MANUFACTURING LECTURE

MODIFIED-RELEASE ORAL DRUG DELIVERY

Oral dosage form

 Widely accepted by patients and easier to

administer
 Has accurate dosing
 Cost effective w/ improved product shelf-life

Introduction

• Purpose of drug delivery system: To provide a
therapeutically effective drug amount to the appropriate
body site for a desired duration of action.
• Purpose of site-specific drug delivery systems: To improve
drug’s efficacy and safety.
 Focus on development on t he duration of release
mechanism with desired release rate w/c may span
for very fast to very slow or controlled release
mechanism
What MR drug delivery means for healthcare
professionals and the pharmaceutical industry?
▪ Provide physician, pharmacist, and patient choice: tailored
treatment based on patient’s needs
▪ Product life extension: extension of product’s patent life
▪ Higher development costs: requires funding
▪ Cost savings for healthcare providers: leading to better
disease management

• Pharmaceutical scientists: Better understanding of GI 4 PROCESSES OF MODIFIED-RELEASE

tract anatomy, physiological barriers to drug absorption, and
1. Devise hydration. The swelling or the dissolution of some
the need for different release profiles for different disease
conditions. components of the modified-release dosage forms are
involved such as polymeric solutions or gels.
• Purpose of modified-release drug delivery: To optimize
2. Water Diffusion into devise
drug performance and to enhance patient tolerance
(reduction in side effects). 3. Drug Dissolution
• Advantage: Patent life extension due to reformulation of 4. Diffusion of drug out of the devise
marketed drug products lead to wider acceptance of the
patients and allowed the manufacturers to extend patent life.
EXTENDED-RELEASE SYSTEM
• Science-based and risk-managed process of drug product
development supported by QbD (quality by design) Definition:
principles.
 Exhibit a lag time in a drug release to target a
2 TYPES: specific site in the body.

1. DELAYED-RELEASE ▪ Achieved by coating an oral solid dosage form with an

enteric polymeric film commonly referred to as polyacids
2. EXTENDED-RELEASE which possess acidic functional groups (carboxyl groups)
and exhibit pH-dependent solubility.

▪ It remains intact in the low pH of the stomach and starts to

What modified-release drug delivery means for the
dissolve at the higher pH of the small intestine (pH 5 – 7).
patient?
- Once they reach pH 5-7, drug will be dissolved and release
▪ Keeping the drug in the therapeutic range.
out of matrix.
▪ Maintaining drug level overnight.
- usually site specific
▪ Chronotherapy.
▪ General purposes of enteric coatings
▪ Reducing side effects.
 To protect the drug from harmful effects of gastric
▪ Improving patient adherence. environment.
 To minimize irritating effects of certain drugs
▪ Treatment of local areas in the GI tract. (NSAIDs) on the gastric mucosa.
 To deliver drug to the intestine for local effects.
 MANUFACTURING LECTURE

MODIFIED-RELEASE ORAL DRUG DELIVERY

▪ General classes: Drug Release Rate Considerations

 Cellulosics (Cellulose Acetate Phthalate, Hydroxy Summary Of Some Equations Describing Drug Release
Propyl Methyl Cellulose Phthalate) Kinetics From The Extended-Release Systems
 vinyl (Poly Vinyl Acetate Phthalate) Kinetics Equation
 Acrylics Zero Order Q=kt+a
 natural polymers (shellac, rosin) Higuchi model (1963) Q=k(t)0.5
Korsmeyer-Peppas Model Q=k(t)n
▪ Gastro-resistant coatings have been used to deliver anti-
Peppas-Sahlin model Q=Kdtn + Krt2n
inflammatory medications such as budesonide,
beclomethasone, and mesalazine in treating ulcerative colitis
in the large intestine. Diffusional Exponent (n) and the Theoretical Mechanism
of Drug release from Swellable Systems having
 should add intermediate film coat to separate the
API from acidic enteric material. Spherical Geometry
Diffusional Drug release mechanism
Exponent (n)
0.43<n<0.50 Fickian diffusion (first order)
0.50<n<0.89 Anomalous release (pseudo-first
order)
0.89<n<1.00 Cass II transport (zero order)
n>1.00 Super case II transport (unknown
release)
Zero order is independent of the drug amount of a dosage
▪ Colonic drug delivery can be achieved by utilizing pH- forms and remains constant overtime.
responsive polymers to target the colon (ex. Eudragit S) or
using gut bacteria (colonic bacteria) as triggers for drug Super case II transport should swell first in the solvent then
release (ex. resistant starch which can be broken down by erode releasing the drug out of the system.
bacterial enzymes in the colon.

Need to reduce the dosing frequency and eliminate the

EXTENDED-RELEASE SYSTEM
fluctuations in blood concentrations associated with
conventional delivery.

Drugs are slowly released over extended time frame and

could be termed as SUSTAINED-Release, slow-release or
CONTROLLED-Release

Use the term controlled-release because the drug delivery at

a predetermined rate for a definite time period.
▪ Drug dissolution from the enteric-coated dosage forms is
evaluated in acidic pH initially (1-2 hrs, as recommended by ▪ Advantages
the drug product monograph for a specific API) and then in
❑ Improved patient adherence due to less frequency of drug
an appropriate phosphate buffer.
administration.

 Expensive or costly but can lead to economic

savings since can retain the blood concentrations.

