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_Docket 2005N-0285 _{Division of Dockets} Managernent (IIFA-34S)

_{Food and Drug} Administration

_{5`630 Fishers} Lane, ltrrt. 1061

Rvckviile, NZD 20852

_{Re :}

_{FDA's direct final}

rule/proposed

biologics from the current, ^good

_{rule to exempt phase 1} irivcstigationaJ drugs and

_{r :tanufactui ing praci.ice (C} ;GMP) regulation

_{Dear Mernbers of the U .S. Food and Drug} Administration .

_{for the} opportunity to comment on the ^{agency's direct final rule/proposed rule}

_{from the CGIAP} regulation . 7_ am opposed

investigatiiznal drugs and ^biologics

_{which is} not legally binding, should ^{not be}

_{the minimurn} requirements for 'he ^safe

	Thank you
to, exempt		phase 1
to	this

_{rule, and} believe that a guidance document,

_{used to replace an existing} regulation that provides

_{manufacture cat drugs or} biologics for human

_{beings, 1} believe that tills rule may ^{place patients in}

_{phase 1 in} jeopardy .

_{Puts patients at risk, and is not} legally binding

_{documents are not legally} binding, and no at-it: is required ^{to iollowiht;m . They also}

human

beir! ~S should be made per

Guidance

cannot

_be enforced- Drugs or biologics ^{made for use u1}

_{assutnes that new sponsors} would keep proper

_{. FDA had always} considered proposing

_{Current Good} MuratrJactur- :ng E't-actcce in

requirements tonYake them ^safely . _{make it very difficult lo} investigate or

In

manufacturing p3actYcc°' is ^{. This} _{records, perform necessary} testing, or

would lake the time to learn ^and

_{CGMI' regulation,} which provides the miniiYium, ^legal

addition to putting

patients at risk., this approach ^will

prosecute serious

approach

_{cases, and to prove} what "current good

_{for later} investigations, or that they

_{were no} regulation requiring thenl

_keep retention samples

_follow CCiMP if there

thernselves'l)

Final Rule,

Holrlifzg, 1978)

be

_{to do so (why would they} incriminate

_{CGMPs for [n-'es} :tigational drugs (Preamble,

Manitjaeturing, F`Yoeessirlg, ^{Packing or-}

_r~ale ana dra:t guidance may

_{. Comments received on tlae direct final} rulelp~opos~d

incorporated instead into a ^{proposed r01e on CGMI's for}

imvtisttgational drugs and ^biologics.

Unethical

_{1n the proposed rule, rDA} states that phase 1 rnaterial ^being

_{which an} Investigational

_{New Drug} application (1ND) has

_using the guidance

available in phase

_{made for} the first time and for

_been submitted to FDA may ^{be made}

_{bua if th : .r} .aterial is already

available, the phase 1 ^{material would}

_{docutttent (rather ',han the CGMP} regtilatie7tl),

_{2 or 3 clinical trials, or} commercially

_{mean that some Phase l} material would be

volunteers in pliase 1 are

they _{are flit,} first humans to

_{have to be made per} CC'xMI'regulatton . This would

_{made per CGiVIP} regulation

., and some

_already shouldering the

receive the compound

tenninally ill, or

may be

_may not. Patients or healthy

_{biggest burden} o," any participants bcaau: e

_{. Of the patients who} participate, many

the

_{of them are', c} hIonrcally i17,

possibilit~y t'zat the Yriaterial ^{they recei=.~e}

immunoconnproinised . Introducing

inanutactt.rec pe .= the : ame ^{standard as material}

contaminated or strpe ^{:cpotent, and not}

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_{the death of one. Other deadly recalls of} pharmacy-compounded

_albuterol inhaler for asthmatics that ^was

contaminated with

know may

_cause rrspiratory infections,

one eye

products have included ^an

_Scr-raliu liyuelaciens, which as you

_{sepsis, or death- One} patient was also recently blinded ⁱⁿ

_that

_were not sterile .

_{due to using} eyedrops prepared by a pharmacy

_{Medical Device} Experience . In the medical

_{device industry} . the number of deadly ^recalls

_{~,~r'oup of FDA war-ning} letters for

_{has increased more than}

_{300°X. since 15W 'Che} single largest

mediGai device

_firms, including a large percentage

_' `noncompliance are currently being ^{issued to}

going

_{to sponsors,} clinical investigators,

human clinical trials . The only ^{part of}

investigational devices is that ^portion

_{requires formal,} documented reviews

_{having an} uninterested party

Questions: Ilas the

_and institutional review boards ^{involved in device}

_{CGMP that must be followed when} manufacturing

_{of device CCiMP} concerning design c:-ontzols ^(which

_{at the end of each design phase during product} development,

_those review:,, ctc .)

