A Brief History of USFDA Good A Brief History of USFDA Good Manufacturing Practices (GMPs)Manufacturing Practices (GMPs)Manufacturing Practices (GMPs)Manufacturing Practices (GMPs)

F ISPE NJ Ch t D J 17 2009For ISPE NJ Chapter Day, June 17, 2009Bridgewater, NJ

Paul A. MelamudValidation Manager

QPharma, Inc.

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QPharma, Inc.

AgendaAgendaAgendaAgenda

Introduction What are the GMPs?

Pre-GMP History (

What are the GMPs?What are the GMPs?What are the GMPs?What are the GMPs?

Good Manufacturing Practices (GMPs)Good Manufacturing Practices (GMPs) Minimum manufacturing and control practices

Sometimes prefixed c (for current) Sometimes prefixed c (for current ) Focus on what to do, not how to do

Apply to food human & animal drugs Apply to food, human & animal drugs, biologics, devices, processed tissues, and (most recently) dietary supplements(most recently) dietary supplements

Failure to comply = adulteration Products subject to regulatory actionProducts subject to regulatory action

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List of USFDAList of USFDA cGMPscGMPsList of USFDA List of USFDA cGMPscGMPs

Canonical List of USFDA cGMPs (by publication year): Part 210: cGMP in Manufacturing, Processing, Packing, or Holding of Drugs;

General (1963; revamped 1978) Part 211: cGMPs for Finished Pharmaceuticals (1963; revamped 1978) Part 226: cGMPs for Type A Medicated Articles (1975) Part 606: cGMPs for Blood and Blood Components (1975) Part 225: cGMPs for Medicated Feeds (1976)Part 225: cGMPs for Medicated Feeds (1976) Part 110: cGMP in Manufacturing, Packing, or Holding Human Food (1986) Part 820: Quality System Regulation (1996)

P t 216 Ph C di (1999) Part 216: Pharmacy Compounding (1999) Part 1271.145-320: Current Good Tissue Practice [for HCT/Ps] (2001) Part 111: cGMP in Manufacturing, Packaging, Labeling, or Holding

O i f Di S l (200 )Operations for Dietary Supplements (2007)

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GMPs are Everywhere!GMPs are Everywhere!GMPs are Everywhere!GMPs are Everywhere!

World Health Organization (WHO)g ( ) http://www.who.int/topics/pharmaceutical_products/en/

US FDA (21 CFR 210-226, 600-620, 800-820): http://www.fda.gov/cder/dmpq/cgmpregs.htm

ICH Q7: GMPs for Active Pharmaceutical Ingredientshtt // i h /LOB/ di /MEDIA433 df http://www.ich.org/LOB/media/MEDIA433.pdf

European Union (in the EUDRALEX) http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev4.htmttp //ec eu opa eu/e te p se/p a aceut ca s/eud a e / o e t

UK Medicines & Healthcare Regulatory Agency (MHRA) Orange Book: http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=613

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I Repeat, GMPs are Everywhere!I Repeat, GMPs are Everywhere!I Repeat, GMPs are Everywhere!I Repeat, GMPs are Everywhere!

Buildings & Facilities Manufacturing Packaging & Labeling Product Development Laboratory Quality Control & Laboratories

Q lit A Quality Assurance Receiving & Shipping

R l t Aff i Regulatory Affairs Training Department Validation Department Validation Department

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Why Review GMP History?Why Review GMP History?Why Review GMP History?Why Review GMP History?

Those who cannot remember the past Those who cannot remember the past are condemned to repeat it.

