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 2009 For ISPE NJ Chapter Day, J une 17, 2009
Bridgewater, NJ
Paul A. Melamud
Validation Manager
QPharma, Inc.
1
QPharma, Inc.
Agenda Agenda Agenda Agenda
Introduction What are the GMPs?
Pre-GMP History (<1963) y ( )
GMP History (1963-2007)
Making GMP History (2007-Present)
Conclusion
2
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 action Products subject to regulatory action
3
List of USFDA List of USFDA cGMPs cGMPs List of USFDA List of USFDA cGMPs cGMPs
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)
4
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 Ingredients
htt // 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.htm ttp //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
5
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
6
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
7
Reactive Government Reactive Government Reactive Government Reactive 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 J anet J acksons 2004 wardrobe
malfunction
FDA todays discussion
8
1880s 1880s--1900s 1900s Progressive Movement Progressive Movement 1880s 1880s 1900s 1900s Progressive Movement Progressive Movement
Decades of lobbying mounting pressure Decades of lobbying, mounting pressure
Consumer groups, mostly women activists
Muckraking journalismexposes 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
9
1902 1902 The Poison Squad The Poison Squad 1902 1902 The Poison Squad The 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) meals free, high-quality (but dosed) meals
gram to 4 grams daily over 5-year study
first five subjects were: first five subjects were:
Na
2
B
4
O
7
*10H
2
O (borax)
C
6
H
4
(OH)COOH (salicylic acid)
H SO ( lf i id) H
2
SO
4
(sulfuric acid)
NaC
6
H
5
CO
2
(sodium benzoate)
CH
2
O (formaldehyde)
2
( y )
10
http://www.fda.gov/ucm/groups/fdagov-
public/documents/image/ucm151032.jpg
1902 1902 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
window window
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
11
1902 1902 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 y
same,
That kind of bill of fare would drive most men
insane insane.
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
12
1905 1905 The Great American Fraud The Great American Fraud 1905 1905 The Great American Fraud The Great American Fraud
11-part patent medicine
series in Colliers series in Collier s
Exposed quackery,
nostrums, & ephemera
False claims by mfrs.
Raised real health
concerns concerns
Lack of quality control
Many contained alcohol,
addictive drugs, or worse!
Led to public outrage and
significant pressure on g p
Congress
13
Patent Medicines Patent Medicines
N d Littl Pi k N d Littl Pi k U ? U ? Need a Little Pick Need a Little Pick--me me--Up? Up?
Carry this package with you always Carry this package with you always
http://theodoregray.com/PeriodicTable/PopularScience/2004/08/2/image3.jpg
14
1906 1906 The Jungle by Upton Sinclair The Jungle by Upton Sinclair 1906 1906 The Jungle by Upton Sinclair The Jungle by Upton Sinclair
Corruption of US meat packing industry Corruption 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 l control laws
15
The Jungle , Chapter 14 (Excerpts) The Jungle , Chapter 14 (Excerpts) The Jungle , Chapter 14 (Excerpts) The Jungle , Chapter 14 (Excerpts)
J onas had told them how the meat that was taken out
of pickle would often be found sour and howthey of 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 p
cut 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 h that was moldy and white it would be dosed with
borax and glycerine, and dumped into the hoppers, and
made over again for home consumption made over again for home consumption
16
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 p
billions 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 too over 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
dungof rats These rats were nuisances and the packers would dung 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 d fairy 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
17
1906: Pure Food & Drug (Wiley) Act 1906: Pure Food & Drug (Wiley) Act 1906: Pure Food & Drug (Wiley) Act 1906: Pure Food & Drug (Wiley) Act
Foremost concern: correct product labeling
Prohibited mfr & sale of adulterated, misbranded,
poisonous, or deleterious foods, drugs, medicines
Banned their interstate transport Banned their interstate transport
Authorized legal enforcement of USP standards
Often considered origin of modern FDA Often considered origin of modern FDA
Required Rx from licensed doctors for some drugs
S 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
18
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
19
1933: Americas Chamber of Horrors 1933: Americas Chamber of Horrors 1933: America s Chamber of Horrors 1933: America s Chamber of Horrors
FDA exhibited real products to pressure fixing the FDA exhibited real products to pressure fixing the
1906 laws flaws, including:
A weight loss drug that caused death g 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
20
1933: Americas Chamber of Horrors 1933: Americas Chamber of Horrors 1933: America s Chamber of Horrors 1933: America s Chamber of Horrors
Lash Lure the Lash 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 law change the law
21
http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118458.htm
1937 1937 Elixir Elixir Sulfanilimide Sulfanilimide
1932 1
st
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 l 10% sulfanilamide, 72% diethylene
glycol, 16% water, elixirflavor,
raspberry extract, saccharin
solution amaranth andcaramel solution, amaranth, andcaramel
107 deaths, 248 survivors
No regulation required toxicity No regulation required toxicity
testing only one law was
broken. What was it?
