Transcript Antihistamine - People Server at UNCW

Chapter 14
Pharmaceuticals
CHM 585 / 490
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2
Pharmaceuticals
• Industry
• Synthetic Considerations
– Nabumetone
– Methotrexate
•
•
•
•
•
Natural Products
Antidepressants
Antihistamines
Chirality
cGMP
3
• 10,300 FDA approved drugs in U.S.
• 50% of all new drugs currently available
worldwide have been launched in the U.S.
• The discovery/preclinical stage takes from
3–7 years and only about 1 of every 10,000
compounds evaluated enters human trials
Drug Discovery and Development November 2002
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5
6
Top 10 Pharma Companies by 2002 Revenues ($B)
GlaxoSmithKline
Pfizer
Merck
AstraZeneca
Johnson & Johnson
Aventis
Novartis
Bristol-Myers Squibb
Roche
Wyeth
28.8
28.5
20.1
17.8
17.1
15.2
15.2
14.7
12.8
11.7
7
Leaders of Life Sciences Dec 2003
GlaxoSmithKline
• Paxil (SSRI -selective serotonin reuptake inhibitor
– depression)
• Advaire (for asthma)
• Augmentin (for asthma)
• Augmentin (antibiotic)
• Avandia (diabetes)
• Combivir (HIV)
• Flonase (allergies)
• Imitrex ( migraines)
8
Pfizer
• Lipitor (#1 prescribed drug) (cholesterol)
$8.6B in revenue
• Norvasc (hypertension)
• Zoloft (SSRI)
9
Merck
•
•
•
•
•
Zocor (cholesterol)
Vioxx (osteoarthritis – joint disease)
Fosamax (osteoporosis – bone loss)
Cozaar (hypertension)
Singulair (asthma)
10
About 12 Years to bring a drug to market
Discovery Preclinical
Clinical
Screening
Phase I
Phase II
Phase III
Commerc
ial
100 grams
1 – 10 kg
500 kg
100 – 300 mT
100 –300
mT
Animal
Studies
10 – 100
human
studies
100 - 1000
100 - 5000
Safety and Effectiveness, Effectiveness,
dose
safety and
safety and
dose
dose
3 years
2 years
1 year
2 years
2 years
2 years
11
$
• Cost for a single new drug averages $1.7 B
C & EN December 15, 2003
12
2003
• $33 B invested in Pharma Research
• 86 new medicines
– 21 new molecular entities (NMEs)
– 14 biologics
– 51 additional drugs
• Over the past 20 years, for every dollar
invested in health care, between $2.40 $3.00 in gains have been realized
R&D Magazine March 2004
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Top Reasons for Drug Recalls in 2001
• Deviations from cGMP
• Subpotency
• Stability data failed to support expiration
data
• Failure of drug to dissolve properly
• Wrong packaging
• Incorrect labeling
• Microbial contamination
Drug Discovery and Development November 2002
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Pharmaceuticals
• Industry
• Synthetic Considerations
– Nabumetone
– Methotrexate
•
•
•
•
•
Natural Products
Antidepressants
Antihistamines
Chirality
cGMP
15
Nabumetone
• See handout for various syntheses and
discussion on this NSAID
16
Multistep Syntheses
• Even when each step is a high yield step,
the overall yield can be low.
• For example a 5 step synthesis where each
step is a 90% yield reaction has an overall
yield of 59%
• 0.90 x 0.90 x 0.90 x 0.90 x 09.0 = 0.59
17
$
• For an effective cost position, important to
have:
– As few steps as possible
– High yield reactions
– Clean reactions – separation of impurities is
critical for pharmaceuticals and can be difficult
when impurities are structurally similar to
desired product.