G S t George Santayana

W li i ti t ti We live in a reactive, not proactive, society Laws & regulations born of tragedies, & catastrophes to prevent

recurrence Federal agencies formed or strengthened in their wake

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Reactive GovernmentReactive GovernmentReactive GovernmentReactive Government

FEMA 1802; assistance to NH town after a fire FTC 1914; anti-trust & monopolies; Black

Tuesday OSHA 1971; coal mining and other disasters USDHS 09/11/2001 FCC Janet Jacksons 2004 wardrobe

malfunction FDA todays discussion

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1880s1880s--1900s1900s Progressive MovementProgressive Movement1880s1880s 1900s 1900s Progressive MovementProgressive Movement

Decades of lobbying mounting pressureDecades of lobbying, mounting pressure Consumer groups, mostly women activists

Muckraking journalism exposes corruption Muckraking journalism exposes corruption Food and drugs exposed Raised public awareness Led to first laws governing their life cycles

Events that can still make a person wince today

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19021902 The Poison SquadThe Poison Squad1902 1902 The Poison SquadThe Poison Squad

Harvey Wileys Hygienic Table Trials Congress approved testing of preservatives Poison Squad of 12 DA volunteers informed & given

free high q alit (b t dosed) mealsfree, high-quality (but dosed) meals gram to 4 grams daily over 5-year study

first five subjects were:first five subjects were: Na2B4O7*10H2O (borax) C6H4(OH)COOH (salicylic acid)

H SO ( lf i id) H2SO4 (sulfuric acid) NaC6H5CO2 (sodium benzoate) CH2O (formaldehyde)2 ( y )

10http://www.fda.gov/ucm/groups/fdagov-public/documents/image/ucm151032.jpg

19021902 The Poison Squad (cont.)The Poison Squad (cont.)1902 1902 The Poison Squad (cont.)The Poison Squad (cont.)

National controversy & bad publicity:National controversy & bad publicity: Reporters interviewed chef through basement

windowwindow Wiley started giving reports to newspapers

Experiments stopped after major side effects Experiments stopped after major side-effects nausea, vomiting, stomach aches, inability to work

Poison Squad even made the minstrel shows Poison Squad even made the minstrel shows See next slide

Effects were fortunately reversible Effects were fortunately reversible

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19021902 The Poison Squad (cont.)The Poison Squad (cont.)1902 1902 The Poison Squad (cont.)The Poison Squad (cont.)

"O, they may get over it but they'll never look the , y y g ysame,

That kind of bill of fare would drive most men insaneinsane.

Next week he'll give them mothballs, a la Newburgh or else plain;

O, they may get over it, but they'll never look the same."

From "Song of the Poison Squad" Lew Dockstader's Minstrels, 1903

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19051905 The Great American FraudThe Great American Fraud1905 1905 The Great American FraudThe Great American Fraud 11-part patent medicine

series in Colliersseries in Collier s Exposed quackery,

nostrums, & ephemera False claims by mfrs. Raised real health

concernsconcerns Lack of quality control Many contained alcohol,

addictive drugs, or worse! Led to public outrage and

significant pressure on g pCongress

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Patent Medicines Patent Medicines N d Littl Pi kN d Littl Pi k U ?U ?Need a Little PickNeed a Little Pick--meme--Up?Up?

Carry this package with you alwaysCarry this package with you always

http://theodoregray.com/PeriodicTable/PopularScience/2004/08/2/image3.jpg

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19061906 The Jungle by Upton SinclairThe Jungle by Upton Sinclair1906 1906 The Jungle by Upton SinclairThe Jungle by Upton Sinclair

Corruption of US meat packing industryCorruption of US meat packing industry Attempting to promote socialism over capitalism,

but became best-seller (to Sinclairs lament)but became best seller (to Sinclair s lament) "not because the public cared anything about the

workers, but simply because the public did not want to eat tubercular beef

Nevertheless critical to shaping first food & drug t l lcontrol laws

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The Jungle, Chapter 14 (Excerpts)The Jungle, Chapter 14 (Excerpts)The Jungle , Chapter 14 (Excerpts)The Jungle , Chapter 14 (Excerpts) Jonas had told them how the meat that was taken out

of pickle would often be found sour and how theyof pickle would often be found sour, and how they would rub it up with soda to take away the smell, and sell it to be eaten on free-lunch counters

There was never the least attention paid to what was pcut up for sausage; there would come all the way back from Europe old sausage that had been rejected, and h ld d hi i ld b d d i hthat was moldy and white it would be dosed with borax and glycerine, and dumped into the hoppers, and made over again for home consumptionmade over again for home consumption