22
1937: Tragedy Aftermath 1937: Tragedy Aftermath 1937: Tragedy Aftermath 1937: Tragedy Aftermath
CEO: "We have been supplying a legitimate
f i l d d d t ld h professional demand and not once could have
foreseen the unlooked-for results. I do not feel
that there was any responsibility on our part that there was any responsibility on our part
Watkins: committed suicide awaiting the trial
Massengill: minimumfine 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 testing safety testing
23
1938: Food, Drug & Cosmetic (FD&C) Act 1938: Food, Drug & Cosmetic (FD&C) Act 1938: Food, Drug & Cosmetic (FD&C) Act 1938: Food, Drug & Cosmetic (FD&C) Act
Requires newdrug pre-marketing safety studies Requires new drug pre marketing safety studies
Origin of what is now the NDA process
Prohibits false therapeutic claims Prohibits 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 substances poisonous substances
24
1941: Sulfathiazole 1941: Sulfathiazole Tragedy Tragedy 1941: Sulfathiazole 1941: Sulfathiazole Tragedy Tragedy
Winthrop Chemical markets sulfathiazole tablets
t i t d ith h b bit l contaminated with phenobarbital
Hundreds of deaths and injuries resulted
FDA's investigation revealed plant control FDAs 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
25
1953 1953--1962: Thalidomide 1962: Thalidomide Tragedy Tragedy 1953 1953 1962: Thalidomide 1962: Thalidomide Tragedy Tragedy
1953 synthesized by Chemie Grnenthal
No side effects, high animal dose tolerances
1956 given freely to employees to help
d i h i ld d determine 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
26
1953 1953--1962: Thalidomide 1962: Thalidomide Tragedy Tragedy 1953 1953 1962: Thalidomide 1962: Thalidomide Tragedy Tragedy
1956 - Richardson-Merrell applies to sell as
K d i US Kevadon in US
Frances Kelsey, new FDA inspector rejected
application: application:
Fetal safety background from working with quinone (malaria
drug) in the 1940s
f 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
27
1953 1953--1962: Thalidomide Tragedy 1962: Thalidomide Tragedy 1953 1953 1962: Thalidomide Tragedy 1962: Thalidomide Tragedy
1956-1962 approx.
10 000 Europeans born 10,000 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
28
1962: Tragedy Aftermath 1962: Tragedy Aftermath 1962: Tragedy Aftermath 1962: Tragedy Aftermath
Kefauver-Harris Amendment Kefauver Harris Amendment
Proof of Efficacyrequired
Adverse events reporting to FDA required p 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
29
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 todays
GMPs
For manufacturing, g
processing, packing or
holding finished
pharmaceuticals pharmaceuticals
30
1970 1970--1980s: Signs of Effectiveness 1980s: Signs of Effectiveness 1970 1970 1980s: Signs of Effectiveness 1980s: Signs of Effectiveness
Led to increased scope and control:
1975 cGMPs for blood & blood components
finalized
1976: 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 Robins y
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 (nowWyeth) 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
31
1976: GMPs for Low Volume 1976: GMPs for Low Volume Parenterals Parenterals 1976: GMPs for Low Volume 1976: GMPs for Low Volume Parenterals Parenterals
Stemmed from 1970-1971 and 1973 epidemics of
septicemia in US hospitals due to contaminated IV fluids p 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 factors Limits 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
6/22/2011
32
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 GMPs y g
Main source of modern-day 21 CFR 210 & 211
Largely considered a writers revision g 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
33
Overview of Modern Overview of Modern--Day GMPs Day GMPs
(21 CFR 211) (21 CFR 211)
Subpart A (1-3) Subpart G (122-137)
General Provisions
Subpart B (22-34)
Organization and Personnel
Packaging and Labeling
Control
Subpart H (142-150)
H ldi d Di t ib ti
Subpart C (42-58)
Buildings and Facilities
Subpart D (63-72)
Holding and Distribution
Subpart I (160-176)
Laboratory Controls
S 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 Reports
Subpart K (204-208)
R t d d S l d D Product Containers and Closures
Subpart F (100-115)
Production and Process Controls
Returned and Salvaged Drug
Products
34
1980: FDAMA 1980: FDAMA 1980: FDAMA 1980: FDAMA
1980 Food &Drug Administration 1980 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