❑ Economic savings as a result from a decrease in

hospitalizations and less lost work time.
 MANUFACTURING LECTURE

MODIFIED-RELEASE ORAL DRUG DELIVERY

▪ Considerations in developing ER dosage form ❖ Hydrophilic matrix system

❑ Physiological and biopharmaceutical factors (GI ▪ aka swellable soluble matrices

conditions, transit time, and the presence and types of food
ingredients such as grapefruit juice enhances BA of
cyclosporin, midazolam, terfenadine, and felodipine due to
inhibition of both efflux transporter P-glycoprotein and
intestinal metabolism.)
 Very simple & cost effective approach
 Prepared by direct compression, roller compaction,
or wet granulation of ingredient of 1 or more suitable
release retardant hydrophilic polymer

❑ Physicochemical drug properties (drug dose and ▪ Drug particles are dispersed in a hydrophilic polymeric
matrix (HPMC / Hypromellose, polyethylene oxide).
solubility)
▪ Drug release occurs by drug dissolution, diffusion through
• BCS Class I drugs: High solubility & high permeability
the gel layer, or erosion of the matrix.
drugs

Type I: high solubility, high permeability

Type II: high solubility, low permeability

Type III: low solubility, high permeability

Type IV: low solubility, low permeability

• It may be difficult to (be coated) sufficiently slow or changes

the dissolution of a drug with very high aqueous solubility. Formulation and Manufacturing Considerations in the
Should also consider the half-life design of Hydrophilic Matrices
Formulation Key Considerations
• Up to 1000 mg potency tablets are available in ER Components
formulations, but this is only achieved by using very large Drug Solubility, dose, pKa, stability,
tablets which may not always be acceptable for some patient and particle size
populations. High viscosity grade of Particle size, type and level
polymer
Filler excipients Level/type, (water
Considerations for dose dumping: soluble/insoluble)
Lubricants and Level/type (stearates,
Dose dumping: a phenomenon which relatively large
glidants nonstearates, and fatty acids)
amount of drug in a controlled release formulation is quickly
Manufacturing
released which may lead to toxicity that will introduced to the
Aspects
systemic circulation.
Direct Compression Flow and compressibility of the
ER labels is importantly put in the packaging. formulation
Dry granulation Double compression and
• Administer whole to prevent damage in the integrity of reworkability
dosage form and release mechanism. Wet granulation Solvent (aqueous or hydro-
• ER patient-friendly formulations: sprinkle capsules or alcoholic, binders, high or low
multiparticulate systems shear, fluid bed methods)
Hot melt extrusion Type, level, and melting point of
 Sprinkle capsules: core is coated and sprinkled in polymer and drug
foods.
 Multiparticulate systems: loaded in the capsule w/
ER system ❖ Insoluble matrix system

• Inform the patient: Avoid concomitant use of alcohol since
it is a good solvent which may dissolve or weaken the rate
controlling system.
▪ Drug is dispersed in a water-insoluble polymers or waxes.
▪ Carnauba wax, fatty alcohol, glyceryl palmitostearate,
stearyl alcohol, beeswax, aluminum monostearate, and
glycerol monostearate

 Prepared by adding drug to Molten fat or wax

 Then mix the other excipients
 MANUFACTURING LECTURE

MODIFIED-RELEASE ORAL DRUG DELIVERY

 Cool to congeal the material then granulate before 2. Osmotic system – It contains osmotic agents in the
compression. coated core (eg. Cellulose acetate).
 Then compressed the tablet
Drug release occurs through an orifice (laser drilling, tablet
The drug release occurs in GI fluid permeate the matrix and indentions, or using of leachable substances) in the coating
dissolve the drug. layer due to an osmotic pressure gradient generated as
the GI fluids permeate into the core. Cellulose acetate is
▪ Drug release is controlled by the pore size, pore number, commonly used polymer for osmotic systems.
and tortuosity of the matrix.

▪ High tortuosity means that the effective average diffusion

path is large and drug release is slower.

▪ Pore-forming agents can be added to increase tortuosity

and facilitate drug release.

 It means the effective diffusion fat is large and drug

release is slower.

❖ Gastro-retention – dosage form which retained in the

❖ Reservoir systems – may be formulated as mini-tabs
(diameter: 2-5 mm which can be coated with great controlling
polymer and fill into hard gelatin capsules), spheres or pellets
(extrusion or spheronization process) and manufactured
either through wet granulation or hot melt extrusion process
before coating with rate-controlling membrane.
1. Simple diffusion system – Drug-containing core is
surrounded by a water-insoluble polymer coating. Drug
release is achieved by drug diffusion through the coating.
stomach for the general purposes of improving drug
delivery. It is used for drugs with local action in the stomach
(ex. treating H. pylori infection), narrow absorption window in
the small intestine, and degraded in the colon.
❖ 3D Printing / Additive Manufacturing
▪ New technique in creating solid objects layer-by-layer using
computer-aided design
▪ Advantage: patient tailored drug combinations
▪ Spritam® (Levetiracetam) is the first 3D printed formulation
using ZipDose® technology.
 MANUFACTURING LECTURE