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The Jungle, Chapter 14 (Excerpts)The Jungle, Chapter 14 (Excerpts)The Jungle , Chapter 14 (Excerpts)The Jungle , Chapter 14 (Excerpts)There would be meat that had tumbled out on the floor, in the dirt and sawdust, where the workers had tramped and spit uncounted p pbillions of consumption germs. There would be meat stored in great piles in rooms; and the water from leaky roofs would drip over it, and thousands of rats would race about on it. It was tooover it, and thousands of rats would race about on it. It was too dark in these storage places to see well, but a man could run his hand over these piles of meat and sweep off handfuls of the dried dung of rats These rats were nuisances and the packers woulddung of rats. These rats were nuisances, and the packers would put poisoned bread out for them; they would die, and then rats, bread, and meat would go into the hoppers together. This is no f i t d j k th t ld b h l d i t t dfairy story and no joke; the meat would be shoveled into carts, and the man who did the shoveling would not trouble to lift out a rat even when he saw one there were things that went into the sausage in comparison with which a poisoned rat was a tidbit

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1906: Pure Food & Drug (Wiley) Act1906: Pure Food & Drug (Wiley) Act1906: Pure Food & Drug (Wiley) Act1906: Pure Food & Drug (Wiley) Act

Foremost concern: correct product labeling Prohibited mfr & sale of adulterated, misbranded,

poisonous, or deleterious foods, drugs, medicinesBanned their interstate transport Banned their interstate transport

Authorized legal enforcement of USP standardsOften considered origin of modern FDA Often considered origin of modern FDA

Required Rx from licensed doctors for some drugsS f Several flaws, however: Therapeutic claims were not limited

Did t i k t i ti l Did not require pre-market inspections or approvals

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A Step Back: US Pharmacopeia (USP)A Step Back: US Pharmacopeia (USP)A Step Back: US Pharmacopeia (USP)A Step Back: US Pharmacopeia (USP)

1820 217 most fully established & best understood drugs published: Standards (ultimately, GMPs) QC system national formulary (NF)y ( )

1846 recognized by Drug Import Act 1906 standards became enforceable as 1906 standards became enforceable as

law by Bureau of Chemistry BoC becomes FDA in 1926 BoC becomes FDA in 1926

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1933: Americas Chamber of Horrors1933: Americas Chamber of Horrors1933: America s Chamber of Horrors1933: America s Chamber of Horrors

FDA exhibited real products to pressure fixing theFDA exhibited real products to pressure fixing the 1906 laws flaws, including: A weight loss drug that caused deathg g A hair remover that caused baldness, even if not used

on the head An eyelash dye that blinded women (next slide) Lotions & creams that caused mercury poisoning

Fi t L d El R lt t k thi hibit t th First Lady Eleanor Roosevelt took this exhibit to the White House and appealed to America's women to campaign for stronger protections for consumers

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1933: Americas Chamber of Horrors1933: Americas Chamber of Horrors1933: America s Chamber of Horrors1933: America s Chamber of Horrors

Lash Lure theLash Lure the New and improved Eye Brow and Eye L h D Lash Dye

H i k However, it took another tragedy to change the lawchange the law

21http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118458.htm

1937 1937 Elixir Elixir SulfanilimideSulfanilimide

1932 1st sulfa antimicrobial 1937 S E Massengill devised 1937 S. E. Massengill devised

liquid dosage form for children: Chief Chemist Watkins creation:

10% lf il id 72% di th l10% sulfanilamide, 72% diethyleneglycol, 16% water, elixir flavor, raspberry extract, saccharin solution amaranth and caramelsolution, amaranth, and caramel

107 deaths, 248 survivors No regulation required toxicity No regulation required toxicity

testing only one law was broken. What was it?