_{pre .s-r.nt and actively} ~LontYibuting during

_{agency yet done a} root cause analysis

tc$ cic,t.errri:rte what is causing ^the

_{.; in the device} sector? Wl-ly

_`

_`

_{deadly proc .uct recalls,} warning letters, and compliance ^problem,

_{want to emulate} this sector (in reducing

what is

_would the agency

_{drug,-, or biologics) without first} understanding

_{CGNIP requirements :or} rnvest.gational

_{causing the probie-rns} ~x7 the device sector?

Violates _{U .S. and European Union CGNII's, and lacks} understanding of QC unit role

_{The draft guidance} published with the proposed

_{the material to} release it to the clinic, and

_{rule allow-, the same person who} manufactured

_{allows a} non-QC unit employee to release ^{material .}

practice, which requires that a

_{product, It is also a clear} violation of the

_{a Qualified Person (qualified by} training and

_{This is a clear violation of U .S . current good} manufacturing

_{member of the Quality} Control unit (QC unit)

_{European Union CGiV1Ps,} which require

experience) release investigatiorlal

and

that

release

_{that Arhen} compounding sterile or

_conlinercial material. Even phar-inuc ~s¢s ^{learn that}

aseptic product, they must ^{incorporate nccPssaz-y checks and}

balances .

_{the importance of having an} experienced

_quality assurance urn ~s required ^for

_This approach does not appear to recognize

_{QC unit} (or pei son) to

_manufacture the materials safcly, The; ^{agency is}

_{that ;s} responsible _{for ensuririg}

_and knowledgeable

undermining the

_{QC unit, lz-1c one group inside} organizations

_CGIv1Y requirements

.

If a

_{patient safety} and enforcing

_animal testing, why would

_material being used

_{the agency propose that one is riot needed to release} investigationat

_{in human} beings for the first time'?

_Off Mission

_{The tnissic7n of the L7.S . Food and Drug} Administration, ^mandated by ^{Congress in The}

Food, Drug

_and Cosmetic Act (Sect. 903, U .S .C. 393)

states, that the Food and Drug

Administration shall "promote ^{the public health by}

_promptly and efficiently tly reviewing.

_{clinical research and taking} appropnati: action on

timely

that .

_..

_{the marketing} oz _regulated products in a

_{protect the} public health by ensuring

_{effective ." The direct final rule} states that

the drag dcVeloPnitnt

scone of the. ^agency's mission ^.

_{manner" and} "with respect to such products,

_{human and} veterinary drugs are safe and

_the agency is making this proposal "to ^{streamline and prornote}

_{proces :." If my} understanding is correct,

_{this is} outside, th~

_{The FDA} was established to serve as a

_consumer protection agency, and 3 check ^{and a}

_mandatC includes promptly and

appropriate action on the ^{rnarketi.ng of}

_{becoming a drug} develoPrneiit organization_

_{balance c.n regulated industry .} The Cungczssiona1

efficiently reviewing clinical ^{research and taking-}

reg:tilat.ed products in a timely manner ^{. not}

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Insufficient itesting ^requirements

_{document issucd with the proposed rule strongly} recorrFinends performing

_{but it does} not requlre

The guidance,

_{confirmatoty identity testing on active} pharmaceutical ingredient,;,

_is a violation of current, good

manufacturing practice . As you

_that occurrec in the 1930s in

it. This

tragedy

_{recall, in the} sulfanilamide

_{the Un] Led States,} diethylene glycol

without

_(the equivalent o` antifreeze)

_{sufficient testing} or controls, and

_{was used in manufacturing an "elixir" of} sulfanilamide,

resulting in the death of more than ^{100 patients, many}

reeornmen.ds hut does not require ^{that testing}

safety-rclated purposes

clearance or

_does not require

appropriate to

_such as -viral loads,

_{of them children .} The guidance document

products be done for

_of biological/biotecluxrzlagy

_biobuuden, detoxification of

bacterial toxins, viral

inactivation, and clearance at ^{antibiotics . The guidance}

_{that laboratozy testing oi' tbc} ipvestigational

_documc-nt r-ecominend_s but

_{product be} performed _"as

_evaluate identity, strength, potency, ^purity,

_and quality attribictcs ." This is clearl_y

insufficient .