MODIFIED-RELEASE ORAL DRUG DELIVERY

❖ Gastro-retention
 MANUFACTURING LECTURE

INNOVATION IN ORAL SOLIDS FOR DRUG DELIVERY BY DR. PAUL HENG

CONTENT Pelletization through Spray dring
FORMATION OF DROPLETS Spray congealing
 Era of Change – Personalized Medicine
Cryo-pelletization
 Introduction to multi-particulates
 Pellets, Mini-tablets and 3D printed tablets
 Research in pellet technologies EXTRUSION-SPHERONIZATION: MULTIPLE STEPS
 Conclusion
 Dry blending
ERA OF GENOMICS  Wet massing
Opportunities:  Extrusion
 Spheronization
 Personalized medicine with advances in genomics  Drying
 Dose based on genes
 Portable sequencer, much reduced cost PELLETS/SPHEROIDS: ADVANTAGES
Cost per sample, for genetic analysis, costing less Highly spherical granules
and less
- Narrow size distribution
PERSONALIZED MEDICINE (PM): CUSTOMIZATION - Mean size about 0.5-1.5 mm
- Aesthetic appeal
- Smooth surface characteristic
- Excellent flow
•Pellets - High bulk density
Diagn •Physical Dosag •Physical Dispe
osis •DNA e •DNA nsing •Minita - Low friability
blets
- Minimum surface area to volume

Well suited as drug cores for multi-particulate dosage

Challenges: In situ dosing &
forms
packaging
Good understanding of dose-patient
 Individualized Coated pellet
relationships
fraction blend - Sustained release layer
Suitable product design and dispensers  Individualized - Drug layer
Highly trained health practitioners amount
- MCC core
 Variable multi-
Higher costs with personalization drug ratio PELLETS FOR MULTI-PARTICULARE DOSAGE FORMS

Example: Combination systems or Customized/Modified

Release Systems
POTENTIAL DOSAGE FORMS FOR PH

 Pellets (0.5-2 mm)

MINI-TABLETS: PREPARATION
 Mini-tablets (2-4 mm)
Requires specialized dispenser/packer and put into  Multiple-tip tooling for sizing Minitablets <6 mm
ensemble personalized dosage form  Wide orifice: Powder particles -> Feed shoe -> air
 3D Printed Products escape
 Narrow orifice: Backpressure opposes powder entry
Introduction to multi-particulates
Therapeutic advantages over conventional tablets:
SPHEROID PRODUCTION (PELLETIZATION)
 Greater ease of swallowability
DIRECT PELLETIZATION Aqueous-based  Higher dose of flexibility
palletization  Individualized patient therapy (when used in
Melt-based pelletization multiple unit systems)
PELLETIZATION THROUGH Extrusion spheronization
EXTRUTION STEP (quite slower)
Hot-melt extrusion
Pelletization by LAYERING Powder layering
onto starter SEEDS Solution layering
Suspension layering
 MANUFACTURING LECTURE

INNOVATION IN ORAL SOLIDS FOR DRUG DELIVERY BY DR. PAUL HENG

PRODUCTION OF MINITABLETS Innovative Research in Multi-Particulate Dosage Forms
 FILL CONDITIONS RESEARCH GAP
- Die orifice properties
1. In MUPS tablets, the contribution of pellet-pellet vs
- Feed shoe velocity
pellet-die wall vs. pellet-upper/lower punch collision to
- Powder head height
coat damage cannot be clearly elucidated
- Turret speed
 Powder entry into die 2. While compaction-induced physical damage of pellet coat
 FILL REGIME was observed, its impact on drug release remains unclear
- Suction fill
- Gravity fill PROPOSED STUDY
- Forced feeding
Single pellet in mini-tablet (SPIM) system
 Powder entry into die
 FEED FRAME - Pellets were placed singly at seven different
- Paddle speed suppositories
- Paddle design - Compacted into mini-tablets with microcrystalline
 Powder entry into die cellulose (MCC) as the cushioning filler.
 Powder flow - (3 mm diameter)
 Powder entry into die
PHYSICAL CHARACTERIZATION OF PELLETS

MINI-TABLETS AS TABLETES “PELLETS” Pellet size and shape

Possible for mini-tablets be pellet-like, using deep concave  Area

punches  Perimeter
 Mean diameter
MINI-TABLETS AS DELIVERY SYSTEMS  Aspect ratio
- Mini-tablets in capsules  Roundness
- Opportunities for personalized medicine
- Pharmacogenomics-based dispensing Crushing strength
- Geriatric patients
OPTIMIZATION OF COMPRESSION PRESSURE AND
- Mini-tablet dispensing device
FILLER COMPOSITION

Disintegration Test
3D PRINTED PRODUCTS

Considerable advancements in 3D printing - Ensure that SPIM disintegrates completely to

release the pellet within the SPIM
Costs of printers, much reduced
Factors examined
Challenge: can it compete with the highly efficient traditional
tablet presses? - 5 compression forces
PERSONALIZED MEDICINE BY 3D PRINTING - 2 levels of disintegrant (sodium starch glycolate:
SSG) concentration (*few seconds)
 From physician - Control: MCC only mini-tablets
 To pharmacist
 3D printed medication TABLETING
Standardization to personalization
Question: Regulatory compliance? Fixed or flexible 1. Selection of compression pressure
dose? - Most common compression used in tableting ---
10kN or 1 tonne for 10 mm tablets (65 MPa)
- Area of each punch face: 7.35 mm2
- 7.35x8 =58.8 mm2
- 0.0588 mm2 x 65 = 3.8 kN
2. Excipient blend used
- 1% SSG to ensure complete disintegration to
release the tablet
 MANUFACTURING LECTURE

INNOVATION IN ORAL SOLIDS FOR DRUG DELIVERY BY DR. PAUL HENG

PREPARATION SPIM PROPOSED DRUG RELEASE MECHANISM

Intact Coat (Uncompacted pellet)
Difficulty: delivering centrally - Slow diffusion, zero-order
- Slow release
DRUG RELEASE TESTING
Punctured Coat (Pellet with Small cut)
Mini-test tube
- Osmotic pump, zero order
PHYSICAL PROPERTIES - Latent but fact release

- Roundness Large Cracked Coat (pellet with large cut)

