NCI guidelines for the formulation of investigational cytotoxic drugs

ecial s&P

EORTC/CRC/NCI

Guidelines

of Investigational J. PAUL *Pharmaceutical Bethesda,

for the Formulation Drugs

and ‘1‘.JOIANDE DAVIGNON,* JOHN A. SLACK,t JOS H. BEIJNEA 1,: 1v. KOGEK VlXIS$ SCHOEMAKER:I( on behalf of the EOR7‘CICRCINCI Joint Formulation \Yorking Party Resources

MD,

tiniversig,

Cytotoxic

Article

Branch,

The Triangle,

EC Amsterdam,

Developmental

t CancerResearch

c’.S.11..

Birmingham

The Xetherlands

Therapeutics

Campaign

B4 7ET,

Program,

Experimental

I)‘.K.,

:Slotervaart

and 5 Cancer Research

Dikion

Croup, Pharmaceutical

Hospitcrl/~~etherlands

Campaign

,Vatronal (,‘anrer Institule,

of Cancer Treatment,

Chemotherapy Formulation

Science., In,tilate,

Cancer Institute.

I ‘nit. Department

(I/ Pharmacy,

Strathrivde, Gla,gou

laborate

INTRODUCTION THE

New

Drug

Dcvclopment (NDDCC) of the

Committee ization

for

(EORTC), Rcscarch lized

Research and Trcatmcnt in collaboration with

Campaign

a procedure

of investigational

(CRC),

has

recently This

three

of a Joint will

dcvclopmcnt the assure

program

chemical

strength

I.YLt: I:.K.

fi)rmulation

pro-

agreed

to the

\Vorking

Part)

the use of pharmaceutical

provide

new

( niz’er,\i
(;l

ha\.c

Formulation that

of the proper

of thr

and

organizations

it is our hope

guidelines

forma-

dcvclopmcnt

in Europe.

on crrtain The

formation and

of Cancer the Cancer

for the prcclinical drugs

jects.

and Coordinating European Organ-

‘Iston

Louwe~rt eg 6, 1066

some

continuit)

investigational identification. drug.

Such

in

pr-oduct purity controls

the and and

will also

is intcndcd to organize the prcclinical drug dcvclopmcnt process and to reduce the lag-time bctwccn

provide the necessary atory acceptancr and

documcntalion fi)r rcgulcnablc thcx prcclinical toxi-

disco\,cry of Phase

cology

clinical

of promising new agents I clinical trials. Through

NDDCC/CRC

coordinate

and this

a prcclinical

opmcnt effort by monitoring phases of product dc\clopmcnt.

initiation cflort the

drug dcvcl-

the various The critical

include bulk production (or acquisition) thctic or natural products, formulation mcnt,

and

pharmaceutical

best

rcsourccs

of rquipmcnt

and

cstablishcd

critical phase

Since

cxpcrtisr

regulatory

not exist. The formulated

the

NDDCC/CRC

arc dis-

products arc

rtrorts within

It has been the acccptcd

State

National

Cancer

Institute

(NCI)

may

new investigational Phase I clinical

col-

bolus fccrptcd 28 April 1988. Present address: C.rntocor Europe B.V.. PO AC; Ixidcn, ‘Thr Nrthcrlatlds. (brrrspottdcrtcr and reprint rrqursts to: 1)rJ.A. Rrsrarch Campaign Experimental Chcmothcrapy maccutical Sciencrs Institutr, Aston University. Birmingham B4 7ET. U.K.

Box

251,

ccntcrs

the EORTC/CRC

at different locations likely that the United

injection

to supcrscdr of‘ the \Gous

dt*\&pcd

intcndcd

those

conducted It is also

clinical

to bc the par-

but to bc used as a brnchpractice whcr(. guidrlincs do

pcrsrd among the mcmbcrs of the EORTC/CRC, it is likely that the preformulation and production will bc Europe.

in~cstigations

controls

ticipating countries, mark tb acccptablr

of syndcvclop-

production.

and subsrqucnt

conducted with confidcncc. This document is not intcndcd

rcgistcrcd

Phase

undrr

the

Tar distribution

to

to participate

in

I and II clinical trials [ I]. practice fi)r the majority of

agents to bc administcrcd in trials as cithcr an intravenous or via

intr.a\.cnous

itilitsion.

