1 Chapter 14 Pharmaceuticals CHM 585 / 490 2 3 Pharmaceuticals Industry Synthetic Considerations –Nabumetone –Methotrexate Natural Products Antidepressants

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Chapter 14Pharmaceuticals

CHM 585 / 490

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3

Pharmaceuticals• Industry• Synthetic Considerations

– Nabumetone– Methotrexate

• Natural Products• Antidepressants• Antihistamines• Chirality• cGMP

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• 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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6

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Top 10 Pharma Companies by 2002 Revenues ($B)

GlaxoSmithKline 28.8

Pfizer 28.5

Merck 20.1

AstraZeneca 17.8

Johnson & Johnson 17.1

Aventis 15.2

Novartis 15.2

Bristol-Myers Squibb 14.7

Roche 12.8

Wyeth 11.7

Leaders of Life Sciences Dec 2003

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GlaxoSmithKline

• Paxil (SSRI -selective serotonin reuptake inhibitor – depression)

• Advaire (for asthma)• Augmentin (for asthma)• Augmentin (antibiotic)• Avandia (diabetes)• Combivir (HIV)• Flonase (allergies)• Imitrex ( migraines)

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Pfizer

• Lipitor (#1 prescribed drug) (cholesterol) $8.6B in revenue

• Norvasc (hypertension)

• Zoloft (SSRI)

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Merck

• Zocor (cholesterol)

• Vioxx (osteoarthritis – joint disease)

• Fosamax (osteoporosis – bone loss)

• Cozaar (hypertension)

• Singulair (asthma)

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About 12 Years to bring a drug to market

Discovery Preclinical Clinical

Screening Phase I Phase II Phase III Commercial

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 dose

Effectiveness, safety and dose

Effectiveness, safety and dose

3 years 2 years 1 year 2 years 2 years 2 years

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$

• Cost for a single new drug averages $1.7 B

C & EN December 15, 2003

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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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16

Nabumetone

• See handout for various syntheses and discussion on this NSAID

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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

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$

• 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

N

N N

N

NH2

H2N

N

CH3

O

HN

H

CO2H

CH2CH2CO2H

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N

N N

N

NH2

H2N

N

CH3

O

HN

H

CO2H

CH2CH2CO2H

N

N

NH2

H2N

NH2

NH2

N

CH3

O

HN

H

CO2H

CH2CH2CO2HHO

Br

Br

H

H

H

H

N

N

NH2

H2N

NH2

NH2

N

CH3

O

HN

H

CO2H

CH2CH2CO2HH

CH2

CHO

Br

Br

Br

+ +KI3

or

+ +

MethotrexateConvergent Synthesis

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“ 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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STRUCTURAL FORMULA

Lovenox – low molecular weight heparin by Aventis

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

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Steroids

• Steroid is a general term for a large number of naturally occurring materials found in plants and animals.

A B

C D

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HO OCholesterol

OO

CH2OH

OH

Cortisone

O

OH

HO

OH

testosteronemale sex hormone

estradiolandestrogen female sex hormone

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Taxol

• From the bark of the Pacific Yew tree

• Anticancer drug

http://www.bris.ac.uk/Depts/Chemistry/MOTM/taxol/taxol.pdb

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Classes of Antidepressants

• There are five classes of antidepressants1 Tricyclics (TCA)2 Monoamine Oxidase Inhibitors (MAOIs)3 Second-Generation (Atypical)

Antidepressants or Heterocyclics4 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.

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TCAs

• Structures:– Imipramine HCL Amitriptyline HCL Nortriptyline HCL

C 19H24N2 HCL C20H23N HCL C19H21N HCL

mw: 316.88 mw: 313.86 mw: 299.84

N

N

HCl

N

HCl

HN

HCl

(11)

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MAOI (MonoAmine Oxidase Inhibitors)

Cl

NH

O

HCL.

Wellbutrin

NH

NH2

Nardil

H2SO4.

Early treatments for depression

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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)

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SSRIs

• Some examples of SSRIs:1. Paroxetine (Paxil®) - 1992

2. Fluvoxamine (Luvox®) - 1994

3. Clomipramine (Anafranil®) - 1990

4. Sertraline (Zoloft®) - 1991

5. Fluoxetine (Prozac®) - 1987

6. Venlafaxine (Effexor®) - 1993

7. Citalopram (Celexa®) - 1998

(1)

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SSRIs - Paxil®

• Used for – Depression

– OCD (Obsessive Compulsive Disorder)

– Social Anxiety

• Generates sales in excess of $1.5 billion/year (2000)

NH

F

O

Paroxetine Hydrochloride

O

O

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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

• Manufactured by Pfizer, Inc.

• Blocks the uptake of serotonin into human platelets

Cl

Cl

NHCH3 . HCl

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Histamine

• Histamine acts upon two sites in the body, H1 and H2 sites. H2 sites are located in the gastrointestinal system and H1 sites are located in the respiratory system.

• AntihistamineMedication that prevents symptoms of congestion, sneezing, and itchy, runny nose by blocking histamine receptors.