- Aspect ratio
- Diameter - Diffusion plus leaks
- Crushing strength - Moderate release

DRUG RELEASE FROM PELLETS AT DIFFERENT KEY FINDINGS

SPATIAL POSITIONS
1. Pellet spatial position played a definitve role in the extent
of coat damage

TAKEAWAYS FROM OBSERVATIONS - pellets placed at the top-radial position was most damaged

1. Compaction-induced coat damage to pellets is - the other pellets in the contact to tablet surfaces, at the top.
asymmetrical within a tablet (more damage to pellet in lower Bottom and mid-radial positions were also damaged but
quadrant) slightly less than pellets at the top-radial position

2. Pellets did not fail completely – burst release (indicative of - Pellets located at the middle and upper quadrant positions
immediate failure) of drug was not observed were least damaged

DIFFERENCE IN PUNCH FORCE APPLIED 2. Compacted pellets did not fail completely despite
damage on sustained release coat
Simultaneous movement of upper and lower punches in
opposing directions - A gradated degree of failure was observed for the
compacted pellets
1. Compression pressure exerted by the lower punch was
more sustained compared to the upper punch (dwell=1-5 ms)

2. Disparity between upper and lower punch pressure – SUMMARY (Single Pellet in mini-tablet system)
lower punch pressure was 8-16% higher than that of upper
punch  Beneficial for evaluating the effect of pellet spatial
position on the extent of coat damage
- Pellets located at the periphery were more
susceptible to damage by compaction, with pellets
CONTROLLED RELEASE MECHANISM OF located at the radial position showing the largest
POLYMETHACRYLARE COATING extent of coat damage

- Methacrylic ester copolymers  Emphasizes the importance of formulating MUPS

R= CO-OCH2 tablets below the critical pellet volume fraction
Time-controlled release - Reduces the number of pellets located at the
surface of the tablets. Thereby ensuring that the
- Ammonioalkyl methacrylate copolymers damage caused to the pellet coat could be kept to a
R= CO-OCH2-CH2N(CH2)2-Cl minimum
Time controlled release
 MANUFACTURING LECTURE