Insufficient aseptic or ^{sterile information}

_{would be used} to replace the existing ^CGMP

_The guidance,

_{which if under} the current proposal,

_{for the} manufacture of some phase I

materials, contains little ^{more than one page on}

regulation
sterile or aseptic
guidance	on
63 pages
chenucal
would

_{and makes no reference to, media fills.} Manufacturing

manufacturing sterile or aseptic ^products,

_dosage forms requires

_{a higher level of skill and judgment,} The, agency's

_{Sterile Drug Products Produced} by .,Iseptic

F'rocessin,- is very ^{detailed and contains}

_{dot-,s not contain detailed} inforrraation on

_{to assume that a drug} manufacturer,

_{. Even though} the current CG111P regulation

rnanufacturing sterile or aseptic ^{product, it is illagical}

manufacturer or (medical research)

_{laboratory making clinical material for} the. first time

_{material saicly_} It is illogical to

_{FDA guidance} documents or take the

_{be aole to} follow this guidance arid make ^{sterile or aseptic}

_{read or} become familiar with other

_assume that they would

_{time to} learn or follow

_{C~C'TMP without having to do so per a C ¬'sM4'} regulation,

Insufficient employee training ^requirements

_{does not} lcrow how rnariy entities ^would

_The direct final rule states that ^{even though the agency}

_{be affected by the rule, that} they believe that "all of

_personnel with skills necessary to comply

_training required for aseptic technique

_{the e .ntitics} aFfec:ted by this rule have

_with requirements

."

_{This is} illog~~cal, The amount of

_{alone is} substantial, and not yet well ^{described in the}

,guidance,

_'

_{:Based on} assumptions

; _{no data} provided

entities may be affected ^{by this rule,}

_this rule . Since FDA only ^performs

_{as "for cause" or during} treatment

_{The FDA} aclcnowiedges that they do ^{not Icnow how many}

and that they do not keep

_{a database of} firms affected by

_limited inspections of

_[NDs), what data

phase 3 material manufacturers ^(such

_{What arc;} the results cri the agency's ^"for

_{do FDA} have to support their position?

_adverse drug event,; ^{reported during phase l?}

_{cause" in~ipccfions, treatment-IND} inspections, or

What do the data show? Does ^{the agency}

_have

_{enough information} to be T] taking rl7is proposal'?

_{What data are FDA using to} support their position?

Proponents of this approach

Pharrnac~=utical Ingredients, an

state that ICH Q711,

_{Good A7aria} .rf~ctzrg-irzg Practice fo-r Active

internationally harmonized ^{guidance, has been successfully used}

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_{without the need for a} regulation . ICH Q7A

_manufacture material that will be further

_{also has 57 detailed} pages, and is used to

_processed before being ^delivered to patients . '1 he draft

phase 1 guicaance is currently 17 pages

_{biologics that} may be delivered by

_{the material} is improperly prepared

rnanufacturers, although again, the

_{long and provides} recontmendalian,s for drugs and

_injection, or inhalation, resulting .n patient injury ^{or death if}

_{or contaminated . FDA also at} least inspccts AN

_{agency does not} routinely inspect in phase 1 unless for cause

_{(or in certain} specified circurnstances, such as for "Treatment ^{INDs) .}

_Too risky for estimated benefits

_{The proposed} savings of $1,440 per IND in documentation, ^{training, and o?hea' "i'ed-Lsced"}

requirements (or the equivalent of paying

_{seminar) is} not justified by the additional

tuition to send one person so an industry two-day

risk to patients in phase 1 . 7n

adclitiOn, the ^potential

costs (estimated a! an additional $g 14 per INi)

_{have never {nade these} materials before) is a

manufacturc sterile or aseptic

product

required equipment

_and other

or

manufacturing environment

movement ^. has caused

As far as

_{for chemical} manufacturers and Ia~burat .ories which

_gross underestimation of how much it will cost to

_{for the first time . The draft} guidance doer ~~sat yet discuss

_{facilities far these i)rpes of products, such as biosafety} cabinets, isolators

_{is required in the European Union CGMPs} ; not iitnitiYig this

_{equipment . Nor does it} limit niovernent from an animal colony to ^{the human}

(which

_{contamination in facilities} manuf:ictuYing material for "humans .)

Nvould be affected . This is a

_{how many people} may be affected by the proposed rule each ^{year, using the}

_{tip to 80 patients pcr} trial, would mean

_agency's estimate of 255 LNDs per year, and estimating

that approximately 20 ;400 -patiQnts and volunteers

substaritlal ^number

_of people who would be exposed to more risk.

Confusing

_{When the 2 .geney takes an} existing regulation,

_using guidance documents, 01- issuing

_a rule

_{causes a} great deli of confusion in

regulatory

material

affairs executive who stated that

_and attempts to negate portions of the regulation

_{that affects part of the rule (but not} a11), the agency

_{industry . I have} already received one email message from ^a

from nou- can, when they plan to use ^non-CifV1P

in a phase 1 trial, they will provide more ^{data for FDA in their chemistry, manufacturing}

and controls (C1VIC) sectan ofthe dND .

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^T11 _Se rie s

_'

.

.

