

what needs to be done for pivotal scale 2

Three batches produced at this scale for stability and submission purposes.

➢ Stability collected in several packaging formats (close and open bottles,

blister, final packaging, ...).

➢ Drug product put under several stability conditions.

what are the conditions for stability tests

• Accelerated

  • 40C+-2C

  • 75% RH

• Intermediate

  • 30C

  • 5% RH

  • 6 months

• long term

  • 25-30 C+-2 C

  • RH +- 5%

  • 12 months

what is CMC

Chemistry and Manufacturing Controls

what is necessary for drug submission

New Drug Submission (NDA).

➢ Chemistry and Manufacturing Controls (CMC) part from all the data

collected.

➢ A validation commitment is given to be performed at Commercial Scale.

➢ Pre-approval inspection will be conducted (PAI).

what is process validation1

Establishing by objective written evidence that a process

consistently produces a result or product meeting its

predetermined requirements (specifications).

what is process validation 2

All equipments have to be initially validated: Installation qualification,

operation qualification, and process qualification (IQ/OQ/PQ).

➢ All process parameters established.

➢ Protocol and report have to be done.

➢ Traditionally three consecutive batches

Process Validation (III

➢ Extra sampling and testing will be performed.

➢ Batches manufactured may be used commercially.

➢ Batches put on stability.

what is the % of pill usage?

More than 80% of the drugs are formulated in solid

dosage form.

what are the types of tablets

• Uncoated tablets.

• Film coated tablets.

  • non functioning ex: colour flavour, easier to swallow

  • functioning modifered release enteric coating effecting relase rate of drugs SR slow relase, extended relase MR modified release

• Sublingual tablets.

• Effervescent tablets(disolving)

• Chewable tablets.

➢ Orally disintegrating tablet or Oro-dispersible tablet (ODT). disolves on tongue rapidly

advantages of tablets

• simple and cheap to manufacture

• most chemically and microbial stable

• convenient packaging/shipping/storage

• easy for pt, uniform dose

tablet disatantages

-difficult to swallow

• some API damaged in compression

• GI irritation

• API with low solubility=slow disolution=low apsorption

• some API ex: insulin damaged by stomach acid or can’t be absorbed from the GI lumin

what are the components of tablets

• Diluents(API dose is soo small it needs the bult to be handled, cohesion, allows direct compression (10-90%)ex:lactose,direct compressed starch, Microcrystalline cellulose

• binders(needed to compress the tablet together to stick) increase strength also used in granules(Cellulose derivatives- Methyl cellulose, Hydroxy propyl methyl cellulose, Hydroxy propyl cellulose: 2-10% (w/v) or glucose: 25-50% (w/v), etc)

• disintegrants(makes the tablet fall apart)(➢ Cellulose derivatives- Ac- Di-Sol (sodium carboxy methyl cellulose): 1-5% of tablet weight. Crosspovidone- cross-linked povidone (polymer): 1-5% of tablet weight

• Lubricants. increases powder flow reduce inter particle friction during the compression, help eject from , machien, 0.5-2% of the tablet weight Stearic acid, Magnesium stearate and Talc

• glidants: promote flow of granules or powder/reducing the friction between the particles Corn Starch: 5-10% conc., Talc: 5% conc., Silica derivative -

  Colloidal silicas such as Cab-O-Sil, Syloid, Aerosil in 0.25-3% conc.

• colour: hiding off colour, ID of drugs/strength, elegant product

• flavoring/sweetening agents. chewable=sugar/mannitol. saccharine 500x of sucrose&bitter. Aspartame not stable with moisture

types of tablets

• direct compression→all together mixed with lub the last step→ compression

• dry ganulation(api/diluent/lub mix)→compression→comminution→screening→mix(disintegrat/glid/lub)→compression

• wet granulation (api/diluent mix)→wetting (binder/solvent)→granulation→dry→screening→mix(disintegrant/glident/lub)→compression→fill die→compessed tab→eject tab→metal check→dedusting→coating

advantage and disadvantages of direct compression

ad

• fewer steps/less time

dis

• difference in particle size/density of api caused from seperation in hopper.

• static=seperation

• low uniformity in low dose production

  • flow issues cause variation

advantage and disadvantages of direct granulation

adv

• improved flow=increasing particle size

• improved uniformity pof density

dis

• more steps

• over compaction / some granules have higher api %

advantage and disadvantages of wet granulation

adv

• improved flow=increasing particle size and sphericity

• uniform aip distripution&colour

• less dust

• lowest conpression pressure/good for bulky powders

dis

• most steps

• more equiptment

• more time

dispencing is the most critical part and why

➢ dust control (laminar air flow booths, glove boxes)

➢ weighing accuracy

➢ multiple lots of active ingredient with different assays, moisture and residual solvent content

➢ cross contamination

why do drying for wet granulation

to keep residule moisture low

to prevent deteriation,

keep free flowing properties

Benefits of milling:

➢ Will increase the surface area - this may enhance rate of dissolution

➢ Will improve content uniformity due to increased number of particles per unit weight