INNOVATION IN ORAL SOLIDS FOR DRUG DELIVERY BY DR. PAUL HENG

CONCLUSION

 Personalized medicines will require multi-particulate

dosage forms
 Multi-particulate delivery systems require good
knowledge and technologies to design
 MUPS tablets are attractive design options for
controlled drug delivery systems
 Much research is still needed, to understand and
optimized MUPS tablet-based dosage forms
 MANUFACTURING LECTURE
PHARMACEUTICAL AEROSOLS
INHALATION THERAPY
▪ Used primarily to administer drugs directly to the respiratory
system (ex. asthma treatment)
▪ Used to deliver drugs to the bloodstream going to the
desired action site (ex. insulin, steroids, cardiac agents,
immunizing agents)
▪ Drug deposition in the airways is dependent on four
factors:
 Drug’s physicochemical properties
 Formulation
AEROSOLS
 Delivery / Liberating device
 Patient’s breathing patterns and clinical status
▪ Colloidal system consists of very finely subdivided liquid or
solid particles dispersed in and surrounded by a gas
▪ These products depend upon the power of a liquefied or
compressed gas to dispense the active ingredient(s) in a
finely dispersed spray, foam, or semisolid.
▪ Physicochemical characteristics of the active
ingredients: lipoid solubility, pulmonary absorption rates,
dissolution characteristics in pulmonary fluids
▪ Drug’s particle size & shape:
 Porous particles (20um) are efficiently delivered to
and deposited in the lungs because of their low
density.
 Large particles are less prone to aggregation,
offers formulation advantages, and cleared from the
airways by alveolar macrophages.
- (irregular shape may cause irritation)
▪ Type & concentration of surface-active agents:
Influence droplet evaporation, particle size, & hydrophobicity
reaching the respiratory passageways and pulmonary fluids.
 Lecithin, oleic acid and sorbitan trioleate 0.1 – 2%
 Ethanol has been added to increase their solubility.
▪ Vapor pressure & metered volume of propellants
(CFC: Chlorofluorocarbon-propellants but can cause ozone
layer depletion. It was replaced with HFS)
▪ Forms: nebulizer/atomizer, dry powder inhaler, nasal
inhaler, metered-dose aerosol inhaler
*WATCH ON HOW USING INHALERS
NEBULIZER
▪ Formulated as sterile aqueous solutions or suspensions,
and are inhaled by the patient through an atomizer,
nebulizer, or other similar devices.
▪ Devices convert liquids into aerosols, frequently used for
drugs that cannot be conveniently formulated into pMDIs or
DPIs, or where therapeutic dose is too large for delivery
▪ Jet nebulizers, Ultrasonic nebulizers, Mesh nebulizers
o Ultrasonic nebulizer - Energy is necessary to
atomize liquids coming from piezoelectric crystal
vibrating at high frequency.
o Mesh nebulizers - Aerosols are generated by
passing liquids through a vibrating mesh or plate
with multiple apertures.
▪ Formulation: Nebulizer fluids are formulated in water with
addition of ethanol and surfactants for suspension
formulations.
DRY POWDER INHALER
▪ Capsule was punctured so a small amount of powder fell
into a chamber while the patient inhaled. This procedure was
repeated until all the powder was inhaled.
▪ The first-generation MDI was formulated with
chlorofluorocarbons (CFC), was compact and portable, and
contained epinephrine HCl or albuterol as the active
ingredient.
▪ Dry powders containing about 25 – 30 to 60 doses of active
ingredient were developed and become commercially
available from 2000 to 2003 (ex. salmeterol, fluticasone,
budesonide, mometasone-dry powder that do not contain
propellant).
▪ Formulation: Desired size is 5 um. Micronized powders
have poor flow properties and can be improved by adding
lactose to reduce agglomeration of small drug particles &
facilitate fluidization during the inhalation process, &
modifying adhesive properties by adding leucine and
MgSO4.
▪ Alternative process: spray-drying (porous), spray-
freezing-drying, & supercritical fluid technology.
▪ Spinhaler®, HandiHaler®, Aerolizer® / Cyclohaler®
▪ Diskus® Inhaler, Clickhaler®, Turbohaler®
▪ Nektar Therapeutics produced a device for the delivery of
insulin as a very fine powder and marketed by Pfizer but was
withdrawn due to cost, cumbersome design of the delivery
device, and the need for insulin injection to supplement
inhaled drug.
 MANUFACTURING LECTURE
PHARMACEUTICAL AEROSOLS
NASAL INHALER
▪ Produces an aqueous spray consisting of active ingredient
and excipients
▪ Formulated using propellants and nasal actuator
METERED-DOSE INHALERS (MDI)
▪ Consist of pressurized container filled with active
ingredient, excipients, propellant, and a metered-dose valve.
▪ Pressure package: convenient, ready-to-use form with
tamperproof pressure container that requires sterilization
▪ Container:
 Tin-plated steel (light wt and relatively inexpensive,
afford sufficient protection),
 Aluminum containers (produced by impact extrusion
process so seem less, extremely strong and relatively
high pressure, commonly used for MDI)
 Plastic-coated glass (preferred since no
incompatibility and aesthetic value limited for products
with lower pressure and propellant percentage)
In terms of prevention of permeation problems, plastic
coated is preferred.
In terms of cost, Tin-plated steel is much preferred.
In terms of withstanding to strong/high pressure, aluminum
containers are preferred.
▪ Propellants: CFCs are replaced with hydrofluoroalkanes.
At room temperature and pressure, these are gases that
readily liquefies by decreasing temperature or increasing
pressure.
- Liquefied gases are relatively inert and nontoxic
- Hydrocarbons are less expensive and
environmentally acceptable as compared to CFC
▪ Metering valve: Permits reproducible delivery of small
volumes (25 – 100 uL) of product. Its primary purpose is to
regulate product flow from the container. Its various forms
are continuous spray valves & foam valves (with large
openings and used to dispense rectal and vaginal foams).
▪ Actuators: Provides a rapid and convenient means for
releasing the contents from a pressurized container.
▪ Formulation
 Two-phase system - adding cosolvents such as
ethanol or 2-propanol to retard propellant
evaporation
 Three phase system - harder to formulate because
of formulation problems like caking, agglomeration,
and particle growth
▪ Filling pMDI canister: Cold filling or Pressure filling
 Cold filling – Excipients and liquified propellant are
chilled, and the canister is filled with at - 60C.
Additional propellant is added at the same
temperature and the canister is sealed with the
valve.
 Pressure filling – Most frequently employed; A
concentrated solution or suspension of drug in
propellant under pressure is filled in canisters
through the valve followed by addition of further
propellant.
 Filled canisters are leak tested by placing in water
bath at elevated temperature (50 – 60C), then
stored to allow equilibration of the formulation and
valve components. The containers are weighed to
further check for leakage prior to insertion into
actuators and spray testing
Spacers (valved holding chambers) – extension devices
used to overcome problems associated with actuation-
inhalation coordination and premature deposition of high
velocity.
TOPICAL AEROSOLS PRODUCTS
▪ Popular because these are easier to administer and have
better feel than ointments and creams
▪ Formulated as spray, foam, and semisolid
▪ Used to deliver therapeutic agents to topically, rectally, and
vaginally
▪ Consist of a liquid, emulsion, or semisolid concentrate and
liquefied gas or compressed gas propellant (ex. nitrogen,
nitrous oxide, and carbon dioxide)
▪ Used in dental creams, hair preparations, ointments, and
aqueous antiseptic and germicidal aerosols and are
extremely useful in contact lens cleanser saline solution and
barrier systems.
 MANUFACTURING LECTURE

PHARMACEUTICAL AEROSOLS

NOVEL DELIVERY DEVICE

▪ Respimat® Soft Mist Inhaler: Non-pressurized metered-
dose system that is mechanically actuated without propellant
use. This handheld device is with multidose reservoir
releasing a cloud of 1.5 seconds’ duration.

▪ AERx® pulmonary delivery system: Drug is contained in

unit dose blister packs. The device electronically monitors
patient’s inspiratory flow rate, and releases drug at the
inspiratory flow rate determined to be optimal for drug
delivery.

PARTICLE SIZE DISTRIBUTION

▪ Particles emitted must be below 10um (2 – 8 um in
diameter)

▪ Particle size determination: Cascade impactor,

Microscopy, Laser diffraction

▪ Cascade impactor is used to determine the particle-size

distribution for MDIs wherein it depends upon the principle of
carrying particles in a stream of air through a series of
consecutively smaller jet openings.

The heavier and larger-diameter particles are impacted on a

slide under the larger opening, and as the openings get
smaller, the velocity of the stream increases, and the next
larger particles are deposited on the next slides.

QUALITY EVALUATION
▪ USP tests for topical pharmaceutical aerosols: delivery
rate, leak testing, microbial limit test, and assay

▪ USP tests for MDIs: description, identification, assay of the

active ingredients, microbial limits, moisture content, net
weight, degradation products & impurities, extractable, and
others such as:

 Dose uniformity – determines the amount of active

ingredient delivered through a mouthpiece per a
specified number of actuations.

