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Development and Scale

up in API Manufacture

(Part 2 Quality

Assurance

Considerations)Tuesday 6th October 2009

Dr. Claire Mc Donnell, D.I.T.

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Contents

Regulation of API Manufacture

Comparison of API and finished drug production

Process Stages involved in API synthesis

Generation of Impurities

Case study; therapeutic grade peptide synthesis at Kinerton Ltd

Technology Transfer

Summary

Bibliography

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Regulation of API Manufacture

FDA applies cGMP regulations to bulk API manufacture

Mutual recognition agreement is finalised (EU, Japan and USA are the 3 ICH regions)

Inspections on API manufacturers carried out using ICH Guideline Q7A “GMP Guide for Active Pharmaceutical Ingredients” (August 2001)(www.fda.gov/cder/guidance/4286fnl.htm)

API’S regulated in EU according to Eudralex GMP guide, Annex 18 (July 2001/ (May 2004 (2004/27)) . Same as ICH Q7A. (http://pharmacos.eudra.org/F2/eudralex/vol-

4/pdfs-en/v4an18.pdf )

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Comparison of API and Finished

Drug Production API Manufacture –

– Raw materials undergo some significant chemical

change.

– Purification will be required to remove impurities,

contaminants, solvents, unwanted crystalline /

molecular forms etc.

– Purification achieved by various chemical, physical

and / or biological processing steps.

– Effectiveness of the purification confirmed by

chemical, biological and physical tests on the API

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Comparison of API and Finished

Drug Production cont’d

Finished Drug Product Production –

– Quality of the drug ingredients and the care exercised

in handling them predetermines purity of finished

product.

– Purification steps not usually involved.

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Types of API Manufacturing

Process

– Chemical synthesis

– Natural product extraction

– Fermentation

– Enzymatic reactions

– Recombinant DNA technology

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Process Stages Involved in API

Chemical Synthesis 1. Reaction

– (continuous/batch, multi-purpose/dedicated)

2. Separation

– (extraction/phase separation, centrifugation)

3. Purification

– (filtration, distillation, crystallisation,

chromatography)

4. Drying

– (dryer, lyophiliser)

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1. Reaction Reactor usually glass-lined steel with jacket and

fixed agitator.

- Need reactor vessel cleaning validation. Test to confirm

removal of residues

Usual Process Steps;

Addition of raw materials and solvents.

Mixing.

Heating / Cooling.

In-process monitoring.

– Carry out testing at maximum, middle and minimum of ranges quoted in SOP’s

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Reaction Stage - Purpose and

Limitations

Chemical transformation of raw materials to generate product/intermediate of specific molecular structure.

Wide general application.

Temperature range available usually 20 to 140oC.

Solid reagents can cause handling difficulties

Effective sampling method required.

Good reactor design will ensure an effective process that’s in control.

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2. Separation

Extraction/phase separation – extraction involving aqueous and organic phases separates inorganic and organic material.

– Some purification usually obtained.

– Rapid, effective phase separation required.

– Significant partition difference between product and impurities required.

Centrifugation – highly efficient and enclosed filtration system.

– Product then requires manual transfer to dryer however.

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3. Purification Filtration – used to remove residual solid impurities from a

liquid or solution.

– Wide applications.

– Filter components must be appropriate to solvents / chemicals.

Distillation – commonly used purification /separation process

for liquids.

– Requires b.p. difference of 15oC and easily achievable pressure

and temperature conditions.

– Won’t separate mixture if an azetrope (constant boiling mixture)

forms between starting composition and purity required.

– Can’t separate compounds of very similar chemical structure.

– Sampling difficult under vacuum conditions.

– Energy costs can be significant.

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3. Purification cont’d

Crystallisation – common method for purification of

solids.

– Cooling rate affects particle size.

– Consistent crystal morphology required from process.

– Requires filtration and washing; need efficient removal of

mother liquor and washes.

Chromatography – very efficient purification.

– Dilute solutions necessary (large solvent volume and low

throughput) specialised equipment – high cost.

– Expensive technique on large scale. Only applicable to

high value products.

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4. Drying

Dryer – oven, vacuum, spray, fluid bed (many models /

types available). Removal of residual solvent.

– Manual transfer often necessary – exposure/degree of

protection assessment.

– Organic vapours may be given off.

– Not applicable to heat-sensitive product.

Lyophilisation – freeze-drying.

– Used for heat-sensitive products.

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Double

drum dryer

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Critical Steps in API Manufacture

Design of API manufacturing plants traditionally

like chemical manufacturing plants (traces of

contaminants usually acceptable).

