API Development - PANalytical · 2019-12-20 · ICH Q6A –Decision Tree 4 ... Sources of Elemental Impurities in Developed API 22 19 August 2019 Adapted from ICH Q3D Manufacturing

© Malvern Panalytical 2017

API DevelopmentPurity and Stability

Dr Michael Caves


API?

• Active Pharmaceutical Ingredient (API) – Any

substance or combination of substances….intended

to furnish pharmacological activity (WHO)

• DMF – Drug Master File, a submission to the FDA

providing confidential detail about the manufacturing,

processing, packaging, and storage• ASMF – EU equivalent

• DMFs are created for API and follow the API

(whether used in house or sold to a 3rd party)

• Responsibility of Regulatory Head

19 August 20192

Generally refers to the active ingredient in chemical drugs


Scientific Terminology

• Polymorphs: Different crystalline forms of the same API.• Considered the same APIs

• Pseudopolymorphs: Differently Solvation/hydration

forms of the same API• Considered the same API

• Salts: Any of numerous compounds that result from

replacement of part or all of the acid hydrogen of an acid

by a metal or a radical acting like a metal• Considered different APIs.

• Co-crystals: Crystalline materials composed of two or

more different molecules• one of these is the API

19 August 20193

Important for patents etc.


API Chemical Development

19 August 20194

Control the Crystal form to ensure good yield and

processability

Discovery Formulation



19 August 20195


processability


XRD



19 August 20196


processability


XRD

Particle

Size



19 August 20197


processability


Elemental Analysis

XRD

Particle

Size


What parameters can be considered CMAs?

International Conference on Harmonization

Guidance on Q6A Specifications:

Test Procedures and Acceptance Criteria for New Drug

Substances and New Drug Products:

Chemical Substances

• Specific tests and criteria:

• Physiochemical properties (pH, melting point, RI)

• Particle size

• Polymorphic forms / amorphous content

• Chiral identity tests

• Water content

• Inorganic impurities, based on process knowledge

• Microbial Limits


Same Reg. Issues as Finished Product

• Poor API design and manufacturing leads to

poor finished product

• Regulation of API manufacturing as stringent

as that of finished product (GMP principles)

• Fallout can be worse, with API sold to 3rd

parties being used in multiple finished products

19 August 20199

Fallout often worse


Polymorph Selection and CrystallizationSolubility optimisation

& Patentability


When is solid form considered a CMA?

Do the forms have different

properties (e.g. stability, solubility)

Characterise the forms (e.g. XRD,

DSC, Spectroscopy, Microscopy)

No further test or acceptance

criterion for drug substance

No

Yes

Yes

Yes No

No

Can different polymorphs be

formed?No further actionConduct polymorph screening

Is the drug product safety,

performance or efficacy affected?

ICH Q6A – Decision Tree 4 (1&2) – Drug Substances

Set acceptance criterion for

polymorphic content in drug

substance


When is solid form considered a CMA?ICH Q6A – Decision Tree 4 (3) – Drug Product

Does drug product performance

testing adequately control if polymorph

ratio changes (e.g. dissolution)?

No

Monitor polymorphic form during

stability of drug product

Does a change occur which could

affect safety or efficacy?

Yes

No need to set acceptance criteria

for polymorph change in drug

product

No

Yes

Establish product acceptance criteria

which control safety / efficacy

Establish acceptance criteria for

relevant performance tests

Need to specify polymorphs due to differential solubility


Why is Polymorphic Form a CMA?

• Changing polymorph can alter bulk properties of API➢dissolution rate and solubility

➢bioavailability

➢chemical and physical stability

• Can have a direct effect on the ability to process and/or

manufacture the drug substance and the drug product• Polymorph monitoring used to improve production efficiency

• Knowledge of the complete set of possible polymorphs is

also important for patent protection. • A new crystalline form can be patented as a new

pharmaceutical product

• Polymorphic contamination can infringe on existing patents

Polymorphism can affect the quality, safety, and efficacy of

the drug product

✓ It is desired to produce and

characterize all accessible

polymorphs of a given drug

substance


Poorly Soluble Drugs

• Polymorphic form modification optimises solubility• 70 % of API under development practically insoluble