 Leakage rate – used to estimate the weight loss

over a one-year period; determines the integrity of
the gaskets, as well as the proper crimping of the
valve onto the container.

 Total number of discharges per container –

number of actuations per container and is not less
than the label claim.

 Spray pattern and/or plume geometry – evaluates

the type of spray pattern emitted for the MDI and
relates to the characteristics of the metering valve
and oral adapter.
 MANUFACTURING LECTURE
NANOMEDICINE
Nanomedicine
▪ Using of nanomaterials (1 – 100 nm) for diagnosis,
monitoring, control, prevention, and treatment of diseases.
▪ Impart pharmacokinetic, efficacy, safety, and targeting
benefits when they are included in drug formulations by
surface conjugation or encapsulation of a therapeutically
active agent to an NP.
▪ Advantages:
(1) improved solubility and pharmacokinetics,
(2) enhanced efficacy,
(3) reduced toxicity, and
(4) increased tissue selectivity
Three fundamental aspects to identify the presence of
nanomaterial:
❑ Particle size (top down / bottom down process)
❑ Particle size distribution (polydisperse)
❑ Surface area (larger than 60 m2 / cm3)
▪ Equipment used for particle visualization:
Transmission Electron Microscopy (TEM), HighResolution
TEM, Scanning Electron Microscopy (SEM), Atomic Force
Microscopy, and Particle Tracking Analysis.
▪ Equipment used for particle size distribution:
Dynamic Light Scattering (DLS), Small-angle Xray Scattering
(SAXS), and X-ray Diffraction (XRD)
▪ Nanopharmaceuticals: Liposomes, polymers, micelles,
nanocrystals, metals/metal oxides, and other inorganic
materials, and proteins.
Nanopharmaceuticals
❖ Liposome – spherical vesicle (usually 90 – 150 nm)
composed of a lipid bilayer membrane arranged around an
empty core. It is self-assembling and can carry and deliver
either hydrophilic or hydrophobic therapies in their empty
cores.
❖ Polymer NPs – either natural, synthetic, or
pseudosynthetic material with 10 nm – 1 um size. It is a
promising carriers for numerous medications including
treatments of cancer, cardiovascular disease, and diabetes,
bone-healing therapies, and vaccinations. Polymer
nanodrugs are usually
(1) degradable polymer forms for controlled release
applications, and
(2) polymer-drug conjugates that increase circulation time
and drug half-life or improve biocompatibility / solubility.
❖ Micelle NPs – self-assembling polymeric amphiphile NPs
that can be customized for the slow, controlled delivery of the
hydrophobic drugs they may carry. They have a hydrophobic
internal core which can be used to encapsulate drugs that
have poor aqueous solubility. However, the exterior surface
of a micelle has enough polarity to allow dissolution in
aqueous solutions.
❖ Nanocrystal NPs – versatile NPs used to improve the
PK/PD properties of poorly soluble organic or inorganic
materials by increasing their BA and solubility. They are
composed of an optically active core surrounded by a shell
that provides a physical barrier against the external
environment, making them less sensitive to photooxidation
or medium changes.
❖ Inorganic NPs – inorganic materials such as metal oxide,
metal (gold, silver), or silica are used to create NPs. Iron
oxide NPS are studied as contrast enhancement reagents for
MRI.
❖ Protein NPs – include drugs conjugated to protein carriers,
formulations where the protein itself is the active therapeutic,
and complex combined platforms that use proteins for
targeted delivery. Example is RSV-F (Novavax, a protein-
based NP containing a respiratory syncytial virus (RSV)
fusion protein that was developed to treat RSV in infants).
❖ Dendrimer NPs – composed of iterative monomers
arranged concentrically around a central core.
General issues to consider during the development of
nanomedicine products:
o physicochemical characterization
o biocompatibility,
o nanotoxicology evaluation
o pharmacokinetics and pharmacodynamics
o assessment
o process control
o scale-reproducibility
Challenges in nanopharmaceuticals:
 need for better characterization
 possible toxicity issues
 lack of specific regulatory guidelines
 cost-benefit considerations
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NANOMEDICINE

 waning enthusiasm among some healthcare ▪ Multifunctional nanovaccines can significantly increase the
professionals. immune response generated by the target-specific, effective,
and stable delivery of an antigen. However, the use of
many-component nanovaccines with complex
structures can increase production costs and
complicate the manufacturing process. Many
nanovaccines have been manufactured in small batches for
research use. Batch-to-batch variations with respect to
particle size, shape, and quality are critical problems in the
area of nanoparticle synthesis, and these problems must be
addressed during scale-up for clinical trial testing.

Quality by Design (QbD)

• QbD supported by Process Analytical Technologies

(PAT) is one of the pharmaceutical development approaches
that were recognized for the systemic evaluation and control
of nanomedicines.

• Its basis relies on the identification of the Quality Attributes

(QA) which refers to the chemicals, physical or biological
properties or another relevant characteristic of the
nanomaterial.

• Some of them may be modified by the manufacturing and

should be within a specific range for quality control purposes.
In this situation, these characteristics are considered Critical
Quality Attributes (CQA). The variability of the CQA can be
caused by the critical material attributes and process
parameters.

• As defined by FDA, PAT is a system for designing,

analyzing, and controlling manufacturing through timely
measurements of critical quality and performance attributes
of raw and in-process materials and processes, with the goal
of ensuring final product quality. The PAT tools analyze the
critical quality and performance attributes. The main point of
the PAT is to assure and enhance the understanding of the
manufacturing concept.