‘I‘his

routr of administration a\-oids the problems associatcd with incomplrtc absorption and the local GI toxicity often scrn with oral administration. Conscqucntly, thcsc guidclincs and comments mainly

2300

Slack. Cancrr Group, Phar‘l‘hc Triangle.

address the issue associated with the dc\,rtopmcnt of stcrilc and stable injcctabl(, products. I535

Special Article

1536

The new drug substance (NDS)

potential

The acquisition of high quality NDS and other ingredients is essntial and may circumvent many

kinetic studies. Criteria to be applied

formulation

cyto-

the reference

non-

include:

toxic

problems.

agent’s

are

pharmaceutical chemical and initiation always

Most

initially

obtained

from

sources and require a complete physical assessment prior to

of pharmaceutical helpful

investigational

to obtain,

development. if possible,

It

methods

materials.

The

suppliers

of the NDS

??elemental

be

informed that their materials are intended for pharmaceutical work and that certain documentation and controls

arc required.

the documentation following minimal

??Certificate

batch identify

to facilitate

and evaluation of the NDS the information should be provided

with each supply: ??Name and address ??Manufacture

In order

flow sheet of analysis

for characterization

and all NDS

of

lots should

such as i.r., u.v., MS, etc. analysis such as HPLC, TLC

analysis description

such as color, appcarancc,

odor ??other

properties when appropriate such as physical constants, M.P., optical rotation, etc.

A complete

analytical

profile may not bc fcasiblc

for certain complex materials especially if they arc dcrivcd from biological or natural origin; howcvcr, every effort should be made to adcquatcly characterize each new bulk substance. The test methods and

results

of each

new batch

of NDS

should

be recorded and compared to acceptable limits previously cstablishcd with the rcfcrcncc sample.

only certain tests for confirmation

control

may be rcquircd.

Stabili& and solubilig of NDS

and purity analysis

If stability

data arc not available

on the NDS,

a study should be initiated to provide useful storage

(if known).

Characterization of NDS On receipt of the NDS the pharmaceutical scicntist should verify the identity of the sample and confirm that it is of the highest purity available.

In

the first stage of dcvclopmcnt an interim reference standard should be idcntificd. A small proportion of the batch of highest purity should bc analytically characterized

and in pharmaco-

The suppliers of the NDS may bc willing to provide some or all of the above information. In such casts

of the supplier

date of analysis ??Storage rcquircmcnts

analysis

??physical

products

standard

??chromatographic

is

purposes such as starting should

??spectral

of

synthesis (or extraction) and purification of the NDS. This information will be used for regulatory documentation and also for analytical to identify possible trace contaminants solvents or unreacted undesirable

formulated

and set aside as the interim rcfcrcncc

and handling

information

ation

The

dates.

and for projecting

stability

should

cxpir-

bc dctcrmincd

under scvcral storage conditions including clevatcd temperature, fluorescent light and high humidity (optional).

These studies should bc carried out over

a period of 3-6 chromatographic

months and a stability indicating assay used for the quantitation

of the drug in the prcsencc uct(s). The solubility

of its degradation

prod-

study should include equilibrium

standard. The use of a reference sample greatly facilitates the development of suitable analytical mcthod-

solubility determinations in water, acid, base, and organic solvents such as ethanol, dimcthylaccta-

ology.