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Methotrexate
NH 2
N
N
H2N
N
N
CH 3
N
H
N
O
H
CH 2CH 2CO 2H
CO 2H
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Methotrexate
Convergent Synthesis
H
NH 2
NH 2
N
+
N
H2N
Br
H
H
+
O
NH 2
CH 3
N
Br
H
N
H
H
O
H
CH 2CH 2CO 2H
CO 2H
KI3
or
NH 2
NH 2
N
H2N
Br
CH 2
O
+
Br
N
NH 2
Br
NH 2
N
N
H2N
N
CH 3
N
+
CH
N
H
N
H
O
CH 3
N
H
N
O
H
CH 2CH 2CO 2H
CO 2H
H
CH 2CH 2CO 2H
CO 2H
20
Pharmaceuticals
• Industry
• Synthetic Considerations
– Nabumetone
– Methotrexate
•
•
•
•
•
Natural Products
Antidepressants
Antihistamines
Chirality
cGMP
21
“ Natural Products”
• Heparin
• Premarin
• Taxol
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Heparin
• Anticoagulant
• By extracting the intestines of pigs
• Used for ~ 70 years
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Lovenox – low molecular weight heparin by
Aventis
STRUCTURAL FORMULA
Fragmin (Pfizer) – another low molecular weight heparin
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Commonly Prescribed Anticoagulants
• Warafin
(Coumadin®)
• Heparin
• Clopidogrel
(Plavix®)
• Dipyridamole
(Persantine®)
• Enoxaparin
(Lovenox®)
•
•
•
•
Ardeparin (Normiflo®)
Dalteparin (Fragmin®)
Ticlopidine (Ticlid®)
Danaparoid
(Orgaran®)
• Tinzaparin (Innohep®)
• Aspirin
• Thrombin Inhibitors
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Premarin
•
•
•
•
•
Number 1 drug of 1999 list
Steroid
Estrogen drug used for menopause
Made from urine of pregnant horses
Pregnant Mare Urine
26
Steroids
• Steroid is a general term for a large number
of naturally occurring materials found in
plants and animals.
C
A
D
B
27
CH 2OH
O
OH
O
HO
O
Cholesterol
Cortisone
OH
O
testosterone
male sex hormone
OH
HO
estradiol
andestrogen female sex hormone
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Taxol
• From the bark of the Pacific Yew tree
• Anticancer drug
29
Pharmaceuticals
• Industry
• Synthetic Considerations
– Nabumetone
– Methotrexate
•
•
•
•
•
Natural Products
Antidepressants
Antihistamines
Chirality
cGMP
30
Classes of Antidepressants
• There are five classes of antidepressants
1 Tricyclics (TCA)
2 Monoamine Oxidase Inhibitors (MAOIs)
3 Second-Generation (Atypical)
Antidepressants or Heterocyclics
4 Serotonin-Specific Reuptake Inhibitors
(SSRI)
5 Dual-Action Antidepressants
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Tricyclics (TCAs)
• One of the first classes of antidepressants
developed were the tricyclics.
• Tricyclics produce a sedative effect by blocking
the passage of norepinephrine and serotonin in and
out of nerve endings.
32
TCAs
• Structures:
– Imipramine HCL
C19H24N2 HCL
mw: 316.88
Amitriptyline HCL
C20H23N HCL
mw: 313.86
Nortriptyline HCL
C19H21N HCL
mw: 299.84
H
N
N
HCl
HCl
N
HCl
N
(11)
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MAOI (MonoAmine Oxidase Inhibitors)
O
NH 2
N
H
N
H
. HCL
.
H2SO4
Cl
Wellbutrin
Nardil
Early treatments for depression
34
Serotonin-Specific Reuptake
Inhibitors (SSRIs)
• SSRIs were discovered in the 1980s
• They are better tolerated than some other
antidepressants, with less severe side effects and
have a wide margin of safety in overdose.
• SSRIs inhibit the reuptake of serotonin into the
presynaptic neuron.
(17)
35
SSRIs
• Some examples of SSRIs:
1.
2.
3.
4.
5.
6.
7.
(1)
Paroxetine (Paxil®) - 1992
Fluvoxamine (Luvox®) - 1994
Clomipramine (Anafranil®) - 1990
Sertraline (Zoloft®) - 1991
Fluoxetine (Prozac®) - 1987
Venlafaxine (Effexor®) - 1993
Citalopram (Celexa®) - 1998
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SSRIs - Paxil®
F
• Used for
– Depression
– OCD (Obsessive Compulsive
Disorder)
– Social Anxiety
• Generates sales in excess of
$1.5 billion/year (2000)
O
N
H
O
O
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Paroxetine Hydrochloride
SSRIs - Prozac®
Fluoxetine Hydrochloride
F3C
O
CHCH2CH2NHCH3
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SSRIs - Prozac®
• First SSRI to be put out on the market.
• Indications:
–
–
–
–
Depression
Obsessive compulsive disorder (OCD)
Bulimia
Others (unlabeled uses)
• Sales of Prozac reached 1.2 billion in 1995 and in
2000 reached 2.7 billion for Eli Lilly.