▪ Nanocarrier-based delivery systems offer an opportunity to

enhance the humoral and cellular immune responses to
vaccines. This advantage is attributable to the nanoscale
particle size, which facilitates uptake by phagocytic cells, the
gutassociated lymphoid tissue, and the mucosaassociated
lymphoid tissue, leading to efficient antigen recognition and
presentation.
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NANOMEDICINE

o QSAR aims at identifying the physicochemical

characteristics which lead to toxicity, so as to
provide alterations to reduce toxicology.

Regulatory challenges

Nanomedicine were introduced under the traditional

framework of the benefit/risk analysis. Another related
challenge is the development of a framework for the
evaluation of the follow-on nanomedicines at the time of
reference medicine patent expiration. Nanomedicine
comprises both biological and non-biological medical
products. In order to introduce biological and non-biological
nanomedicines in the pharmaceutical market, a more
complete analysis is needed that goes beyond the plasma
concentration measurement. A stepwise comparison of
bioequivalence, safety, quality, and efficacy in relation to the
reference medicine which leads to therapeutic equivalence.
Table 45.1 Examples of licensed products that can be considered as
nanomedicines
Product Drug Type of Attributes offered by the
System nanotechnology
Abraxane® Paclitaxel Nanoparticles These albumin-bound
nanoparticles increase
the delivery of paclitaxel
by overcoming the low
solubility of paclitaxel
and improving tumour
cell drug delivery.
Caelyx®/ Doxorubicin Liposomes This formulation
Doxil® contains PEGylated
liposomes which can
increase systemic
circulation times and
enhance delivery to
tumour sites.
Emend® Aprepitant Nanoparticles These nanoparticles are
prepared by a wet
milling method and
increase drug solubility
and bioavailability.
Mepact® Mifamurtide Liposomes Entrapping the drug
within liposomes
facilitates drug delivery
and activation of
macrophages.
Myocet® Doxorubicin Liposomes Incorporation of
doxorubicin into
liposomes increases
tumour tissue
distribution and reduces
cardiac toxicity
Pegasys® Interferon 2a Polymer- Pegylation improves the
protein stability of the protein.
conjugate
Quantitative structure-activity relationship models (QSAR) Rapamune® Sirolimus Nanoparticles The formulation of a
nanodispersion
stabilized with
o first application of computational tools applied in
poloxamer offers
toxicology increased stability and
o QSAR models are based on the hypothesis that the bioavailability.
toxicity of nanomaterials and their cellular fate in the Rapamune® Ibritumomab Antibody- Conjugation of a radio-
body can be predicted by their characteristics, and tiuxetan conjugate isotope to the antibody
different biological reactions are the result of promotes targeting and
physicochemical characteristics, such as size, destruction of B-cells.
shape, zeta potential, or surface charge gathered as
a set of descriptors.
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NANOMEDICINE

▪ Health Technology Assessment is developed to provide

information about medicine safety, effectiveness, and cost-
effectiveness to support health and political decision-makers.

▪ Pharmacoeconomic studies assess both the social and

economic importance of nanomedicine through the added
therapeutic value, using indicators such as quality-adjusted
life expectancy years and hospitalization.
 MANUFACTURING LECTURE

WEBINAR: VALIDATION & MONITORING SOLUTIONS

OUTLINE: - Demonstrates that the stated performance

properties of a measuring system are achieved.
PART I - Prove the correction + expanded uncertainty is
within specifications
I. Overview
Uncertainty (ISO definition):
II. Company Introduction
Parameter associated with the result of a measurement that
III. Validation, Calibration & Verification (Thermal) characterizes to dispersion of values that could reasonably
be attributed to the measurement.
IV. Requirements in Thermal Validation
Uncertainty may result from:
V. Tools used in Validation
- Sensor tolerance
PART II - Instrument accuracy
- Drift in the characteristics of the sensor
I. What units should be validated (temperature, cycling, ageing)
- Thermal effects resulting from the installation, such
as electric potentials created by junctions
II. What should be documented
- Human error
III. Application, ValSuite Software Simulation and Data
Analysis
CALIBRATION – WHY?

- Ensure that specific process is within specifications-

CALIBRATION – WHAT?
Calibration is performed to verify sensor/instrument
performance.
Calibration is the process used to ensure that a
sensor/instrument maintains specification over time and
changing ambient conditions.
Calibration is the process used to maintain traceability of
parameters with reference/international standards.
Calibration (GAMP definition):
- The set of operations which established, under
specified conditions, the relationship between
values indicated by a measuring instrument or
measuring system, or values represented by a
material measure, and the corresponding known
values of a reference standard.
*GAMP – Good Automated Manufacturing Practice
Calibration (ISO definition):
- Determines the performance characteristics of an
instrument
- Calibration is achieved by means of a direct
comparison against measure standard
- Determination of error i.e. correction and expanded
uncertainty.
Verification (ISO definition):
- Confirmation through examination of a given item
and provision of objective evidence that it fulfills
specified requirements
every time/ every day
- Avoid overheating (change/ loss of product)
- Avoid insufficient heating (risk of invalid lethality
value)
- Ensure that control system is working according to
optimal performance
“Because all sensors drift”
CALIBRATION – WHEN?
Intervals to be defined according to:
- Potential failure of instrument device
- Impact to product quality
- Past history
- Manufacturer’s recommendation
- Instrument reliability and accuracy
- Danger of too long intervals (safety)
Calibration secures product integrity
- Measurements are taken throughout the life cycle of
the instrument device to avoid changes in
performance (drift) over time
PROCESS VALIDATION
Specific processes must be validated because:
- Critical to product safety
- Critical to product quality
- Contributes to process optimization
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Process Validation (FDA): 6. Knowledge on performing validation studies