NNH

NH2

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Antihistamines

• First generation– Chlor Trimetron– Benadryl

• Second generation– Do not cause sedation– Do not cross the blood-brain barrier

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

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• 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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Haloperidol

Terfenadine

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)


• Fexofenadine HCl(Allegra®)– Hoechst Marion Roussel’s replacement for

Terfenadine• Licensed rights in 1993 from Sepracor

– FDA approved on July 25, 1996

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• Fexofenadine HCl(Allegra®)– Metabolite of terfenadine

• Terfenadine carboxylate

Terfenadine Fexofenadine


• 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


• Loratadine (Claritin®)– Schering-Plough, Inc.– FDA approved in April 12, 1993

• Developed from Azatadine

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Azatadine Loratadine

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Patent #6,084,100


• 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


• Loratadine (Claritin®)– #1 prescribed antihistamine– $2.3 billion US sales, $2.7 worldwide (1999)

• 30% of Schering’s revenue


• Cetirizine (Zyrtec®)– Pfizer, Inc and UCB Pharma Inc.– FDA approved on December 8, 1995– Metabolite of hydroxyzine– Racemic compound

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Hydroxyzine

Certirizine

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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

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Decongestants

• Examples: Pseudoephedrine, Phenylpropanolamine

Pseudoephedrine Phenylpropanolamine

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Chirality

C

COOH

OHH

H3C C

COOH

CH3HOH

R-Lactic Acid S-Lactic Acid

Enantiomers

66

Chirality

C

C

COOH

CH3

NH2H

OHH

C

C

COOH

CH3

NH2H

HHO

Diastereomers

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Chirality

C

C

COOH

COOH

OHH

OHH

Meso Cmpd

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l-isomer is 10 times more active as a vasoconstrictor than d-isomer

Epinephrine

d-isomer is a potent central nervous system stimulant, while the l-isomer has little, if any, effect.

Amphetamine

Drugs

BioactivityEnantiomer Compounds

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-l-Isomer is antitussive(cough); -d-isomer is analgesic(pain)

Propoxyphene

Racemic cmpd is used as the drug; however, only the (S)-(-)-isomer has the desired -adrenergic blocking activity

Propranolol

Drugs

BioactivityEnantiomer Compounds

O NH

OH

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d-isomer is much more toxic than the l-isomer

Bermethrine

Insecticide

(+)-Isomer is a good antiscorbic (prevents scurvy), while (-)-Isomer has no such properties

Ascorbic acid

BioactivityVitamin

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D-Asparagine tastes sweet, while L-enantiomer tastes bitter.

Asparagine

S-(+)-Carvone smells like caraway, while R-(-)-Carvone smells like spearmint

Carvone

S-Limonene smells like lemons, while R-limonene smells like oranges

Limonene

BioactivityFood

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How Enantiomers are IsolatedI. 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)

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Current Good Manufacturing Practices

cGMP Training

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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)

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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)

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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

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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.

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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.

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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?

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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.

82


• 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?

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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.

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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

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• 1992: Generic Drug Enforcement Act imposes disbarment and other penalties for illegal acts involving approval of new drug applications (NDA).

• Why?

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• Result of the Court’s ruling in the case of USA vs. Barr Laboratories

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• 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.

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Milestones in FDA History

• Increased regulation has advanced in quantum leaps because of abuses, catastrophes and the winds of political change.

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Current Good Manufacturing Practices

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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.

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Why the “c” in cGMP?

The U.S. regulations are called “current” Good Manufacturing regulations, to emphasize that the expectations are dynamic.

92

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.

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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.

94

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.

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The Goal in ManufacturingProduce a medically useful product

• GMP regulations ensure that products are:

• Pure

• Safe

• Effective

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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.

97

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

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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

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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

100

Organization of GMPs• Subpart A - General Provisions

– The following elements represent the minimum cGMP requirements for drug products

– Industry standards vastly exceed baseline requirements

101

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

102


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

103


– 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

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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

105

Organization of GMPs• Subpart D - Equipment

– Filters and equipment must be calibrated and, if appropriate, validated or qualified

106

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.

107

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

108

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

109

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

110

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

111

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.

112

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

113

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)

114

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

115


• A strong quality organization is a critical element of GMP compliance

116


• SOPs are critical to GMP compliance

117


• 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

118


• 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

119


• Change control for processes, equipment, test methods and documentation are critical

• Documentation retention requirements must be adhered to and documents must be readily retrievable

120


• 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

121


• 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

122


• 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

123


• 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

124


• 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

125


• Good Documentation Practices

– Write it down

– Leave no doubt

– Signature & Date

126


• GDP definedOriginal 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.

127


• 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

128


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

129


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

130


• 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

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Good Documentation Practices

It is very Important that the following points be understood and complied with

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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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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?

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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.

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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?

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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.

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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?

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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.

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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?

Documents

1 Chapter 14 Pharmaceuticals CHM 585 / 490 2 3 Pharmaceuticals Industry Synthetic Considerations –Nabumetone –Methotrexate Natural Products Antidepressants