inspections inspections
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
35
FDA furthers pursuit of international harmonization
1980s 1980s--1990s: Increased FDA Guidance 1990s: Increased FDA Guidance 1980s 1980s 1990s: Increased FDA Guidance 1990s: 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 Ingredients Processing or Holding Active Pharmaceutical Ingredients
36
A Step Back: Guidance Documents A Step Back: Guidance Documents A Step Back: Guidance Documents A 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/GuidanceComplianceRegul
atoryInformation/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 topic p 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 followthe guidance you are expected to follow the guidance
37
37
1980s 1980s--1990s: Looking Forward 1990s: Looking Forward 1980s 1980s 1990s: Looking Forward 1990s: Looking Forward
Numerous cGMP violations by industry; Generic Drug
Scandal Scandal
FDA eventually recognized more direction was necessary:
to provide a uniform standard to the entire industry to 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 newsubparts L M N O &P to 21 CFR 211
38
This would add new subparts L, M, N, O & P to 21 CFR 211
1996: Proposed New Rule 1996: Proposed New Rule Examples Examples 1996: Proposed New Rule 1996: Proposed New Rule Examples Examples
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
39
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 pharmaceuticals
Replaced FDAs 1998 draft guidance Replaced FDA s 1998 draft guidance
API Starting Material used in production of an API
that becomes a significant structural component g 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 t the production process through final API stages
Provides a table illustrating when GMPs should begin
(see next page) (see next page)
40
41
2001 2001--2004: Pharmaceutical cGMPs for the 21 2004: Pharmaceutical cGMPs for the 21
st st
C t C t Ri k B d A h Ri k B d A h Century Century a Risk Based Approach a Risk Based Approach
Working Group created to analyze related cGMP g p y
requirements in effect in the US and internationally,
particularly those related to quality systems
Ulti 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 regulations and international regulations
From final 2004 report: "FDA will take an incremental
approach to modifying parts 210/211, while pursuing
42
international harmonization through ICH and PIC/S."
2007 2007--2008: First Incremental Change 2008: First Incremental Change 2007 2007 2008: First Incremental Change 2008: 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 FDA After careful consideration of all comments, FDA
published new final rule (effective December 8, 2008)
First increment of modifications to parts 210 and 211
43
2008: cGMP Revisions 2008: cGMP Revisions 2008: cGMP Revisions 2008: cGMP Revisions
The final rule revises the drug cGMP regulations g g
primarily 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 Individual y
Certain operations may be performed by (validated)
automated equipment and verified by a person, rather than
one person performing an operation and another person
44
p p g p p
verifying that the operation was correctly performed
Top 10 ranking of total GMP deficiencies 1995-2005
Rank 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
45
45
GMP GMP E R ibilit E R ibilit !! GMPs are GMPs are Everyones Responsibility Everyones Responsibility!!
Products can be considered adulterated! Products can be considered adulterated!
Enforcement Actions e.g. 483, Warning Letter,
Consent Decree; Recalls, Seizures, Injunctions Consent 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 GMP Operator / Technician who failed to follow GMPs
Persons can be debarred from working in the
industry! industry!
46
Paul A. Melamud 2009
Summary of GMP History Summary of GMP History Summary of GMP History Summary 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 efficacy y 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
47
ANY ADDITIONAL QUESTIONS? ANY ADDITIONAL QUESTIONS? ANY ADDITIONAL QUESTIONS? ANY ADDITIONAL QUESTIONS?
48
Acknowledgements & Contact Information Acknowledgements & Contact Information Acknowledgements & Contact Information Acknowledgements & Contact Information
Thank you to ISPE-NJ C
d th Ch t D
Paul 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) 462-0653
if you have any
questions, please do not
hesitate to contact me!
49