➢ Will uniformly size the wet granules which promotes uniform drying

➢ Will enhance flow properties of raw materials

what are the types of blenders

• ribbon blenders- non pharma- less uniform more volume

• vblender for pharma- lower vol, better blending

types of granulation drying

• oven tray drying/static/direct - not reliable clumps form

• fluid bed/dynamic heating- control air velocity and temperature

impeller at the bottom

verticle chopper keeps particles small

because you need to control lv of moisture during blending 2-4%

dynamic heating =less time

stages of blending

• dispencing with balencing

• sieves(20-60 mesh)f is only mied with 60 the rest with 20 to start

• blending with v blender

issues with blending

• mix longer to make more even

• difficulty since density and particle size is different

• almost imposible if particles are a different size

types of compression

single punch/single station presses

multi station/rotart presses

stages of compression

• powder vol control(more filling lowering of lower punch metering cam controls)

• stripped excess material

• compression:pressure roll comes first to pree press(loweing of upperpunch)

• tablet eject scrapper push out upper punch moves out of the way first)

what does QC do

• perform analytical testing

• To perform sampling of RM

• To develop analytical method

• Responsible for cleaning validation

• Responsible of stability program

➢ Safety

➢ Efficacy

➢ Quality

➢ Compliance (i.e. FDA regulatory, Health Canada)

• reactive quality process

• finished product and RM

• set of activities for

  ensuring quality of product. The

  activities focus on identifying

  defects in the actual products

  produced

what does qa do?

To review, approve/reject protocol, reports, tests

• To establish procedures and specifications

• To audit compliance to the quality system

• To ensure investigation of non-conformity

• To describe responsibilities in writing

• To keep management informed

• set up activities quality in the processes by which products

are developed.

• proactive quality process

QC equiptment

Spectroscopy techniques

➢ Ultra-violet (UV)

➢ Infra-red (IR)

➢ Chromatography techniques

➢ TLC (thin layer chromatography)

➢ HPLC (high pressure liquid chromatography)

➢ GC (gas chromatography)

➢ Titration

➢ Acid-base titration

➢ Physical test

what causes quality variation

Materials:

a) Variations among suppliers of same substances (supplier-to-supplier variation)

b) Variations among batches from same suppliers (batch-to-batch variation)

2) Methods:

a) Wrong procedures

b) Inadequate procedure

c) Negligence of procedure

3 Machines

a) Variation of equipment of same process

b) Difference of adjustment of equipment

c) Aging of machines and bad maintenance

4 Personnel

a) Improper working conditions

b) Inadequate training

c) Negligence and lack of interest

what is on the CoA

name

acceptence values

criteria

if tablet breaks

do a cause effect study and brianstom with the head of each department

what is material control

• selection of materials

• maintain lv of material

• inventory system is adequate

• control of RH & temp

• testing of RM

• procedures of receiving, storage, testing of RM

• -label Quarenteen

• sample

• pass-” production, fain-” rejection

• manufactuing practice control→GMP, follow manufactuing procedures

• design of building and location, size

• equiptment fixt min and max of batch sizes

• each room is for a dedicated step

• airlock system so one door at a time opens

• slope of the ground allows for draining

• for more effienency and less variation outsource or lower batch size if the equiptment can’t handle a large batch

• equiptment is easy to assemble and disessemble and clean, and empty

• 
  

QA personnel

They should be properly selected and well trained.

➢ They should be dedicated for this job (saving life of sick people).

➢ They should be warned about the consequences caused by their mistakes and errors.

➢ QA should be present during manufacturing of drug product.

what does the FDA regulate?

Human Prescription and Non-prescription Drugs

➢ safety, effectiveness, quality, and labeling

➢ manufacturing standards

USP-NF

united states pharmacopeia and the national formulary

-monographs 4700

-270 step-by-step guidance for assays, tests, and procedures.

• reagents, indicators, and solutions, plus reference

  tables

• ensure complience

• establish and validate inhouse standard operating procedues and specs

• expedite new product developemnt and approvals

• in 140 countries

what is the US pharmacopeia

develops standards for drug products

healthcare delivery

products and practices

to USP standarss

dev authoriation and unbiased info on drug use

to gelp ensure srandars to safety and quality

standards for handeling and prepareing radiopharmaceuticles sterile and non sterile

how to handle hazardous drugs

standars for prepaing sterile drugs aseptic techniques, enviromental quality, microbial control, qa

standards for preparing creams

how is a monograph generate

• submit draft with api strength and excepitants

• USP staff verdict refineor finalize

what are the 5 essential general chaptes of USP NF

<795> Pharmaceutical Compounding—Nonsterile Preparations

➢ <797> Pharmaceutical Compounding—Sterile Preparations

➢ <800> Hazardous Drugs —Handling in Healthcare Settings

➢ <825> Radiopharmaceuticals —Preparation, Compounding, Dispensing and Repackaging

➢ <1160> Pharmaceutical Calculations in Pharmacy practice