• Amorphous forms more soluble but less stable

• Problems with API stability can arise• Soluble amorphous forms may rapidly transform to the

less soluble crystalline form during storage

• Polymorphism must be controlled to ensure

reproducible bioavailability after administration also

19 August 201914

What would once have been considered poorly soluble API

now dominate pharma development


Developing Poorly Soluble API

• “~50% of drug candidates that

enter clinical trials fail due to

efficacy and safety concerns,

and the remaining 40% fizzle

due to patent concerns and

issues like solubility and drug

interaction” GSK CEO

• Available data suggest a 20 %

chance of costly solubility

problems during development

• Most stable polymorph not

observed in 15-45 % of API – post-

development stability risk19 August 201915

Polymorph Control Essential

Rotonavir (Norvir®)

Low Stability

High Solubility

High Stability

Low Solubility

Storage

at RT

6 months stop-

production

100s of M USD


API Development. Polymorophism

• Rotonavir (Norvir®) capsules for treatment of AIDS• Selection of a less stable polymorph led to dissolution problems 2 years into production

• Disruption of production for 6 months, costing hundreds of millions of dollars

• Rotigotine (Neupro®), a transdermal medicine used to treat Parkinson’s disease• ‘Snowflake’ crystals appeared during storage due to formation of less soluble polymorph

• Led to product requiring reformulation in order to return to USA market – took 5 years

• Mebandazole• Form A is more stable but inneffective, whilst Form C is soluble and preffered as the active form

• Traces of form A in final formulation reduced shelf-life to a month in 4 cases – all failed to win

FDA authorisation

• Carbamazepine (Tegretol®)• Transition to thin anhydrous particles, with smaller particle size actually leads to slower

dissolution, due to the narrow shape of the small particles enabling conversion to the dihydrate

19 August 2019Title of the presentation16

(Brazilian Journal of Pharmaceutical Sciences vol. 50, n.1, jan./mar., 2014)


Polymorph Identification Methods

• XRPD provides unequivocal proof of

polymorphism

• Other methods are helpful to further characterize

polymorphic forms

17

FDA Guidance


Compound/form selection and characterization

• Automated polymorph, hydrates/solvates, co-crystals, salts screening

• Structural stability and phase transition determination under elevated temperature/humidity/light

• Highly sensitive Structural/polymorphic purity determination


API Chemical development

19 August 201919 August 2019

Empyrean and Aeris


Case study: oral solid dose products

Success

• Pfizer patented Atorvastatin (Lipitor)

polymorphs at the turn of the century• In 2003, Ranbaxy patented a new polymorph

• Pfizer claimed infringement of 2 of their patents

• Patent expiry in 2016-17

• Generic version sold in parallel since 2011

• Value of first-to-file: $600M (Dec 11 – May 12)

19 August 201919

Using a different (unpatented) polymorph as a generic

Failure

• In 1984, Glaxo released Zantac using Form

2 Ranitidine API (3.4 B USD sales by 1992)• In 1998, TorPharm applied for approval for a

generic version of Zantac, using polymorphic

Form 1 of the API (Ranitidine), the 1978

Glaxo patent for which had expired

• GSK demonstrated the existence of 0.5 %

Form 2 (still under patent) in the generic and

successfully barred entry of this until 2002

• GSK sales: ~$1.5 billion annually in 1997

• Loss to generics: ~$115M per annum• Assumes 25% market penetration and a 70%

price reduction

Sector Training: Complex Generics


Elemental AnalysisCatalytic Residues

Toxic elements

Process-wear



19 August 201921


processability


Elemental Analysis

XRD

Particle

Size


Sources of Elemental Impurities in Developed API

19 August 201922

Adapted from ICH Q3D

Manufacturing

Equipment

Elemental

Impurities in

API

Catalyst

Residues

Container

Closure System

Drug

Substance

Water

• Impurities come from reactor vessels and from catalysts

used in reactors

• Main Toxic Elemental Impurities are the ‘The big four’:

As, Cd, Hg, Pb

• Further other elements possible (used in the process)

like Cr, Ni, V, Mo, Ir, Pt, Os, Rh, Ru, Cu

• Concentration levels are a few µg/g (few ppm)

• Even at this level, may be toxic for human consumption


ICH Q3D

• Control strategy – if the risk

assessment concludes that elemental

impurities are below 30% of PDE, it

should be acceptable to rely on cGMPs

without regular testing of each batch

Heavy metal permissible limits


ICH Q3D

• Transition metals frequently used:• Platinum

• Osmium

• Iridium

• Ruthenium

• Rhodium

• Palladium

• Catalysts intentionally added –

always require measurement

19 August 201924

Catalytic Residues


USP chapters <232/233>

• New chapters to replace USP<231> Heavy metals

• <232> Elemental impurities – Limits• Drug product analysis and summation options