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SSRIs - Prozac®
• Patents
– The original synthesis patents were 4,314,081 and
4,194,009 and were approved in 1982 and 1980,
respectively, to Eli Lilly and Company.
– Synthesis patent 6,028,224 in 2000 to Sepracor Inc.
– Other patents owned by Eli Lilly are:
• 4,018,985, 4,313,896, 4,590,213, and 4,626,549
– Patents owned by AAI:
• 6,258,853, 6,310,250, and 6,310,251
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SSRIs-Zoloft®
• Zoloft® is primarily used to treat:
–
–
–
–
Major depressive disorder
Obsessive/Compulsive disorder (OCD)
Panic disorder
Post-traumatic stress disorder
NHCH 3
. HCl
• Manufactured by Pfizer, Inc.
• Blocks the uptake of serotonin
into human platelets
Cl
Cl
41
Pharmaceuticals
• Industry
• Synthetic Considerations
– Nabumetone
– Methotrexate
•
•
•
•
•
Natural Products
Antidepressants
Antihistamines
Chirality
cGMP
42
Histamine
N
NH
• Histamine acts upon two sites in
the body, H1 and H2 sites. H2
sites are located in the
system and H1
NH2 gastrointestinal
sites are located in the respiratory
system.
• Antihistamine
Medication that prevents
symptoms of congestion,
sneezing, and itchy, runny
nose by blocking histamine
receptors.
43
Antihistamines
• First generation
– Chlor Trimetron
– Benadryl
• Second generation
– Do not cause sedation
– Do not cross the blood-brain barrier
44
First Generation Antihistamines
(Alkylamines)
• Chlorpheniramine maleate (Chlor Trimeton®)
– Schering (1949)
– Currently sold OTC by Schering-Plough
Healthcare Products
First Generation Antihistamines
(Ethanolamines)
• Diphenhydramine HCl (Benadryl®)
– Parke Davis (1946)
– Currently sold OTC by Pfizer, Inc., Warner Lambert Consumer Healthcare
Second Generation
Antihistamines
• Terfenadine (Seldane®)
– Marion Merrell Dow
– FDA approved in 1985
Second Generation
Antihistamines
• Terfenadine (Seldane®)
– Developed from Haloperidol
• Haloperidol - antipsychotic drug having
antihistaminic properties
• Replaced the phenyl ketone group with
phenyl butanol group to inhibit the capability
of the drug to pass through the blood-brain
barrier
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Second Generation
Antihistamines
Terfenadine
Haloperidol
49
Second Generation Antihistamines
• Terfenadine (Seldane®)
– Non-sedating
– Caused potentially fatal heartbeat irregularities
when taken with certain drugs and foods (1992)
• Ketoconozole, erithromycin, grapefruit juice
interfered with drug metabolism increasing the
concentration of terfenadine in bloodstream
– Racemic mixture
• One enantiomer caused cardiac toxicity
– Removed from market (1997)
Second Generation
Antihistamines
• Fexofenadine HCl(Allegra®)
– Hoechst Marion Roussel’s replacement for
Terfenadine
• Licensed rights in 1993 from Sepracor
– FDA approved on July 25, 1996
Second Generation
Antihistamines
• Fexofenadine HCl(Allegra®)
– Metabolite of terfenadine
• Terfenadine carboxylate
Terfenadine
Fexofenadine
52
Second Generation
Antihistamines
• Fexofenadine HCl(Allegra®)
• Aventis Pharma’s top-seller
– $1 billion in 2000
– Ranked by IMS Health in 2000 as the world’s
fastest-growing drug for safe, effective
treatment of SAR
– Product expected to go off patent 2005-2007
• Expected sales $6 billion by 2005
Second Generation
Antihistamines
• Loratadine (Claritin®)
– Schering-Plough, Inc.
– FDA approved in April 12, 1993
• Developed from Azatadine
Second Generation
Antihistamines
Azatadine
Loratadine
55
Second Generation
Antihistamines
Patent #6,084,100
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Second Generation
Antihistamines
• Loratadine (Claritin®)
– Non-sedating (FAA, Airforce, Navy approved)
– Loratadine is a prodrug that is metabolized in
the same pathway as terfenadine
• No reported cardiac side effects up to 160 mg
– Metabolite (Descarboethoxyloratadine) is many
times more potent than loratadine
• Sepracor-2002
Second Generation
Antihistamines
• Loratadine (Claritin®)
– #1 prescribed antihistamine
– $2.3 billion US sales, $2.7 worldwide (1999)
• 30% of Schering’s revenue
Second Generation
Antihistamines
• Cetirizine (Zyrtec®)
–
–
–
–
Pfizer, Inc and UCB Pharma Inc.