- Establishing documented evidence which provides KEY REQUIREMENTS FOR PHARMA

a high degree of assurance that a specific process
will consistently produce a product meeting its pre- About the validation
determined specifications and quality
characteristics - Prospective
- (Actual performance of the instrument) - Retrospective
- Guidelines (USP, GMP, FDA, ISPE, PDA)
Benefits of Performing Validation - Type of study (HPT, HDT, TD, Challenge test)
- Calculations (Lethality)
Optimization - Acceptance criteria

- Time savings Description of the plant/system

- Increased profits
- Number of units
Security - Brand
- Type
- Product complaints - Mechanism
- Product recall - Opening/provisions
- # racks, trays, etc.
Quality - Process scheme
- Process/program
- Peace of mind - Last calibration date and result
- Customer loyalty - Last maintenance date and result

Implications of not validating Description of product

- Unnecessary cost on energy, time, and labor - Product

- Inconsistency on product flavor, quality, and - Filling material
appearance - Packaging
- Product recall - Volume
- Cold spot location
SUMMARY
The right validation equipment
CALIBRATION – the set of operations which establish, under
specified conditions, the relationship between values - What type of study will be done?
indicated by a measuring instrument or measuring system, - Will the measuring point be mounted inside or
or values represented by a material measure, and the outside the container?
corresponding known values of a reference standard. - Will there be challenges in fixing measuring point?
- Will there be challenging process conditions?
VERIFICATION – demonstrates that the stated performance - What is the accuracy requirement for the measuring
properties of a measuring system are achieved device?

VALIDATION (Thermal Validation) – a process of quality Documentations

equipment and storage facilities to prove that they will create
maintain the temperature and other parameters they are - Consider regulation
designed for with full process evidence and documentations. - Consider the study design

KEY REQUIREMENTS

1. Knowledge about the process

2. Knowledge about the product

3. Available regulations and acceptance criteria

4. Appropriate tools for Validation

5. Documentation required
 MANUFACTURING LECTURE

VALIDATION EQUIPMENT TrackSense LyoPro (1/2)

(Durable, smart, and immensely precise validation The ultimate solutions for lyophilization temperature mapping
equipment) and batch control

Wireless Data Loggers (1/2) Wired Thermocouple System (1/2)

TrackSense Pro – Features & Benefits Compact, precise and extremely efficient

Wireless System (means saving time) E-Val Pro – Features & Benefits

Highly versatile product line – a system for every need With nodules and software

- (Micro, Mini, Compact, Fringo & TrackSense Pro) Compact and light design

Interchangeable Sensors for temperature, pressure, - Only 3 kg

relative humidity, CO2 and Conductivity - No fans
- Up to 40 sensors
- (Adds versatility and flexibility; cost efficient)
Large Memory
Small sized Loggers
- 11.5 million samples
- Minimizing the thermal impact on a product - 10 independent studies
- Smallest logger on the market
Integrated and rechargeable battery backup
Reader Stations can be expanded to program 16 loggers
simultaneously using 4 reader stations - Up to 8 hours

- Save time during programming and download Standalone or Networkable through USB or LAN

Stainless steel ANSI 316 housing - Up to 3 E-Val Pros can be used together to have
120 sensors in one continuous study
- Fully immersible in steam, water, and oil that is up - Reporting takes place on PC or tablet
to +150C

Large Logger Memory: 120, 000 data points non-volatile

Electronic Bowie Dick Test
SKY option for Live Data
Get peace of mind with SteriSense
- Sends information to a Networkable Access Point
FEATURES & BENEFITS
Superior Temperature Specifications
SteriSense is a new innovative device for electronic Bowie
- Logger Body (-90 to 150C) dick tests that is unmatched in accuracy, performance, and
- Sensors (-196 to 400C) reliability.
- Rigid flexible options
- High accuracy +/- 0.05C SteriSense is by far more insight into critical sterilization
parameters than previously possible.
20+ years of experience with Wireless Technology
- Accurate electronic bowie dick test
Transmission by induction - Reliable and cost efficient
- Very compact size
- Fast and reliable over time - User friendly and intuitive software
- Eliminates guesswork and provides and objective
result
- Replaceable PCD to run several cycles in a
sequence
- Verification of critical sterilization parameters
beyond traditional methods
- Up to 1000 test cycles between each calibration
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ENVIRONMENTAL MONITORING VALIDATION & MONITORING SOLUTIONS

Ultimate peace of mind MOIST HEAT STERILIZATION

Environmental Wireless Monitoring Solutions Steam Sterilizer/Autoclave

Unrivalled wireless range with Hanwell Pro

Hanwell Pro – complete and high-end environmental

monitoring system available today. With as immensely
accurate sensors, LCD display and superior radio power,
Hanwell Pro can overcome even the most complicated
obstacles.

SOFTWARE SOLUTIONS

Time-saving and user-friendly with the highest data integrity

Able to analyze the data gathered for validation

Validation & Calibration Software

The ideal solution for any thermal validation process

ValSulte

- Intuitive & User-friendly Software

- Data acquisition to database
- Validated Software
- Excellent Documentation Features
- Useful Monitoring features

Ellab Monitoring Software

Supports from one sensor to thousands of sensors across

multiple sites
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