_{A Brief} History of the GN1Ps

_{The Power of} Storytelling

_{"I f you hc~vc lm irnpor tarit poirlt to} n1alee, dor~'t

_{tr~ robe subt(r vr} (fever

_{~Ise u ;~i~e dri,-~r} Hit tfle point 011c,-'

^{Wins to I I cluir"Jij I I}

_{Thoi came back and hit it} aguin. Tllier2 hit it a ih I r4 tbnc with a o'cole ^{rt CIO us V) h}

'

_{riedich Nietzcheorice} siild,"IT you lLnow the whv for

F

_{living, you} can endure any how ." Everyone ⁱⁿ

_our ittdusuy Should know the story of how the ^good

_{manufacturing} pract;ces (GMPs) have corne to be .

_{To obtain and} inaintain G?v1P compliance, every

manager _and supc:rvisur should provide FreGuer.t,

_meaningful GMP reminders, train arid dcvelap ^all

p

em

loyees

,

programs

.

make it

_{and i`ullN/} participate in fot~nial, ongoing

_Senior nianagenLent must state publicly

training

_and

_{GMf's is}

_clear through _their actions that following

_{the only way}

_their company does business .

THE 1900s

Early

_{in this cuuntn~'s history,} travelin~ medicine show,-;

,

" irom the backs

_{sold bottles of ointment} or "miracle elixir

_{olsvagons . Such} u,r,dication was said w be oond for aches

_{and pains : for} catanh, rheuruatisnt, and gout -

of course

_it completely cured cancer - and

^{it worked on horses, too.}

Luckily, those days are long gone .

_{1n 1905, a} boo}: called

The Jvrrgle helped catalyzc

are ^{false or riiislc~dingas weii as to the failure to provide}

required information ill labeling (2). ^{Over tic years,}

th e

Wo r

_{d "adulterated"} has )een expanded to include prudacts

fnunufactureEi withoui 1oJ[owin, . GMPs ^.

_{Before the} publication _{of The Jur7gle~,} II nrvuy ti '

iie,y

_{tiand others} had been pressing, forn ~uch a law for 25 ^years.

_{The Act} created one of the first government ^regutatory

agencies, 11ow kziowri as ~'A, ^{and it also allowed Cut the}

_{seizure of} illegal foods, and drugs

chief chemist cfthe bureau

_(3). Wiley iater became

_given authority to ^enforce

_{that act (the Iiuteau of} c~hemistry, U .S . Department of

AgricuVLUre), a 1'orerunner of FDA (4).

Biologic

_{products acre first} regulated a few yeact;

died fruii i

before 71«

_{Jungle, whe,n} at Ieasc ;Z children

_{a i :iphthei ia} ailiicexin thii was contaminated ~vith live.

_tetariu= bacilli (3). Conj ,

_passing the Biologics

r~~ss responded to that tra,Tedy by

_{~_onircsl} Act of 1902, which required

inspections of

_{3nan~~f~i~~ :-~lrers and} seliers of biological

products and testing c+t such products for ^{purity wid}

^{strength (5)~}

_public opmion for change .

"Muclcraker"social reformer

• i n~j

Upton Sinclair ~,vrotc about the Chicago ^{ineat pack}

i

n us rv -

d

t

tile uasanitar

y

_conditions in which animals

_were slaughtered and processed and the practice of ^selling

_{ruU.en or diseased meat to the} public- 'He also reported

_{that ground} nieat sonietimes contained remains of

'

_{poisoned rats arid} even unfortunate workers who iell into

_the tnachii7eiy. Sinclair's main incecest was in bringing

_{attention to the miserable working} conditions and the p1ight

_Che

pt

Impoverished

_{factory workers,} inany of whorn were

,

,

IIt11111g,7~aI1t5 (1

_The Pure

)

.

_{Food and} Drug Act. 7°he Jungle had a ^major

~

itnpact

Food

, _{oil the American} public . Congress passed the ^{i ure}

_{and Drug Act in} 1906, arid for the first time it becan~e

_{illegal to sell contaminated} (adulleruied) fooci or meat . Also

_for the first time, labelin v had to be truthful -- n0 (On ^TeC

b

`.L;OLI~i~ 811y017C promise On

_~l

^~i1b01

^"i}"le

moon

atand tt7c

Syrup

_{to calm} "colicky" babies and "tonics" for

adults

_{ofte.n coritained} alcohol, opium, o~ moi~t~ine,

stars

.

_{which aCldtcteci mariy} people who used T~fatn . SO the

_{1906 Act also} required selected dangerous

_{be labeled} on all drugs. Inaccurate or

_false

in~rzdi~~lts to

_{labeling was}

_THE 19305

_{A 1933 FDA exhibit oi} dangerous _food, medicines, medicai

_{devices, and c;osrneL ;c.5 illustrated} the shortconung, of

' t},e

• 1906 law .