FDA approved on December 8, 1995
Metabolite of hydroxyzine
Racemic compound
Second Generation
Antihistamines
Hydroxyzine
Certirizine
60
Decongestants
• Relieve nasal congestion by constricting
blood vessels in nasal lining
• Side effects: Increased blood pressure,
stimulant effect
• Often used in combination with OTC
antihistamines in attempts to counteract
sedation
61
Decongestants
• Examples: Pseudoephedrine,
Phenylpropanolamine
Pseudoephedrine
Phenylpropanolamine
62
63
Pharmaceuticals
• Industry
• Synthetic Considerations
– Nabumetone
– Methotrexate
•
•
•
•
•
Natural Products
Antidepressants
Antihistamines
Chirality
cGMP
64
Chirality
COOH
COOH
Enantiomers
C
H3C
H
C
OH
R-Lactic Acid
HO
CH 3
H
S-Lactic Acid
65
Chirality
COOH
COOH
H
Diastereomers
NH2
H
NH2
C
C
C
C
H
OH
CH3
HO
H
CH3
66
Chirality
COOH
H
Meso Cmpd
OH
C
C
H
OH
COOH
67
Enantiomer Compounds
Bioactivity
Drugs
Amphetamine d-isomer is a potent central
nervous system stimulant,
while the l-isomer has little,
if any, effect.
Epinephrine l-isomer is 10 times more
active as a vasoconstrictor
than d-isomer
68
Enantiomer Compounds
Bioactivity
Drugs
O
Propranolol Racemic cmpd is used as the
drug; however, only the (S)(-)-isomer has the desired adrenergic blocking activity
N
H
OH
Propoxyphene -l-Isomer is
antitussive(cough); -disomer is analgesic(pain)
69
Vitamin
Bioactivity
Ascorbic acid (+)-Isomer is a good
antiscorbic (prevents
scurvy), while (-)-Isomer
has no such properties
Insecticide
Bermethrine d-isomer is much more
toxic than the l-isomer
70
Food
Bioactivity
Asparagine D-Asparagine tastes sweet,
while L-enantiomer tastes bitter.
Limonene S-Limonene smells like lemons,
while R-limonene smells like
oranges
Carvone S-(+)-Carvone smells like
caraway, while R-(-)-Carvone
smells like spearmint
71
How Enantiomers are Isolated
I.
Chirality Pool Method-The required
configuration is in the starting materials and maintained
throughout the synthesis. (Example:Penicillin)
•
Resolution Method-The precursor of the enantiomer is
provided as a racemic mixture and has to be separated
Membrane extraction-has one phase that contains the
racemate and the other phase has a chiral selector which will
selectively draw out one of the isomers
Kinetic Resolution-converts one of the two enatiomers into
another compound
(Examples:NSAIDS-Naproxen)
•
Asymmetric Synthesis-introducing asymmetry
directly into a nonchiral molecule.
(Example:Levodopa)
72
Pharmaceuticals
• Industry
• Synthetic Considerations
– Nabumetone
– Methotrexate
•
•
•
•
•
Natural Products
Antidepressants
Antihistamines
Chirality
cGMP
73
Current
Good Manufacturing Practices
cGMP Training
74
Objectives
• Provide a brief history of the FDA
• Provide an overview of cGMPs
• Discuss the requirements and their
application in the manufacturing operations
• Provide principles of Good Documentation
Practices (GDP)
75
Inside the FDA
• FDA is an agency within the Department of Health
and Human Services and consists of nine centers
• Center for Biologics Evaluation and Research (CBER)
• Center for Drug Evaluation and Research (CDER)
• Center for Devices and Radiological Health (CDRH)
• Center for Food Safety and Applied Nutrition
(CFSAN)
• Center for Veterinary Medicine (CVM)
• National Center for Toxicological Research (NCTR)
76
Types of Products Regulated by the FDA
• Drugs
– Small molecule chemicals, some recombinant
proteins, botanicals, etc.