• Specifies Permissible Daily Exposure (PDEs) limits for different drug delivery routes

• NOW covers same elements and limits as ICH Q3D

• <233> Elemental impurities – Procedures• Describes two analytical procedures (ICP-OES & ICP-MS) + the criteria for acceptable alternatives

• Defines validation requirements for Accuracy, Precision, and Specificity

• <735> X-ray Fluorescence for metal impurities testing• Describes the use of Wavelength Dispersive XRF & Energy Dispersive XRF as qualitative and

quantitative method for heavy metal impurity analysis in

• Liquids

• Powders

• Solid Materials25

From 1st January 2018 onwards


XRF not sensitive enough to replace ICP

• ICP-MS/OES - late stage development• Highly sensitive

• Methods already set

• Why take the risk

• XRF - API development stage• API, and impurities, undiluted here

• Good enough for people to predict what

the levels will be after formulation

• Production support – rapid response

time allows efficient optimisation of

manufacturing processes

19 August 201927

Works for API Development Assessment however

Technology LOD, typical

Drug impurities,

(ppt)

ICP-MS 1

ICP-OES 1000

XRF - General 1000,000

XRF – E4 100,000


Case Study

• Optimisation of Palladium scavenging process to bring down to USP acceptable levels

19 August 201928

E1 – Pilot Plant for API Production Process Development

Method Feedback time Development Time

ICP-MS 1 week 6 months

Epsilon XRF 1 hour 2 months


Summary

• Sensitivity• Detect trace differences

• Feedback time and ease of continuous operation• Reduced Development time

19 August 201929

API Development

Produce High Quality Drugs more efficiently and with less financial risk


API DevelopmentMorphological Characterisation

Dr Michael Caves



19 August 201931


processability


Elemental Analysis

XRD

Particle

Size


Why API Particle Sizing?

19 August 201932

API SupplierAPI Development

Lab of an

integrated company

Contract

Manufacturer

(CMO)

API must be milled to a specific size

Tabletting

optimisationBioavailability Formulatability


Is Particle Size critical to:

• Dissolution, solubility, or

bioavailability?

• Drug Product Processability?

• Drug Product Stability?

• Drug Product content uniformity?

• Maintaining Product appearance?

No drug substance particle size

acceptance criterion required for

solution dosage forms

When is Particle Size considered a CMA?ICH Q6A – Decision Tree 3 – Drug Substance

Is the Drug Product a solid dosage

form or liquid containing undissolved

drug substance

Yes

No

No Acceptance Criterion Required

No to

ALL

Yes to

ANYSet Acceptance Criterion

Drug Product Test

Decision Tree

ICH Q6A

Decision Tree 3


Why Particle Size Matters

• Changing particle size can alter bulk properties➢dissolution rate and solubility

➢bioavailability

➢physical stability

• Can have a direct effect on the ability to process and/or

manufacture the drug substance and the drug product,

Particle Size affects bioavailability, processability and stability


Processability


Processability and particle size and shapeTabletting – Problems associated with direct compression


• Particle size• Reducing the size of the particles increases the strength of the tablet

• However, greater adhesion can lead to voiding, cracking and breakage

• Affects flowability of powder into the die

• Particle size distribution• Close overlap between actives, excipients and binders

• Narrow distributions improve content uniformity

• Wider distributions increase packing density

• Particle shape• Affects the way particle pack together (max packing fraction)

• Affects flowability

Processability and particle size and shapeTabletting


Size / m

1 10 100

Vo

lum

e (

%)

0

1

2

3

4

5

6

7

Fine Material

Fines + 10% Coarse

Fines + 20% Coarse

Fines + x% Coarse

Fines + 30% Coarse

Processability and particle size and shapeTabletting – Controlling the Packing Fraction


Processability and particle size and shape

Flowlac 100 InhaLac 230 SpheroLac 100

Predicting processability for excipient powders

Fu, X., et al. Effect of particle shape and size on flow properties of lactose powders.

Particuology (2012), doi:10.1016/j.partic.2011.11.003

Particle size Particle shape

Flowlac 100

InhaLac 230

Flowlac 100

InhaLac 230

SpheroLac

100

SpheroLac

100


What is important for processability?Predicting processability for excipient powders

Fu, X., et al. Effect of particle shape and size on flow properties of lactose powders.