"America's Chamber of Horrors,

"

nicluCfed a

womb su pp

_{urc;r (also used as a} contraceptive) that could

_{puncture the} utertis if insertLd inConcctiy ; a Weight-11D66

This znricle wa,-wrimn hy Barbara

Kesourcca Lt_C, t c~,a~sulii,~g

cE~mpL

t"o1°ri"

:Lncc~, quality

1.h`

;`1

Inuy,eI,

prv~~tdcne of t,mz,et

_{nnJ publishing} firtn,pLfdalizi«g in

.

a~sti.:~nce, and n~:~inui~+ ^{for thr rhx .rmaccuncd,}

_{a`"LT .`°`Ii`} `R`t<.,ndustctty .

I~.ciLat

_{:iisthccdtr~~r it,-chief ;,Icf,<"} '~unelRcr :rr,a~ticwslc~eerrpro .id~ns;

_{~Edvite and guid, :nce for i11 insgcrs ir+} MA-tegulatc<? industries . Shc~

_{s also or. tha~} Fdiuoriul A,I~~i,ory R,;ird

die h.t5 ~vavcd a., th,~ir (IMP iind

since !Y96 }ler ^articles i)

_P~, ;n,ncr .e reai I~:c

inL~caCi

_of liioP6uim

"v1agu,itec ^where

lur;utacory compl,ai«< c,'lu°uqlsc

rnwr i.nr ::; ^{l cn , c ~ ~s ;,}

_{ivc also} ;yppe ;ered in 1 I,

_{: ~)Pr,} !~i~~P,,jrc,sincrro,u!i~,nr,i, .~nel ^{aaea~coi~~rli,:~~}

^2nd DLRTt« )Il~ t7 ;! 1'F.

^~

(}rSfiin :~l)

Mana

_{tLu ; uiticlr ap~7 :~rcct i:i ehr} .At~qusc 2000 issue u( !ii Pli'a nr

_{:.ine, and in the i~cr~~cinbe,} 2002 su~~plement, !lie Hu,i" ^{.urir 6ui:ic}

rnGr",1%lhs

by ch~

oly.

_Itc~~nne }«~~n~ssian wn ; gr:~nted

publtyh~-r, .~~dvan,t:.r C~,liun~~rucqti~n~,

r"gnz, Oregon

.

^.

:

_called misbrandinL~, and that became Illegal . "Misbranded"

applies to statements, designs, or pictures ill ^{(abetitl~, that}

_{&. cli ) i-2( .1 , ntmV MCguurccs L LC ;}

_epro(tIwho :l, p 1aLUCtspytng,slalcnecor ^{lru.7Sri:1sS'tctl`. 7, makneUC 6r e rci7onic nr_aI7S slncl y pr~.~ tn;i tc} 1y aw

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drug

_{that caused death ; a hair remover} .hat caused baldness,

_{even if not used on} the head; lotions and creams that could

_{cause me-rcury Poisoning} : hair dyes that could cause lead

_{pui;oninp, and an eyefasli dye} that blinded wornc;n (3) _.

_Eleanor Roosevelt cook that exhibit to the White

_House,

asking Americans to campaign for stronger ^consumer

protections

_{.4 traLedy was} ~{-aiting around the corner thaY

_would make her case for her.

_Sulfa drugs were

_{introduced in 1935 . Many}

manufacturers _{began making the} new Anti-infectives .

One

company used d_iethytetle, glycol, a poisonous solvent

_{and chemical} analog of anti-freeze, in ari oral "elixir of

sulfanilamide

."

Before the problem was discovered, 107

_people

_In

_{died, many of them} children (3) .

_response, Congress passed the Federal t o.xl, Drug

_and Cosmetic (PD&C) Act of 1938 . For

_{companies were} required to prove that

the. fi	i rst t me
tlie .irproducts were
	FDA oversight

_{safe before} marketing thLnm (3) . Still the major act coverim ;

_our subject _{n)atter On ihe} books, it extended

_to Cosmetics _and therapeutic devices,

_{explicitly au?hori«d}

• _{- factory} inspections, required

_{standards for foods, arid added}

injunctions to previous

_{penalties of seizures and a sminal}

prosecutions (6) .

THE 1940s AND 19505

In

1941 nearly 300

_{people were} killed or injured

~

,

jured by one

company's sultiathiaz

_{ole tablets, a} sulfa drub tainted with

_{the sedative,} phenobarbit<il . That incident caused FDA to

teratogenic

^f:etLsses

_{: it} caused serious deformities in developing

. e'hiiclren whose ^mothers took thalidomide ^{in the}

_first trimester were horn with ^severely deformed anns and

_legs. Att estimated t0,000 cases of

infant deformities ⁱⁿ

_{EUrOpe Were linked to} thalidomide use (3).

_{I'hv product} was not allowed on the market in the

United States

.