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1937: Tragedy Aftermath1937: Tragedy Aftermath1937: Tragedy Aftermath1937: Tragedy Aftermath

CEO: "We have been supplying a legitimate f i l d d d t ld hprofessional demand and not once could have

foreseen the unlooked-for results. I do not feel that there was any responsibility on our partthat there was any responsibility on our part

Watkins: committed suicide awaiting the trialMassengill: minimum fine guilty only of labeling Massengill: minimum fine guilty only of labeling this an elixir when it contained no alcohol

Product seizure by FDA by near technicality Product seizure by FDA by near technicality

Result: Highlighted need for pre-market drug safety testingsafety testing

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1938: Food, Drug & Cosmetic (FD&C) Act1938: Food, Drug & Cosmetic (FD&C) Act1938: Food, Drug & Cosmetic (FD&C) Act1938: Food, Drug & Cosmetic (FD&C) Act

Requires new drug pre-marketing safety studiesRequires new drug pre marketing safety studies Origin of what is now the NDA process

Prohibits false therapeutic claimsProhibits false therapeutic claims Authorizes factory inspections Allows FDA to request court injunctions Allows FDA to request court injunctions

(previously: only seizures & prosecutions) Extends control to cosmetics and devices Extends control to cosmetics and devices Requires safe tolerances for unavoidable

poisonous substancespoisonous substances

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1941: Sulfathiazole1941: Sulfathiazole TragedyTragedy1941: Sulfathiazole 1941: Sulfathiazole TragedyTragedy

Winthrop Chemical markets sulfathiazole tablets t i t d ith h b bit lcontaminated with phenobarbital

Hundreds of deaths and injuries resulted FDA's investigation revealed plant controlFDA s investigation revealed plant control

deficiencies and irregularities In both production & recall processes

R lt FDA d ti ll i l Result: FDA drastically revises rules on manufacturing & quality controls Hailed as the birth of GMPs, though GMP , g

regulations wont be issued for 23 more years

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19531953--1962: Thalidomide1962: Thalidomide TragedyTragedy19531953 1962: Thalidomide 1962: Thalidomide TragedyTragedy

1953 synthesized by Chemie Grnenthal No side effects, high animal dose tolerances

1956 given freely to employees to help d i h i ld ddetermine what it could do

One brought it home to his pregnant wife child b ith t !born without ears!

Drug soon approved & sold in >40 countries antiemetic (morning sickness) sleeping aid

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19531953--1962: Thalidomide1962: Thalidomide TragedyTragedy19531953 1962: Thalidomide 1962: Thalidomide TragedyTragedy

1956 - Richardson-Merrell applies to sell as K d i USKevadon in US Frances Kelsey, new FDA inspector rejected

application:application: Fetal safety background from working with quinone (malaria

drug) in the 1940sf f f Application reflected major dearth of safety data and no

mechanism of action, as required by 1938 FD&C Act Despite political pressure and 6 reapplications, Kelsey

refused to approve the drug for sale

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19531953--1962: Thalidomide Tragedy1962: Thalidomide Tragedy19531953 1962: Thalidomide Tragedy1962: Thalidomide Tragedy 1956-1962 approx.

10 000 Europeans born10,000 Europeans born with phocomelia

Kevadon kept off US market

Kelsey earns highest Congressional honor

http://www thalidomide ca/fr/informations/images/baby jpg

Congressional honor

http://www.thalidomide.ca/fr/informations/images/baby.jpg

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1962: Tragedy Aftermath1962: Tragedy Aftermath1962: Tragedy Aftermath1962: Tragedy Aftermath

Kefauver-Harris AmendmentKefauver Harris Amendment Proof of Efficacy required Adverse events reporting to FDA requiredp g q Informed consent for clinical studies Drug ads must disclose side effects 2-year inspection mandate Authorized FDA to issue GMP rules

For manufacturing, packaging, or holding of finished pharmaceuticals

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1963: First Drug GMPs (28 FR 6385)1963: First Drug GMPs (28 FR 6385)1963: First Drug GMPs (28 FR 6385)1963: First Drug GMPs (28 FR 6385)

Foundation for todays Foundation for today s GMPs

For manufacturing, gprocessing, packing or holding finished pharmaceuticalspharmaceuticals

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19701970--1980s: Signs of Effectiveness1980s: Signs of Effectiveness19701970 1980s: Signs of Effectiveness1980s: Signs of Effectiveness