Particuology (2012), doi:10.1016/j.partic.2011.11.003

Flowlac 100 InhaLac 230 SpheroLac 100

Air Permeability / Compactability Shear stress / Flowability

Effect of shape

Effect of size

Effect

of size

Effect of shape


“Should include, at a minimum, control of the critical process

parameters and material attributes”

“Control of input material attributes…based on an understanding

of their impact on processability or product quality”

“Controls for unit operations that have an impact on downstream

processing or product quality (e.g.…particle size distribution)”

Processability and particle size and shapeICH Q8 (R2) – QBD Control Strategy


• Having determined the ideal size and shape of particles during discovery;• How are these parameters affected by production processes and excipients?

• Surface abrasion (chipping) or fragmentation affect the dissolution behaviour differently

• Morphologically Directed Raman Spectroscopy (MDRS) allows us to follow the size and

shape of the API• Through different process

• And with different excipients

August 19, 2019Title of the presentation43

How do production processes affect particle shape

Chipping

Fragmentation


© Malvern Panalytical 2017 19 August 201944

Understanding the effects of processing using MDRS

––– initial AP (Active Pharmaceutical Ingredient);

– – – API with lactose,

+ + + API with lactose & MCC;

–– + –– API with MCC.

John Gamble et. al. International Journal of Pharmaceutics 470 (2014) 77–87

Chipping

Fragmentation

Processing

Tumble blended



––– = initial API; – – – – = API in lactose formulation; + + + = API in lactose and MCC formulation; –– + –– = API in MCC formulation.

Understanding the effects of processing using MDRS

Cone milled Roller compaction

Similar low level attrition seen with tumble blended and cone milled processes

More pronounced, high level attrition from the roller compaction process

Both excipients caused more attrition than API alone

MCC caused higher level of attrition than lactose



What is important for processability?

19 August 2019Resolving analytical challenges in the deformulation of complex generics46

Polymorph CPolymorph B

➢ Combination of Raman and

size + shape enables

polymorph detection.

➢ Polymorph B is more regular

in shape (not needles) so will

be easier to process (high

flowability, less propensity to

break,).

VoC

Kevin Dahl Associate Director, Particle Characterization Core Facility, KBI Biopharma

Very positive about the G3-ID and the M4-ID is clearly an improvement. The new laser and spectrometer

make it -5x more sensitive which is a significant improvement for small molecules and leads to a

reduction in run time of approximately 1/3rd”

Detecting the presence of different API polymorphs using

MDRS. M4-ID


Bioavailability


What is important for bioavailability?

Läkemedel och kristaller

Karin Lilltorp, Soren Lund Kristensen, Particle Analytical APS

Kemiivärlden Biotech, No. 9, September 2013

Xs = mass of solid drug

t = time

D = drug diffusion coefficient

S = surface area

Cs = drug concentration in diffusion layer

C = drug concentration in bulk

h = diffusion layer thickness

𝑑𝑋𝑠𝑑𝑡

=𝐷𝑆

ℎ𝐶𝑠 − 𝐶

Dissolution rate depends on particle size

Noyes-Whitney equation


Controlling bioavailability

• If the particle shape is well understood and the production processes controlled• Then changing the dissolution behaviour can be a simple change in particle size distribution

Particle size distribution

0

1

2

3

4

5

6

7

8

9

10

0.01 0.1 1 10 100 1000

Vo

lum

e d

en

sit

y /

%

Size / um

Long Lasting

Fast Acting


Controlling bioavailabilityHow does particle shape affect dissolution?

Particle size in

these 2 drugs is

the same

Why the different

dissolution

profiles?


Bioavailability and particle surface area

High surface

roughness increases

particle surface area

and yields rapid

dissolution

Low surface

roughness decreases

particle surface area

and yields slow

dissolution

Convexity = Perimeter of circle with equivalent area

Perimeter of particle

Correlating dissolution performance with API particle shape from MDRS


What is important for content uniformity?

August 19, 2019Title of the presentation53

Large particle size hinders uniform distribution of ingredients

XRPD data

RECALLS AND FIELD CORRECTIONS:

PRODUCT : Xactdose Phenytoin Oral Suspension, USP, 100 mg/4 mL unit dose cups, anticonvulsant. Recall #D-217-6.