_{The drug reviewer} responsible for the

_{tlialidosnidr application in i~~,, United} States was Frances

_{Kelsey, tn 1962 l'resident} Kennedy awarded lier the

President's Distinguished

Federal Civilian Service Award,

_{the highest} honor a oovenmrnent ^employee may earn as a

civilian (3)

Thalidotnide, calvani, ed ^public oDutirnt ^{lNV o}

IegssLator,, ri.cfaciver and Harris, pushed inore ^strin~ent

_lcy;islaeion through Congress that required comuzuues ^to

_{Yrst not only to etlsuce that} products wefe safe. 'Out that they

_{were efficacious} fur their ii:tencied uscs, Regulating clinical

_{n -ials, thc a ;nendttis.iits} reqtcired ciru,t;s tu be tested in

_{animals belfor;,'} people . The) rnade investigators responsib!e

_foi supervising

_{dru~~s under study .} Manufacturers Were

expected _{to inform partimp<tstis} ii ~j drug, was being used

_for irSVCStigational purposes and to obtain their consent

b f

e ore

t

es i

t

n

g

it on therin .

_{Drugs had} to be shown it) work

_{before going t3n the} iriarket . Manufacturers were required to

report unexpected

authority to

fiari2t (adverse events) . FDA was givcn

_regula~e advertising of prescription drugs (3).

And in 1963 ,

_{th:, GESt,} Civ7Ps tar tmishcd pharmaceuticals

_Nvcre :nacfe filial (14).

_revise rn~unutacturinG and quality control requireirrents,

leading to what would later be

called GNIF's (ti).

The Public

_Health Services (YH5)

Act

_{passed in}

_{1944 covc;r<tl n l,roau}

spectrum of concerns

_including regulation of biological

_{products and} control of communicable diseases (?j.

_{Also dnrin- the ~1"Nll} era, batch certification by

_{FDA became} a requirement for Certain drugs . It requirec

{

_companies to submit samples from each lot to FDA for

_{testing . and the} agency Would give permission for t

h e i r

release

.

_{That practice, t~egun in} 1941 for insulin and 1945

_for penicillin, was later expanded lo include all

_antibiotics.

_{BY 1983, the} requirement _for batch certification of drugs

was dropped (7).

_{In 1955, Jonas} Sail< discovered a way

_{to vaccinate}

_against polio (8)- Many manufacturers

_{began making It is}

_polio vaccine . One

_{conipany failed to inactivate the vieUs}

_{completely in a single lot. About 60} individuals inoculated

developed polio,

niothers,

_and another 89 ofthcir family mvinbe2s

fathers, brotPiers, sisters, and ^{grandparents)}

contracted _{polio iroin them} (9) . We vaccinate out children

to p rcvei

t

t

thein from

.

_{-ettirt g} a disease and also as a public

~

_{11ea1Th measure to protect} sociery froir, tlic~ spread of

disease,

_THE 1960s

`r~ialtaooa,rd~

a, rd~

_was

_{marketed in} Eu rope

as a

sleep ing pih and

to treat morning

i

_{7 sickness} . When regulatory

gul ator

_Y agencies gave

_{~~eriilission to sell the drug, for} that indication, t1~ey had no

_{knoixleclge of} its serious side effects. It turned out, to be

THE 19705

_{The 1 970s were a} watershG d ior product regulation . In

^{1979, good}

Parts zlU

manufaciurir±~ practices fer dru~s (21 CFft

and 211 ) were e .reatly ^expanded anti inedical

_{devic~2s (2l L;FR p2i)) arid} Gkti1F's were, for the first time,

made

fina!

.

Tlley were intended

to help

ensure the safety

and efficacy _of a11 products :

Thc regulatioDs

. . .

_{curitam the} ^minimum current good

m :mtitacturma practice; ',or methods to ^{be used in, and}

the facilities or ^controls cu be used for, the ^manufacture,

processing, packing, or holding of a drug, to assure

_{that such drug meets the} requii2m+:°tits of tfie act as to

_{safety, and has the} identity arid strength and meets dhe

_{yuiAlity and purity} chaiacceeistics

represented to possess . (11}

that it purports or ie .

<=ui'requirenlents

_{for devices} ~,+,~rc: intended "to

methods _{used in and the} facilities and ^controls

govern the

_{used for the desigqi, manu(acture, pacf} :at~ing, labeling,

_{storage, installation, arid servicing of} ail finished .medica l

_{devices intended ior human} use,' as deseribcd in the most

_recent revision (12)-

_{Good Labcratury i'ractec-es (6} l

_{_}

.Ps) were made final in

1979

_They define

"

:

good

_{laboratory pra~:?ices} ior conducting nonclinicai

i~aboratary studies rh~tc support or are intended to

_~1~P3~ort a~plicatsc~ns lot research ur ~naiketing

_{pennits for products} iep lated by the Food and Drug

772001- _2004,

_{Immci T'~c.ocr :,es L1 .C', Repmdueuon . Eihatncopyi7 .510 :qe or transmissfon 6y magncticnr} electronic me-,ins stri, :tly prohfbilcd by law

_:Rpr

₀₃

₀₆ 01°35p

Immel Resources

'o0?