Led to increased scope and control: 1975 cGMPs for blood & blood components

finalized1976: Proposed GMPs for LVPs (next slide) 1976: Proposed GMPs for LVPs (next slide)

1976: Medical Device Amendment Dalkon Shield incident IUD marketed as safe by AH Robinsy Aggressive marketing despite knowledge of safety problems

led to the largest tort liability case since asbestos! Billions of dollars in settlements! Bought out by AHP (now Wyeth)Billions of dollars in settlements! Bought out by AHP (now Wyeth)

By 1978, device GMPs (21 CFR 820) finalized

1978: Drug GMPs (21 CFR 210-211) expanded 1986: Food GMPs (21 CFR 11) finalized

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1976: GMPs for Low Volume1976: GMPs for Low Volume ParenteralsParenterals1976: GMPs for Low Volume 1976: GMPs for Low Volume ParenteralsParenterals Stemmed from 1970-1971 and 1973 epidemics of

septicemia in US hospitals due to contaminated IV fluidsp p FDA questioned manufacturers abilities in ensuring sterility In response, FDA proposed LVP regulations (21 CFR 212)

Contrary to other GMPs, particularly explicit process standards were proposed: Limits for lethality factorsLimits for lethality factors Laminar flow of air, heat distribution & penetration Water quality

Many manufacturers objected, and FDA withdrew draft LVP and pre-draft SVP regulations as a result

Most standards were voluntarily applied anyway Most standards were voluntarily applied, anyway

6/22/201132

1978 Human & Veterinary Drug GMP Revision 1978 Human & Veterinary Drug GMP Revision (43 FR 45013 45076(43 FR 45013 45076 45077)45077)(43 FR 45013; 45076(43 FR 45013; 45076--45077)45077)

Resulted from FDA Task Force studying GMPsy g Main source of modern-day 21 CFR 210 & 211 Largely considered a writers revisiong y

Overhauled section numbering (see next page) Emphasized writing SOPs

L i f l ti Large expansion of regulations 1963 GMPs = 3 pages in FR; 1978 GMPs = 76 pages in FR)

Exempted certain OTC products

Updated in light of current technology for drug manufacturing and [to] delineate requirements more specifically specifically

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Overview of ModernOverview of Modern--Day GMPsDay GMPs(21 CFR 211)(21 CFR 211)

Subpart A (1-3) Subpart G (122-137) General ProvisionsSubpart B (22-34) Organization and Personnel

Packaging and Labeling Control

Subpart H (142-150)H ldi d Di t ib tiSubpart C (42-58)

Buildings and FacilitiesSubpart D (63-72)

Holding and DistributionSubpart I (160-176) Laboratory ControlsS b t J (180 198) Equipment

Subpart E (80-94) Control of Components and Drug

P d t C t i d Cl

Subpart J (180-198) Records and ReportsSubpart K (204-208)

R t d d S l d DProduct Containers and ClosuresSubpart F (100-115) Production and Process Controls

Returned and Salvaged Drug Products

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1980: FDAMA1980: FDAMA1980: FDAMA1980: FDAMA

1980 Food & Drug Administration1980 Food & Drug Administration Modernization Act (FDAMA) Congress required FDA to "make public a plan that g q p p

establishes a framework for achieving mutual recognition of good manufacturing practices inspectionsinspections

Also: prior to this, GMPs were not required for Over-the-Counter (OTC) products OTC products on the market now required testing Products with a safe history were given time to comply

FDA furthers pursuit of international harmonization

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FDA furthers pursuit of international harmonization

1980s1980s--1990s: Increased FDA Guidance1990s: Increased FDA Guidance1980s1980s 1990s: Increased FDA Guidance1990s: Increased FDA Guidance

Some Examples:p 1983: Guide to the Inspection of Computerized

Systems in Drug Processing 1987: Guideline on General Principles of Process

Validation Note: updated draft made available in 2009 Note: updated draft made available in 2009

1998: Draft Guidance for Industry: Investigating OOS Test Results for Pharmaceutical Production Result of the Generic Drug Scandals of the early-mid 90s