– CFR defines drugs as articles intended for use in
the diagnosis, cure, mitigation, treatment or
prevention of disease in man or other animals
77
Types of Products Regulated by the FDA
• Biologics
– Any virus, therapeutic serum, toxin, antitoxin,
vaccine, blood, blood component or derivative,
allergenic product, or analogous product …
applicable to the prevention, treatment or cure of
diseases or injuries to man
– CFR defines Biologics as vaccines, blood & blood
products, monoclonal antibodies, recombinant
therapeutic proteins, cytokines, gene therapy, etc.
78
Types of Products Regulated by the FDA
• Medical Device
– Any healthcare product that does not achieve its
principle intended purpose by chemical action in or
on the body or by being metabolized
– CFR definition includes traditional medical
devices, in vitro diagnostics, some implanted
cultured cells, etc.
79
Milestones in FDA History (1938)
• 1938: President Roosevelt signed the Federal Food,
Drug and Cosmetic Act into law. This law required
new drugs to be tested for safety before marketing, the
results of which would be submitted to FDA in a new
drug application (NDA). The law also required that
drugs have adequate labeling for safe use. All drug
advertising was assigned to the Federal Trade
Commission.
• Why?
80
FD &C Act (1938)
• Continuing problems with dangerous drugs that fell
outside the parameters of the Pure Food and Drugs
Act finally received national attention with the Elixir
Sulfanilamide disaster in 1937. Massengill distributed
this preparation without testing for safety (which was
not required by law). Because it contained diethylene
glycol as a vehicle, over 100 people died, many of
whom were children.
81
Milestones in FDA History (1962)
• 1962: Kefauver – Harris Drug Amendments passed to
ensure drug efficacy and greater drug safety. For the
first time, drug manufacturers are required to prove to
FDA the effectiveness of their products before
marketing them.
• Why?
82
Kefauver – Harris Amendments (1962)
• Thalidomide, a new sleeping pill, is found to have
caused birth defects in thousands of babies born in
western Europe. News reports on the role of Dr.
Frances Kelsey, FDA medical officer, in keeping the
drug off the U.S. market arouse public support for
stronger drug regulation.
83
Milestones in FDA History
(1962 – 1994)
• Other Acts and amendments to FD&C Act
– Fair Packaging & Labeling Act – 1966
– Regulation of Biologics transferred to FDA – 1972
– Medical Device Amendments – 1976
– Vitamins & Mineral Amendments – 1976
– Tamper-resistant Packaging Regulations – 1982
– Orphan Drug Act – 1983
– Waxman – Hatch Act – 1984
– Clinical Laboratories Improvements Amendments (CLIA) – 1988
– Prescription Drug User Fee Act (PDUFA) – 1992
– Dietary Supplement Health Education Act (DSHEA) – 1994
84
Milestones in FDA History (1992)
• 1992: Generic Drug Enforcement Act imposes
disbarment and other penalties for illegal acts
involving approval of new drug applications (NDA).
• Why?
85
Milestones in FDA History (1992)
• Result of the Court’s ruling in the case of USA vs.
Barr Laboratories
86
Milestones in FDA History (1997)
• 1997: Food and Drug Administration Modernization
Act (FDAMA) – Reauthorizes the Prescription Drug
User Fee Act (PDUFA) of 1992 and mandates the
most wide-ranging reforms in agency practices since
1938. Provisions include measures to accelerate
review of devices, regulate advertising of unapproved
uses of approved drugs and devices, and regulate
health claims for foods.
87
Milestones in FDA History
• Increased regulation has advanced in quantum leaps
because of abuses, catastrophes and the winds of
political change.
88
Current
Good Manufacturing Practices
89
What are cGMPs
• Good Manufacturing Practices (GMPs) are
regulations that describe the methods,
equipment, facilities and controls required
for producing
– Human and veterinary products
(21 CFR 210-211, 610)
– Medical devices (21 CFR 820)
to assure that the product meets the
specifications that the product is
represented to possess.
90
Why the “c” in cGMP?
The U.S. regulations are called “current” Good
Manufacturing regulations, to emphasize that the
expectations are dynamic.
91
Why do the GMPs exist?
• GMPs define a quality system that manufacturers use
as they build quality INTO their products. For
example, approved drug products developed and
produced according to GMP are safe, properly
identified, of the correct strength/potency, purity and
of high quality.
• The purpose of GMPs is to safeguard the public
health; set goals for consistent, reproducible,
acceptable products; and to establish a basis for
inspection and assessment.
92
How were GMPs developed?