778

1 ^.818

^{P .11}

_important Definitions

;

_.

t

.

_Drugs, Biologics, and Devices

"

,

_

-

_{The following definitions describing the} major differences

between drugs, bioiogicals,

_the

U

Requirements o

f L a _ws

_and devices, are abstracted from

_and Regulations Enforced by the

_{.S- Food and Drug} Administration (2) .

---

'

i,

Drugs

The Food

,

_Drug & Cosmetic (FD

&C)

Act defines drugs a5

r "articles intended for ^{use in the}

treatment, or ^prevention

and "aiticles (other

_{diagnosis, cure,} mitigation,

_{Or other} animals"

_of disease in mar .

than food) intended ^{to affect tire structure}

_{or other} animals.

"

It is

_or any function of the body of man

_{~ the intended use} that determines

_whether something _{is a}

_{drug. Thus, foods and} cosmetics may

_{requirements of the law} if therapeutic

_{The FD&C Ac,} prohibits

_-

_and requires

_FDA before

that `new

_into three ca t ego

Animal Drug

Application (NADA),

Application

_l,ANDA ; for generic

_be subject to the drug

claims are made for them

adulteration or misbranding ^{cf any dnig}

drugs" be reviewed and ^{approved by}

_{they go tu market,} Drug applications typically fall

ries: a New

Drug Application

(NDA), a

New

or an Abbreviated New Drug

products,

_r Biofogieals

~ The Public

_E

_'any virus,

Health Services Act defines a biological ^{product as}

_{therapeutic serum, toxin,} antitoxin, vaccine, blood,

allergenic

product, or analogous

_{~ blood component} or derivative,

_{product . ,} applicable to the

_{~ diseases or} injuries o'

"

prevention, treatment, or ^{cure of}

_Biologics +rtcVude such vitally

_important products as polio and measles ^{vaccines, diphtheria}

_i and tetanus

whole

_toxoids, and s!<in test substances ^{as well as}

blood and blood components ^{for transfusions Biological}

_{of the FDBG Act.} Because mos

t

derived from living organisms, ^{they are}

_

_{products are subject to all the} adulteration, misbranding,

and registrations provisions

_biological products are

~Y

their nature atEntially dangerous

t

or es

t

e

d

.

_Under the PHS Act

,

_if improperly nreparec

manufacturers wishing ;o ship

biological products in interstate ^{commerce or for import or}

export. must obtain the ^appropriate

_liCa .^sing requirernerits caI'ei1 ^for

_{Product License} Applicatian

_{recently been} sti'eamlineci

^{U .S . license(s) .}

P

re

vious

_{both an} Establishment and a

has

_{(ELA, and PLA) to} be flied . That

_into the single Biologics ^Licensiny

Application (BLA; .

Devices

Medical devices

simple items

heating pa

machines .

_include several 4housand health ^{products from}

_{such as} thermometers, tongue depressors, ^and

d

t

s o

iUDs

,

_heart pacemakers, and kianey dialysis

_{Under the FL78G Act, a} device is defined as "auy

_{that does} not achieve its ^{principal inte~ded}

_health care pro duct

purposes by

metabolized_

action are regulated

Components, Parts,

chemical action in ^{or on the body or by being}

" P

roc uo s

i

t

t!-at work by

_as drugs . The

cheimcai or metabolic,

_!ar!rt devices" also includes

i

ca

l

d

e

vices ,

_o!- accessories 3f med

_{diagnostic aids} such as reagents,

_and

_and

_{test kits for} 1n vitro (outside

_other

conditions . Three

^°

^{Class i, General}

_record keeping

_antibiotic sensitivity disks

_{the body)} diagnosis of diseas~s

_{classes of medical} device exist

_Controls (reaisfration of ^{manufacturers}

_{and !abei+ng} requirements, compliance ^with

GIVIPs)

^Class

standar d

_{11, Spee ;ial Con :ro,s (including} oerforrnance

_s, pos m

t

arker surveillance

,

_{and patient} registries)

_{° Glass II{, Pre market Approval} (;Implanted and life-

support i

ng

_or life-sustainiric devices), ^{Devices 'subs' .antially}

_{and aI : Class III} devices, require filing

equivalent" to others ^{ma/ be filed using a 510(K)}

app

li

ca

ti on ; a

_ll athers ,

a

_{pre market approval} application (PMA),

Administration, including

_{food and} color additives

_aiiunal food aciditives,

_human and animal drugs,

_{nicdical devic~s for hUnnan} use, biological prc~dL4cts,

_and electronic _{products .} Coniplianice with this part

;s intended to assure [he quality

safety data filed . (l2)

and inte~ ;rit~~ of tl~c

_{A few} yeaes earlier, tile Medical i~evicc ^Amendments

{signed
(IUD) that	about two
users \Arere seriously

'the market in 1975

_{as law in 197G)} strengthened FDA's aull~urity to

_{oversee lnedieai} devices . The law was precipitated b~~

_incidents involvin, a ct~ncracepuve tntraut~f'iua ^device

million women ^{were using. Many}

injured (3) . The product was taken ^off

_{b"Buse it was} associated _{with a high}

_{incidence of pelvic infections,} infertility, and sorn~ deaths

_{( i,; j.}

The

Medical Device Ai~~endmenis rc.q~tired

manufacturers of most medical devices ^{(particularly}

_moderate- or hi-risk devices) to provide ^{FDA with}

_{safety and} effectiveness data bcforc rnarketrng klicin ^.