Rigid controls may not be required or feasible in

early processing steps.

cGMP regulations apply to manufacture of drugs in

their final dose form but FDA applies them to bulk

API manufacture and to drug intermediate

manufacture if the manufacture of the intermediate

is a “critical” step.

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Critical step – affects part of the drug’s characterisation

(for example, its crystalline form) or impurity profile.

Critical step must be controlled within predetermined

criteria to ensure the API meets its specification.

– Step after which recovery from process malfunction or

contamination is not possible.

– Not limited to final stage of API process. Can include

intermediate steps that

– 1) Introduce essential molecular structure element or

result in a major chemical transformation

– 2) Introduce significant impurities into the product

– 3) Remove significant impurities from the product

Critical Steps in API Manufacture cont’d

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Critical Steps in API Manufacture cont’d

Therefore, a step can be critical due to its chemistry

(control critical parameters) or with regard to

contamination (control contamination sources such as

operator procedures and environment).

Critical parameter – processing parameter which directly

influences the drug characterisation or impurity profile of a

drug in a critical step (e.g. temperature).

Need to show have consistent control of critical parameters in

critical processes.

Instruments used to measure critical parameters require

enhanced documentation (critical instruments). Reasonable

acceptance criteria – set between vendor claim and process

requirement.

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Critical Areas in Production of Product X

Description Stage Process Step

Agitation Rate Crystallization IV-A, C, H, J, P, Q, AE

Temperature increase Hydrolysis

Temperature increase Isolation III-O

Temperature

holding/maintaining

Hydrolysis

Temperature

holding/maintaining

Crystallization V-E

Temperature

holding/maintaining

Drying

Temperature Cooling Crystallization III-R, III-T

pH Hydrolysis

pH Crystallization IV-R, T, C, H, J, E, N, Q,

R, S, V

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Example of Manufacturing Scale

Process

Extract from Batch Log Sheet for Crystallisation

1.Adjust temperature to 40-50oC

2.While maintaining the temperature at 40 – 50oC, add

10% of the total charge of sulphuric acid.

Note The sulphuric acid should be charged subsurface

3.Seed the mixture with 0.2 – 5% of Product X

4. Agitate the mixture at 40-50oC for 30 minutes.

5. Add the remaining sulphuric acid over 2 to 3 hours

while keeping the temperature at 40-50oC

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Regulatory Requirements

At validation stage (3 batches), all parameters

should be fixed and development complete (beyond

experimental stage)

DESIGN quality in, can’t test it in.

Post approval changes necessary due to continuous

improvement requirement and changes in

circumstances (raw material vendors, vegetable

extracts instead of animal (BSE) etc.).

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Post-Approval Changes

SUPAC (scale up post approval changes)

BACPAC (bulk actives post approval changes)

CBE (changes being effected)

Reporting categories

- Major change (Prior Approval Supplement)

- Moderate change (Supplement – Changes Being

Effected in 30 days or

Supplement – Changes Being Effected)

- Minor change (next Annual Report)

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Post Approval Changes Criteria used are potential for change to have effect

on identity, strength, quality, purity or potency of the drug product.

FDA Guidance Document “Changes to an Approved NDA or ANDA”, Nov 1999 (http://www.fda.gov/cder/guidance/2766fnl.htm)

FDA Guidance Document “BACPAC I : Intermediates in Drug Substance Synthesis”, Feb 2001 (http://www.fda.gov/cder/guidance/3629fnl.htm)

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Generation of Impurities

Impurities - chemical (moisture, solvent, side-products), biological (endotoxin & microbial levels) and physical (particle size, homogeneity, specific bulk density outside specifications).

Before defining critical steps in API manufacture, need to characterise the final drug substance including its impurity profile. (Identify impurities at > 0.1%)

Impurity profile provides fingerprint for acceptance of each API batch.

Recommended to submit relatively “impure” batch for safety/toxicology studies – i.e. acceptance criteria that can readily be met and allow acceptable product quality.

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Case Study; Therapeutic Grade Peptide

Synthesis at Kinerton Ltd.Process Steps for A Specialised API Manufacturing

Process

BACKGROUND

Ipsen Ltd produces synthetic peptides (10-12 amino acid sequences) which are API’S.

Applications – cancer, diabetes, growth disorders

Annual production ~ 20 Kg.

Potent, high value API.

Therapeutic delivery of peptides difficult due to short half-life (< 1 hour) and susceptibility to enzymatic degradation.

Currently Ipsen’s API is finished in sustained release formulation by a sister company in France.

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Case Study; Therapeutic Grade Peptide

Synthesis at Kinerton Ltd.