CODE: Lot numbers: 508608 and 508613 EXP 2/97.DISTRIBUTION: NationwideQUANTITY: 1,947 cases were distributed; firm estimated that 10-15% of the product remained on the market at time of recall initiation.REASON: Due to large particle size, some of the unit doses may not meet potency specifications.


Value of Joined-up Approach

Examples of physicochemical and biological properties that might need to be examined include

solubility, water content, particle size, crystal properties, biological activity, and permeability.

These properties could be interrelated and might need to be considered in combination.

• Polymorph testing and Particle sizing are the 2 most important factors in drug behaviour

characterisation (Critical Reviews™ in Therapeutic Drug Carrier Systems, 21(3):133–193 (2004))

19 August 201954

ICH Q8 (R2)

2.1.1 Drug Substance


Data Integrity


Data Integrity

• “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)” – FDA

definition

• U.S. Code of Federal Regulations, Title 21

(Food and Drugs), part 11 (electronic records

and signatures).


What is it?


Data Integrity – Regulatory Focus

https://www.pharmaceuticalonline.com/doc/an-analysis-of-fda-fy-drug-gmp-warning-letters-0003

8/19/201957

Data-integrity associated with 60 % of FDA Warning Letters

https://www.pharmaceuticalonline.com/doc/an-analysis-of-fda-fy-drug-gmp-warning-letters-0003



19 August 201958


processability


Elemental Analysis

XRD

Particle

Size


Key required Features

General Access Rights Audit Trail Electronic

Records

Electronic

Signature

Installed with

checklist (OQ) &

diagnostic testing

4+ configurable

User levels

Timestamps,

including user ID

and privileges

Records (inc Raw

Data) protected

from change

Cannot be edited,

deleted, copied or

transferred

Compatible with

Windows

Unique logins for

each user

Preserved

alongside data

Include User ID,

Equipment ID,

Sample ID, Time

Done using a

specific ID – no

collective IDs

Last test

recoverable after

a failure

Data can only be

modified by

authorised

Automatically

generated and

updated

Easily storable,

directly printable,

PDF format

Must involve

Password and ID,

with no replication

Allow the back-up

and archiving on

a network server

Use of Active

Directory

Cannot be

switched off

Simultaneous

Generation and

Storage of data

Different Sig. for

creation &

approval


Based on previous questionnaires etc


General Access Rights Audit Trail Electronic

Records

Electronic

Signature

Installed with

checklist (OQ) &

diagnostic testing

4+ configurable

User levels

Timestamps,

including user ID

and privileges

Records (inc Raw

Data) protected

from change

Cannot be edited,

deleted, copied or

transferred

Compatible with

Windows

Unique logins for

each user

Preserved

alongside data

Include User ID,

Equipment ID,

Sample ID, Time

Done using a

specific ID – no

collective IDs

Last test

recoverable after

a failure

Data can only be

modified by

authorised

Automatically

generated and

updated

Easily storable,

directly printable,

PDF format

Must involve

Password and ID,

with no replication

Allow the back-up

and archiving on

a network server

Use of Active

Directory

Cannot be

switched off

Simultaneous

Generation and

Storage of data

Different Sig. for

creation &

approval


Reason for

measurement

termination

given

Malvern Access

Configurator

Audit attached

to record,

separate from

system

Export

according to

SOP (flexible

template and

destination)

Measurer

cannot approve

Key required Features


Cost of a Warning Letter

• Risk-based cost of warning letters is 1.8 million

USD per FDA-approved API Factory per year on

average• 4276 FDA-approved total manufacturing plants

receive Approx.76 Warning Letters associated with

data integrity per year, each costing approx. 100

million USD (a low-end estimate)

• A reduction in the probability of a FDA Warning

Letter by just 5 % would give a risk-based cost

saving of approx. 90,000 USD per facility per year

19 August 201961

Loss of revenue during stoppage, Remedial measures etc.


Summary

• Sensitivity• Detect trace differences

• Feedback time and ease of continuous operation• Reduced Development time

• Versatility• Generate info on all components

• Software usability and compliance• Minimize Regulatory Risk

19 August 201962

API Development

Produce High Quality Drugs more efficiently and with less financial risk

© Malvern Panalytical 2017 Co

mp

any C

on

fidential

www.malvernpanalytical.com

Co

mp

any C

on

fidential

Documents

API Development - PANalytical · 2019-12-20 · ICH Q6A –Decision Tree 4 ... Sources of Elemental Impurities in Developed API 22 19 August 2019 Adapted from ICH Q3D Manufacturing