_{Furthermore, the law} provided for a syscenl of pre- ;ind

_;ti»arket oversight including FDA inspections ^{to ensure}

po

_that couipanies follow GMPs, keep appropriate ^{rccords o«}

_{the clesign and} mt+nufacLure of their products, aucl ^rilairttaitt

systems for Lt,andling complaints (14)

_{THE 1980s} AND 1990s

_[n 1980 : Con~tress paascu t(se Isifant

FDA au~ .7lority
mitriti<xnai
ma	d	e ser	ious;v ill by
f~nnulati (15 ).
each batch of
~ ~o~ number, lteep
analysis,			and so
I 10j,

reuuirert~ents for

^{Formula Act t,~~~i~1~}

_to ere2rl~~ a>>d enforce standards ^{and s1'ieeify}

camiaiercial ^{infant formulas .}

"~11at followeri 1979 rLports ihat ^{mvrc than 100 intau:s were}

_{a lack of chloride} ill two soy-h<iscd

_{~`lan~fa °turer~ arc} now~ requited to anal~ cc,

_{fc~rntula l"or} nutrient tcvcls and make s;~fety

_{2cst5, code eacli} container with

_{checks . cc~nduct} stauil-ty

d~t'~i;ed records of production ^and

_{on (16). The} food C;MPs (21 CFR Part

_which include specie.! provisions for iniant ^formulas,

_we-re finalized in the 1481)~ .

_{In 1982, t2_y,oar-old Macv Kellernian told} her parents

_{ti :at S1112} felt'if:e_ she h~+d a cold. They gave ^{her an extra-}

screogtli'l~yleriol

hours shc: ditd .

acet<nnnincphc :n

capsule, and witl~ ^{.ii~ a few}

_Six other people died in tln, iragic ^iRicidcnt,

_{three membcrs} froin one family (two brothers ^and

including

one of

their wives) jud a woman who had ^{just giyeii birfh to}

_her fourth child (17) .

Johnson k,

_Johnson announced a ^nationwide recall of

_{-) i} wil'tion bottle

..

_{nf "C'ylenol_ l~heir} investigation revealed

_{that a criruinal} tampevtn (who has ncver been ^{(bund oi}

prosecuted) had opened

cyanide . The ^campanv

_the lar;ect-setlin;

_{u~~ and} laced soine capsule : %+itl~

_{destroyed all 31} million bot!:les of

ovcr-the-counter medicine in [tic ^country

• l _ 24,

_{in,ne! r,}

_{777 ~ ,C ; r~3ro ucti~~n.} ^IT _{otocu~~y,Rg, stnragC or} Yfansnus5tor. iy magneUr ^. or e ^{ecUUnii mepns stnclty pro u bi;e}

^{y aH'-}

-,

-

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03

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01 :313p

I mme l

Resources

'?07

'?°78

1918

p .12

A GMP Timeline

₁₉₀₂ Biologics

y Tra

g

ed

y

At

Control Act

_{least 12} children die of tetanus contiaeted from

_" Contaminated diphtheria

_and testing of biologics

_vaccine. Result Requires inspections

ma~ufacturers' facilities and ^products

Pure Food and Drug Act

one of the first

_{government regulatory agencies (now}

°. Creates

'~

known

_{as FDA) ; the} culmination of 25 years of lobbying, ^this

ac

t

akes it ille

m

g

al to sell "adulterated" or "misbranded" ^{food or}

^drugs

1938

Federal Food, Drug and Cosmetic ^{(FD&C) Act}

'' Tragedy

_: Sulfanilamide made with poisonous ^{solvent causes}

10? deaths . Result : Requires ^{manufacturers to prove the safety}

` ot products before ^marketing

₁₉₄₁

_Two Unrelated Events

I

li

nsu n

_{Amendment requires FDA to test and} certify purity and

potency

_{of insulin-} Tragedy: nearly 300 deaths ^{and injuries fran;}

b

ar

bit l

a .

_{: distribution} of suiPathiazole, tablets ^{tainted with pheno}

_{Result FDA revises} manufacturing and quality

,

` drastically, the beginning of what will later ^be

_controls

_{called GMPs}