• Originally, GMPs were based upon the best practices
of the industry. As technology and practices
improved, the GMPs evolved as well. In the U.S.
drug cGMPs were formally introduced in 1963 and
significantly re-written in the 1970’s.
93
How do the GMPs change?
• GMPs change formally and informally. For example,
the cGMPs for drugs and biologics for the U.S., Japan
and countries in the European Union are formally
undergoing significant changes as a result of ICH
guidance documents. (ICH (International Conference
for Harmonization) provides standards for regulatory
information.) GMPs undergo changes informally as
industry monitors recent 483 observations and
warning letters.
94
The Goal in Manufacturing
Produce a medically useful product
• GMP regulations ensure
that products are:
• Pure
• Safe
• Effective
95
GMP Concepts
• GMP is a “mindset” or approach to ensure that the
product produced is a quality product
• GMPs provide continual measures of quality that can
uncover problems and fluctuations as they occur and
before the product is shipped. Thus, GMPs are a more
immediate and consistent way to control quality.
96
GMP Concepts
• GMP compliance is a critical element of pre-approval
inspections and required for product approval
• A drug, biologic or device is considered adulterated if
not made by GMP
• GMP is required for the manufacture of clinical
(investigational) supplies, placebos and marketed
products
97
Code of Federal Regulations
• Organization of cGMP regulations for drugs and
biologics can be found in the following sections of
21CFR
– Part 210: For manufacturing, processing, packing, or holding
of drugs (and biologics), general
– Part 211: For finished pharmaceuticals
– Part 606: For blood and blood components
– Part 610: For general biological products standards
98
Organization of GMPs
• General Provisions
• Organization and Personnel
• Buildings and Facilities
• Equipment
• Control of Components and Containers
• Production and Process Controls
• Packaging and Labeling Controls
• Holding and distribution
• Laboratory Controls
• Records and Reports
• Returned and Salvaged Drug Products
99
Organization of GMPs
• Subpart A - General Provisions
– The following elements represent the minimum cGMP
requirements for drug products
– Industry standards vastly exceed baseline requirements
100
Organization of GMPs
• Subpart B - Organization and Personnel
– The CFRs refer to a QCU, which does not distinguish between
Quality Assurance (QA) and Quality Control (QC). Industry is left
to make this distinction by defining the division of labor between
QA and QC
QC
– develops, validates, samples, tests raw materials, in-process
materials and product
– provides analytical support to validation and environmental
monitoring program
101
Organization of GMPs
• Subpart B - Organization and Personnel
QA
– QAU should be separate from manufacturing personnel
– is responsible for approving or rejecting all procedures or
specifications impacting on the identity, strength and purity of the
drug product
– assures compliance with all procedures and specifications by
manufacturing and QC
– has the authority to review production records to assure no errors
have occurred, or that errors have been fully investigated
– is responsible for the approval or rejection of all drug product
manufactured, processed, packed or held under contract and
determines the fate of nonconforming/rejected material
102
Organization of GMPs
• Subpart B - Organization and Personnel
– Personnel in manufacturing (or support of manufacturing) must be
qualified by education, training and experience to carry out their
respective tasks.
– There should be adequate staffing
– Protective clothing should be worn
– Secured access to the manufacturing area
– Persons with illness or injury should be excluded from the
manufacturing area
103
Organization of GMPs
• Subpart C - Buildings and Facilities
– Facility design should be of sufficient size
– to clean and maintain
– to prevent mix-ups (segregated quarantine and release areas)
– to control flow of operations, personnel and materials to prevent
cross contamination (separate areas for lab, manufacturing,
packaging and labeling)
– Facility design should also be such that all surfaces are sealed and
cleanable, have adequate lighting, temperature and humidity
control, HEPA air filtration system under positive pressure, and
control over environmental and microbiological conditions
104
Organization of GMPs
• Subpart D - Equipment
– Filters and equipment must be calibrated and, if appropriate,
validated or qualified
105
Organization of GMPs
• Subpart E - Control of Components and Containers
– Detailed written procedures for receipt, identification, storage,
handling, sampling, testing, and approval/rejection of components
and drug product containers and closures.
– Each lot of component is given a unique part number and lot
number and must be sampled and tested for identity, purity,
strength and quality
– All materials are held under quarantine until appropriately
sampled, tested and released by the QCU. No material can be used
in manufacturing that has not been released.