maceutical vehicles [3-51. The required solubility is dependent

Chromatographic

developed,

and cvaluatcd,

tcchniqucs

should

for both qualitative

be and

quantitative purposes. Thin layer chromatography (TLC) is frequently used to dctcct the presence of impurities. Howcvcr, it is advisable to USC at least two scparatc chromatographic systems to cnsurc that the impurity is not masked by the parent NDS. Either liquid (HPLC) or gas (GC) chromatography arc usually used as the quantitative analytical procedure. HPLC is often the tcchniquc of choice, as the NDS can frcqucntly be analyzed in the aqueous injection dilucnt without prior cxtraction. The analytical for its sclcctivity,

technique accuracy

should be cvaluatcd and precision. Once

developed the HPLC, or GC, methodology can be subsequently used as the stability indicating assay [2] and adapted for use in the later evaluation of

midc, dimcthylsulfoxidc

and other potential

phar-

on the pro-

jected Phase I starting dose and the estimated human maximum tolerated dose (MTD). The cstimated human starting available

doses is calculated

animal screening

cological indicators.

from the

data and other pharma-

The initial starting dose is then

increased, in the Phase I protocol, via a modified Fibonacci escalation scheme [6], or by further utilization of the relevant pharmacokinetic data [6, 71. These early dosing estimates are critical in dctcrmining the solubility requirements of the new agent and the approach to formulation development.

Formulation An evaluation of the solubility and stability profile of the NDS assists the pharmaceutical scientist

1537

Special Article

in

assessing

problem.

the

The

rclativc.

complexity

of

lack of adequate

to the estimated

In,jcctablc stcrilc

products

liquids

is the

formulation

can

or sterile

solubility,

requirement,

be classified

solids.

The

hlost

products

potency compendia

as either

Moisture

determine dctcrminc

sterile

liquids

ing. .\l~mbranc

PH Completeness and clarity of solution Particulate Sterility

fil-

cxccption of those products of to withstand terminal autoclav-

labelling

sterilized

filtration

by

membrane

has an additional

advan-

The

(set limits) (set limits)

cimpendia compendia

matter

Pyrogen Conformance

arr

(colour) 210% of label

3

vials) Weight variation

form of reconstitution and may some f’urthc’r dilution for infusion administration.

trdtion \lith the sufticic’llt stability

Appearance Assay (minimum

problem

may bc injcctcd directly or may require further dilution bcforc injection dcpcnding on the manufaclurers’ rccommcndations. The sterile solids all rcquirc rcquirv

Specijication

Test

formulation

aqueous

dose

most frcqucntly encountered for injectable products.

the

compendia compendia to conforms

compendia

refers

to European

Pharmaco-

tagc of rcmo\ing uadissolvcd particulatcs. It is gc>llcralIy less rxpcnsivc to prepare injectable liquids than the sterile dry products which usually

poeia tests and procedures. The pH and moisturr values can be established during product devclopmcnt. The release documents for the formulated

involves frcczc drying. ucts provide a method

quality

that arc stable ary stability and

for

approaches de\,clopcd

products

tcstirlg

a small

to cnsurc

other

ill pharmacology

inf&mation obtainrd used f’or the batch

has pilot

stability

been batch

and

stability

screen

prc-clinical

and

similar

com-

with the equipment and The pilot batch product

in the tumor

and

controls

follow form

bc usc.d for additional

nc>ccssar)‘),

plasma

studies,

(if considered studies

such

compatibility.

in the pilot manufactured

documentation

The

run can then be for preclinical

should

bc

pre-

product appropriprocedures and

rc>cordillg such details as order timrs, tcmpcraturcs. filtration

of mixing, solution methods, etc. This

is cxtrrmcly

important

for regul-

ator! control and for rctricval of historical data the c\.cnt of qucstionablc product problems. preparation

all batch

production

and

and

and labelling

investigational

labcllcd

of product

specifications

in for

products

to provide

information

investigator.

proper to the

The

??Storage

pharmacist

fully

and

clinical

should

be pro-

salt or free base)

conditions and address

??Batch

(or lot) number

??Expiration

of manufacturer

date-and/or

If a sterile

manufacture

date

use statement (if applicable) instructions (if applicable). solution

to infusion

is to be used fluids

be diluted before intravenous placed on the label. Details stability

details

be

identification

and potency ingredients

??Name

additive

should

product

following

vided on the label: ??Drug name (state ??Other

as

\vith each lot of finished tictailing the formulation

‘l‘hc

include records.