1998: Draft Guidance for Industry Manufacture, Processing or Holding Active Pharmaceutical IngredientsProcessing or Holding Active Pharmaceutical Ingredients

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A Step Back: Guidance DocumentsA Step Back: Guidance DocumentsA Step Back: Guidance DocumentsA Step Back: Guidance Documents First one issued in 1949, Procedures for the Appraisal

of the Toxicity of Chemicals in Food Full list (36 guidance docs are listed under GMP headings):

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079645.pdf

Today, FDA issues per Good Guidance Practice (GGP) regulation 21 CFR 10.115 (published in 2000) Guidance Docs represent FDAs current thinking on a topicp g p

Optional for Use documents not legally enforceable, but:

If there isnt a good reason for not following the guidance you If there isnt a good reason for not following the guidance, you are expected to follow the guidance

If an alternate practice is not documented as equivalent or better, you are expected to follow the guidanceyou are expected to follow the guidance

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1980s1980s--1990s: Looking Forward1990s: Looking Forward1980s1980s 1990s: Looking Forward1990s: Looking Forward

Numerous cGMP violations by industry; Generic Drug ScandalScandal

FDA eventually recognized more direction was necessary: to provide a uniform standard to the entire industryto p o de a u o sta da d to t e e t e dust y minimize the potential for harm or achieve some other (unspecified) cGMP objective

By 1996, FDA proposed (61 FR 20104) to: Amend cGMPs to clarify certain manufacturing, quality control,

and documentation requirements and q ensure regulations more accurately encompassed current

industry practice

This would add new subparts L M N O & P to 21 CFR 211

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This would add new subparts L, M, N, O & P to 21 CFR 211

1996: Proposed New Rule1996: Proposed New Rule ExamplesExamples1996: Proposed New Rule 1996: Proposed New Rule ExamplesExamples

211.220 would define requirements for process validation q p To preserve the validated status of a process, measures must be taken

that will allow any significant process changes to be recognized and addressed promptly. Such change control measures can apply to equipment, standard operating procedures, manufacturing instructions, environmental conditions, or any aspect of the process system that has an effect on its state of control, and therefore on the state of validation.

211 221 ld d fi i t f th d lid ti 211.221 would define requirements for method validation 211.240 would define requirements for control of physical

& chemical contaminants& chemical contaminants Proposal later (2007) shelved complete paradigm shift

In light of more recent scientific and technical advances and evolving lit t d i k t t

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quality systems and risk management concepts.

2000: ICH Tripartite Guideline Q7(a)2000: ICH Tripartite Guideline Q7(a)2000: ICH Tripartite Guideline Q7(a)2000: ICH Tripartite Guideline Q7(a)

GMP Guide for Active Pharmaceutical Ingredients (API)g ( ) Adopted in 2001 by FDA (66 FR 49028-49029) because 21 CFR

210-226 are specifically for finished pharmaceuticalsReplaced FDAs 1998 draft guidance Replaced FDA s 1998 draft guidance

API Starting Material used in production of an API that becomes a significant structural componentg p Production starts when API Starting Material enters process

GMPs are applied on a sliding scale from the start of th d ti th h fi l API tthe production process through final API stages

Provides a table illustrating when GMPs should begin (see next page)(see next page)

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20012001--2004: Pharmaceutical cGMPs for the 212004: Pharmaceutical cGMPs for the 21ststC tC t Ri k B d A hRi k B d A hCentury Century a Risk Based Approacha Risk Based Approach

Working Group created to analyze related cGMP g p yrequirements in effect in the US and internationally, particularly those related to quality systemsUlti t l f d ti GMP Ultimate goals of updating GMPs: Encourage timely detection and response to emerging defects

or indications that product quality has been compromised Further clarity and modernize the regulations Harmonize various aspects of parts 210/211 with other Agency

and international regulationsand international regulations

From final 2004 report: "FDA will take an incremental approach to modifying parts 210/211, while pursuing

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international harmonization through ICH and PIC/S."