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Organization of GMPs
• Subpart F - Production and Process Controls
– Approved written procedures for production and process controls
must be maintained
– Deviations from approved written procedures must be properly
documented
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Organization of GMPs
• Subpart G - Packaging and Labeling Controls
– Packaging and labeling materials must be sampled, examined or
tested before use
– Printing of labels must be controlled
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Organization of GMPs
• Subpart H - Holding and distribution
– Maintain written procedures describing the warehousing operations
and distribution methods
– Segregated Quarantine, Release and Reject areas
– Access restricted to authorized personnel only
– First in First out (FIFO) principle in storing and distributing the
product
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Organization of GMPs
• Subpart I - Laboratory Controls
– Laboratory controls must be reviewed and approved by QA
– Sampling and testing each lot of components, containers, closures,
labels
– Determine by sampling and testing that in-process materials
conform to written specifications
– Determine the lab is complying with written procedures
– Determine that instruments, etc. have been calibrated according to
written procedures
– Retain reserve samples of drug substances
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Organization of GMPs
• Subpart J - Records and Reports
– Maintain Master and batch production records, laboratory records,
distribution records, complaint files, cleaning logs, equipment logs,
inventory records for drug components, product containers,
closures and labeling for at least 1 year after the expiration date of
the drug product
– Master production records are prepared and approved by
appropriate personnel
– Batch records are generated for each new batch of material made;
these batch records must be an accurate copy of the master and
checked for accuracy, signed and dated.
– Signatures and dates will be recorded for the person performing the
task, and the signature and date of a second person showing that
the original records were reviewed for accuracy.
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Organization of GMPs
• Subpart K - Returned and Salvaged Drug Products
– Any returned drug product must be identified and held
– Returned products must be destroyed if there is any question about
their safety, identity, strength, purity or quality
– Products may be reprocessed if there are approved written
procedures in place
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Key Elements of any GMP Program
• Documentation
• Training
• Auditing
• Corrective/preventive action plans
• FDA Inspections of the a company’s systems to ensure
compliance with the regulations
• Control over all aspects of manufacture
–
–
–
–
–
Process
Raw Materials
Personnel
Equipment
Facility (environment)
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The Quality System Approach to Ensure
Compliance with cGMPs
• Quality must be designed and built into the
process, not tested into the product at the end
114
The Quality System Approach to Ensure
Compliance with cGMPs
• A strong quality organization is a critical element
of GMP compliance
115
The Quality System Approach to Ensure
Compliance with cGMPs
• SOPs are critical to GMP compliance
116
The Quality System Approach to Ensure
Compliance with cGMPs
• A strong training program is essential
“There shall be an adequate number of qualified personnel
to perform and supervise the manufacture, processing,
packing, or holding of each drug product.”
21 CFR, Part 211.25 ( c )
• All training must be documented
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The Quality System Approach to Ensure
Compliance with cGMPs
• Investigation of out-of-specification results,
deviations and failures is a critical element
• Laboratory controls must be in place
– Validation of analytical methods
– Qualification of laboratory equipment
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The Quality System Approach to Ensure
Compliance with cGMPs
• Change control for processes, equipment, test
methods and documentation are critical
• Documentation retention requirements must be
adhered to and documents must be readily
retrievable
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The Quality System Approach to Ensure
Compliance with cGMPs
• Equipment Qualification and Process Validation
are critical
– Installation Qualification (IQ) equipment has been
installed properly
– Operational Qualification (OQ) equipment is operating
within expected operating ranges
– Performance Qualification (PQ) equipment operates
correctly in the actual operating environment
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The Quality System Approach to Ensure
Compliance with cGMPs
• Equipment Qualification and Process Validation
are critical
– Process Validation – the process consistently produces a
product that meets the specifications
– Cleaning Validation – cleaning methods work as
intended and reproducibly
– Analytical Methods Validation – shows that analytical
methods produce consistent, reliable results
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The Quality System Approach to Ensure
Compliance with cGMPs
• Traceability
– Raw Materials must be controlled and traceable to
products in which they are used
– Batch records and equipment use records must show
ingredients, equipment, containers, labeling, personnel
– Distribution records show where products were shipped
– Lot or batch numbering is key to traceability
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The Quality System Approach to Ensure
Compliance with cGMPs
• Environmental control and monitoring
– Environment must be controlled and monitored to
prevent cross contamination by products or
microorganisms or other matter
– Rooms designated as Class 100, Class 1000, Class
10,000 or Class 100,000 must meet requirements for
viable air and surface and non-viable particulate
samples.