* Investigational ??Reconstitution

hlanufacturing

clocumcnlation

Packaging

??Strength

tcrxic~olog!

pared atc.1)

should control

All dosage

of‘ the product of‘manuf:acturc.

ma)’ then

material

but lack the necess-

laboratory

hc prcparcd

patil)ility conditions clIicac\

injectable

in the

dried prodsubstances

The manufacturing

of evaluation. acccptablc

art

should

in the solid state

in solution.

tests

onw

However, freeze for formulating

of the reconstituted

solution should be insert or the clinical

a warning

only

as an

such

as ‘to

injection’ should bc on the storage and product

and

infusion

given in either the package brochure. All stability statc-

mcnts should be supported by laboratory trials and documented in the product history records.

postrnanuGcturc, rclcasc of hnishcd dosage forms ih cssctltial. I‘hc specifications for new products

Shelf life studies

arc often statrd fijr adjustmc.nts

as tentative specifications allowing as more cxpcriencc is gained in

Following the release of the manufactured batch sufficient vials should be set aside for long term

thc> rnanufacturc of subsequent batches. The follo\~inr?; is rt list of-suggcstcd tests and specifications that ma) bc included in a certificate of analysis:

shelf-life evaluation of the product. The shelf-life date will support the products integrity under various storage conditions. The information obtained will allow for future adjustments to the label storage recommendations and provide necessary information for assignments of expiration dates.

Special Article

1538

New products should be evaluated under at least three storage conditions; the recommended storage temperature, storage

one level

temperature,

ommended

above

the recommended

and one level below the rec-

storage temperature.

run for 24 months

The study should

or longer

depending

on the

number of samples that can be put aside and the long range goals for the clinical trial. The following arc suggested that

may

storage conditions

be considered

and test intervals

for new product

evalu-

ation:

system should contain sufficient historical documentation that all investigators holding stocks of the drug

could

??Name

‘Testing

and description

??Amount

??Storage

interval

(months)

PC)

-10

3 3 3 3

4 25 50

6 6 6 6

9 9 9 9

12 12 12 12

18 18 18 18

and date received

at each interval

include:

color, appearance, clarity of solution, stitution time (if applicable).

24 24 24 24

36 26 36 36

48 48 48 48

potency,

pH and con-

A

product

storage

conditions

??Clinical

trial number

??Participating ??Amount

investigators and date shipped

??Manufacturer

and lot number

DISCUSSION The guidelines

described

above are intended

to

bc neither exhaustive nor inflexible. Each NDS can present unique problems for the pharmaceutical scientist

and in solving these problems

certain lib-

erties may have to bc taken. These guidelines arc intended to be used as a check-list for the pharma-

Storage and distribution should be established

and lot number date

Product distribution file

The tests are performed frequently during the first year, then biannually, then annually. The tests performed

of a

??Potency ??Manufacturer

temperaturr

in the event

Product storage jile

??Expiration Storage

be contacted

product recall. The system should be written or computerized and should contain the following lotspecific information.

and

distribution

to ensure

proper

system storage

of

ceutical

aspects

the investigational drug products and to assure that only authorized investigators receive the prod-

facility

ucts for specific clinical protocols.

authorities

The distribution

of new investigational

anticancer

drugs. It is the intention of both the EORTWCRC and the NC1 that data gencratcd within either should

be acceptable

to the

in all the participating

regulatory

countries.

REFERENCES 1. EORTC

New Drug Development Committee. EORTC guidelines for phase I trials with single agents in adults. Eur J Cancer Clin Oncol 1985, 21, 1005-1007. 2. Trissel LA, Flora KP. Stability studies-five years later. Am J Hasp Pharm (in press). 3. Davignon JP, Cradock JC. Pharmaceutical aspects of antitumour agents. Pharmaceutisch Weekblad 1984, 119, 1144-l 149. 4. Chen T, Lausier JM, Rhodes CT. Possible strategies for the formulation of antineoplastic drugs. Drug Develot, Ind Pharm 1986, 12, 1041-l 106. 5. Yalkowsky SH. Techniques of Solubili