Production of API separated into synthesis followed by purification and drying processes.

SYNTHESIS – Solid Phase Peptide Synthesis

- Classical method (Merrifield, 1960’s)

- Amino acids (a.a.’s) can be assembled into a peptide of any desired sequence while one end of the a.a. chain is anchored to an insoluble support (resin).

- 1st a.a. attached to resin via linker, it’s amino protecting group is removed and 2nd a.a. is added. Amino protecting group of 2nd a.a. removed and 3rd a.a. added , etc ……

- After desired sequence of a.a.’s joined together on the support, cleave chain from support and finished peptide is liberated into solution.

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Case Study; Therapeutic Grade Peptide

Synthesis at Kinerton Ltd.

- Critical requirement that carry out in process testing to

ensure complete deprotection and then coupling

(Kaiser-Ninhydrin test).

- No isolation of intermediates.

- Reactors used – 50L glass with sintered glass frit at base.

- Product dedicated, batch production.

After cleavage, crude product extracted and

precipitated. Then solubilised in dilute acetic acid.

Tested to determine crude purity (50 – 70%) and yield.

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Case Study; Therapeutic Grade Peptide

Synthesis at Kinerton Ltd.

PURIFICATION – Preparative Scale HPLC

- Very powerful technique, high reproducibility.

- Expensive, high dilutions.

- Chromatography – distribution phenomenon between

stationary (silica packing) and mobile phase (buffer/solvent

system). All compounds spend same time in mobile phase

but different times in stationary phase.

- Purified product of > 99% (no impurities > 0.5%) obtained

as solution in acetic acid buffer.

NOTE - Potential of SMB (Simulated Moving Bed)

Chromatography instead of Prep HPLC.

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Prep Scale HPLC Systems

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Case Study; Therapeutic Grade Peptide

Synthesis at Kinerton Ltd.

DRYING – Lyophilisation

- Solution of purified peptide freeze-dried to produce dry

solid cake.

- Critical parameters – cycle used (temperatures, times,

pressure), concentration of peptide solution – affect

drying and physical characteristics of product (e.g.

SSA).

-Exposure – vertical laminar flow cleanroom (class 100)

used for lyophilisation and packaging to protect API

product.

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Technology Transfer

Overlap with Development and Scale up.

Several pharmaceutical firms recently used SUPAC guidelines to move products that were former blockbuster drugs to contract manufacturers and renovated their vacated manufacturing sites for new blockbusters

Subtle differences in processing equipment most overlooked area causing delays and failures in technology transfer (e.g. define pumping and spraying systems, mixer / homogeniser types, filter type and porosity for fluid bed)

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Technology Transfer cont’d

Analytical methods transfer very important – define equipment set-up and settings, calibration schedules, weighing and injection techniques and sample preparation methods (visits to new site)

Equivalence of data

between sites must be

assured – economic,

compliance and regulatory

aspects

Stability programme

requires consideration

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Technology Transfer - Factors for Success

Communication – often difficult to achieve. Timely (mechanism?), Clear - nothing left to interpretation, Oral communications documented, All critical departments included.

Quality – Compliance with regulations, continuous evaluation, corporate culture

Timeliness - Expectations clarified, critical milestones clearly identified

Relationship - Cooperation and partnership approach, visits and meetings

Robust process – slight changes in operating parameters should give comparable results

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Summary Are a series of usual process stages and a range of

equipment usually employed in API manufacture

Important to identify critical steps and parameters in process as soon as possible

Specialised techniques and equipment may be employed if process will still be cost effective

Post approval changes – type of change determines reporting category

Technology transfer – communication and analytical data equivalence vital

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Bibliography

Change Control in the Pharmaceutical Industry, Lecture, Patricia Sheehan, Leo Labs, Nov 2000.

ICH Guideline Q7A “GMP Guidance for Active Pharmaceutical Ingredients”, August 2001 (www.fda.gov/cder/guidance/4286fnl.htm)

Chemical Development and Scale-Up in the Fine Chemical Industry, Course Notes from Trevor Laird, Scientific Update, 2000.

Scale Up and Transfer with Manufacturing, Michael J. Valazza, Contract Pharma, Dec 1999. (http://www.contractpharma.com/dec992.htm)

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Bibliography cont’d

FURTHER READING:

Organic Process Research and Development, Journal (Amer Chem Soc / RSC). In DIT Kevin St.

Pharmaceutical Technology Europe, Journal (Advanstar Publishing) - Accessible electronically on DIT library catalogue http://library.dit.ie/ or subscribe to for free at

http://www.ptemag.com/pharmtecheurope/

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RSC Library and Information Centre