20072007--2008: First Incremental Change2008: First Incremental Change20072007 2008: First Incremental Change2008: First Incremental Change

December 4, 2007 to clarify & modernize GMPs, FDA:y Withdrew 1996 proposed rule (72 FR 68111) Published a direct final rule (72 FR 68064)

Published a companion proposed rule (72 FR 68113) Published a companion proposed rule (72 FR 68113) Comment period for direct final rule closed February 19,

2008 On April 4, 2008, FDA withdrew direct final rule due to

significant adverse comments (73 FR 18440) After careful consideration of all comments FDAAfter careful consideration of all comments, FDA

published new final rule (effective December 8, 2008) First increment of modifications to parts 210 and 211

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2008: cGMP Revisions2008: cGMP Revisions2008: cGMP Revisions2008: cGMP Revisions

The final rule revises the drug cGMP regulations g gprimarily in three areas: Aseptic Processing

M d i t t ith 2004 St il D P d t P d d Made consistent with 2004 Sterile Drug Products Produced by Aseptic Processing cGMP

Asbestos Filters Bans limited use of asbestos-containing filters used in

processing injectable drug products Verification by a Second Individualy

Certain operations may be performed by (validated) automated equipment and verified by a person, rather than one person performing an operation and another person

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p p g p pverifying that the operation was correctly performed

Top 10 ranking of total GMP deficiencies 1995-2005Rank Category of GMP deficiency # %

1 Documentation QS Elements & procedures 1341 14.1%2 Design and maintenance of premises 634 6.7%

3 Design and maintenance of equipment 594 6 2%3 Design and maintenance of equipment 594 6.2%

4 Documentation - manufacturing 526 5.5%

5 Potential for microbiological contamination 463 4.9%6 Documentation - specification and testing 432 4.5%

7 Status labeling - WIP, facilities & equipment 371 3.9%

8 Environmental monitoring 323 3 4%8 Environmental monitoring 323 3.4%

9 Process validation 317 3.3%

10 Sampling - procedures and facilities 297 3.1%

# of GMP deficiencies in Top 10 5298 52.5%

# of inspections: 423

# of GMP deficiencies overall 9465

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GMPGMP E R ibilitE R ibilit !!GMPs are GMPs are Everyones ResponsibilityEveryones Responsibility!! Products can be considered adulterated!Products can be considered adulterated! Enforcement Actions e.g. 483, Warning Letter,

Consent Decree; Recalls, Seizures, InjunctionsConsent Decree; Recalls, Seizures, Injunctions For malicious acts, persons can be fined or

incarcerated! A person may be the company, the President, CEO,

a Director, Manager, Supervisor, or even the O t / T h i i h f il d t f ll GMPOperator / Technician who failed to follow GMPs

Persons can be debarred from working in the industry!industry!

46Paul A. Melamud 2009

Summary of GMP HistorySummary of GMP HistorySummary of GMP HistorySummary of GMP History

Regulations over product quality, patient safety, and g p q y, p y,efficacy were born reactively from tragedies over the past 110 years (or so), and becoming more proactive:

1800 i di t/ d t QC d f t i t d d 1800s: ingredient/product QC and manufacturing standards Early 1900s: ingredient/product safety & labeling Mid 1900s: increased safety regulation & product efficacyy g p y

Also: research regulations, GLPs, GCPs (not discussed here)

Late 1900s: harmonizing & implementing best practices Interpretation and understanding production processes Interpretation and understanding production processes

2000s: risk-based design, development, scale-up, and increased scrutiny of these during FDA inspections

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ANY ADDITIONAL QUESTIONS?ANY ADDITIONAL QUESTIONS?ANY ADDITIONAL QUESTIONS?ANY ADDITIONAL QUESTIONS?

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Acknowledgements & Contact InformationAcknowledgements & Contact InformationAcknowledgements & Contact InformationAcknowledgements & Contact Information Thank you to ISPE-NJC

d th Ch t DPaul A. Melamud

and the Chapter Day attendees for allowing me the opportunity to speak

Validation Manager

QPharma Inc.today! 22 South Street

Morristown, NJ 07960 For further reading

material on this subject or if you have any

paul.melamud@qpharmacorp.com

(973) 462-0653if you have any questions, please do not hesitate to contact me! 49