– Alert and action limits must be established for
contaminants, monitored and trended
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The Quality System Approach to Ensure
Compliance with cGMPs
• Principles of Good Documentation Practices
– Documentation is the first major impression given to
internal and external reviewers of the systems.
– Good or bad, first impressions remain for a very, very
long time
– Poor or questionable documentation can lead to 483
observations, a warning letter, product recall, consent
decree or injunction
124
The Quality System Approach to Ensure
Compliance with cGMPs
• Good Documentation Practices
– Write it down
– Leave no doubt
– Signature & Date
125
The Quality System Approach to Ensure
Compliance with cGMPs
• GDP defined
Original raw data:
Factual recorded information that is (1) a result of original
observation and activity and (2) is used as part of the
decision process for determining the acceptability of
materials, processes or products.
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The Quality System Approach to Ensure
Compliance with cGMPs
• Recording Rules
– Permanent indelible black ink
– Reproducible on photocopiers
– Cannot be removed, washed away or erased
– Do not use pencil
– Do not use correction fluid
– Date all entries on the day they are made
– Backdating is not permitted
127
The Quality System Approach to Ensure
Compliance with cGMPs
Recorder’s responsibility
• Handwritten signatures:
– Are to be consistently signed the same
– Signatures and/or initials shall be documented and
provide traceability
– Initials can be used as a substitution for full signature;
the initials must match the official reference
documentation
128
The Quality System Approach to Ensure
Compliance with cGMPs
Recorder’s responsibility
• Whenever a signature is required, it is required to be
dated at the time of signature
• Record all entries at the time they are performed
129
The Quality System Approach to Ensure
Compliance with cGMPs
• Correction of data
– Draw a single line through the erroneous entry
– Do not cancel, erase or obscure recorded data
– Explain the correction
– Make the correction
– Sign and date the correction
130
The Quality System Approach to Ensure
Compliance with cGMPs
Good Documentation Practices
It is very Important that the following points be
understood and complied with
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The Quality System Approach to Ensure
Compliance with cGMPs
Never Falsify Documentation
•
•
•
•
•
Document After a procedure is performed
Document only what You perform
Record the Actual date
Backdating is Never permitted
Keep all originals (Never discard raw data)
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The Quality System Approach to Ensure
Compliance with cGMPs
Your responsibilities
• Educate yourself
– Know the regulations
– Know your own procedures
– Ask questions
• Self audits
– Procedures
– Areas
• If you are a manager, educate your staff
• Set an example
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Situations Happen.
How do you handle them?
134
Scenario #1 “Don’t Touch That Dial”
• You notice an operator increasing the speed setting on the vial sterilizer
tunnel during production.
• You ask him about this, and he tells you that the lead operator in the
filling department told him to do this to prevent the filling area from
running out of sterile vials during filling.
• You also notice that all readings on the batch record have the correct
speed per the sterilizer SOP. The operator tells you that he only takes
the readings when the setting is at the correct speed.
135
Scenario #1 “Don’t Touch That Dial”
• What issues are raised by this discovery?
• What actions do you need to take?
• How do you resolve this situation?
• Which GMP requirements apply to this situation?
136
Scenario #2 “There’s something in the air”
• QC personnel have changed their sampling sites for
environmental monitoring during aseptic operations. The
new locations are closer to the actual level and location of
exposed product. The SOP was revised and issued to
reflect the changes.
• The first test results using the new SOP are out of
specification for both viable and non-viable contaminants.
• It is decided that environmental monitoring should be
conducted at the previous sample sites. The SOP was
revised and reissued again.
137
Scenario #2 “There’s Something in the air”
• What is wrong in this situation?
• What should have been done?
• What would an inspector think of this?
• What would the client think?
• Was this ethical?
• Which GMP requirements apply to this scenario?
138
Scenario #3 “I Didn’t Do It”
• Product solutions have set mixing speeds and times for
each phase of production, which are recorded on the batch
record.
• Production is running slightly behind schedule, and you,
the supervisor, don’t want to stay late. Your operators feel
this pressure and increase the mixing speeds and reduce
the mixing time to speed things along.
• Product yields are lower than expected for this batch.
139
Scenario #3 “I Didn’t Do It”
• Although you did not change the mixing speeds and times
yourself, how did you contribute to this action?
• What can you do to prevent occurrences such as these?
• What is your responsibility in this situation?
• Which GMP requirements apply to this situation?
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