A Perspective on Oversight of
API Manufacturing Sites
Albinus D’Sa, Ph.D.
Deputy Country Director India Office
U.S. Food and Drug Administration
Department of Health and Human Services
1
Current US Pharmaceutical Industry Landscape
• Increased generic drug demand
– Increase in median age of population
– Innovator patents expiring
– Downward cost pressure from payers
• More outsourcing and globalization of finished dosage
manufacturing
– Specialization in facets of upstream manufacturing
• API manufacturing is an example of a 40-year
trend in outsourcing to specialists culminating by
shift away from domestic (in this case specialty
chemical) manufacturing base
 Manufacturers will gain competitive edge through high
quality and superior management of supply chains 2
Registration Statistics
Registered Domestic and Foreign Establishments
as of FY2012 3rd Quarter
domestic manufacturer
foreign manufacturer
17%
domestic API Manufacturer
3%
44%
foreign API Manufacturer
36%
”Manufacturers” exclude API manufacturers as well as contract sterilization,
analytical labs, PET, repackaging/packaging, labeling/relabeling
3
Foreign GMP Inspections
All Drugs
350
300
250
GMP
200
PAI GMP
GMP China
150
PAI GMP China
100
50
0
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
4
Drug Inspections in India
US FDA Inspections in India
140
120
100
80
60
40
20
0
2008
2009
2010
2011
2012
5
Quality Problems Traced to Supply Chain are
Driving a Heightened Focus on
Ingredient Manufacturing
•
•
•
•
•
API – Highest Expectations for GMP
Excipients
Dietary supplement ingredients
Food ingredients
Cosmetic ingredients
Higher Quality Standards for Ingredients
6
Examples of Recalls Traced to Excipient
Variability or Low Levels of Impurities
• Four recalls in 2010 due to dissolution
failure were ascribed to excipients
– Aldehyde impurity (OTC drug)
– Properties of Zein (OTC drug)
– Intra-batch variability in Ethylcellulose used in
MR coating in capsule formulation (2 events
involving the same product)
– Acid value of Glyceryl Behenate matrix carrier
in a microsphere formulation
7
FDA Detects High Levels of Peroxide in Imported
Crospovidone and Issued a Drug Safety Advisory
10/21/2010
http://www.fda.gov/drugs/drugsafety/ucm230492.htm
• Peroxide levels found (1700 ppm) were 30-40x typical
levels in this excipient
• Peroxides can degrade APIs resulting in sub-potent drug
• Impurity levels were not being monitored by the
manufacturer of Crospovidone
• Certificates of analysis were not indicating presence of
such high levels of peroxide
• USP to revise monograph to add limit of peroxide
8
Observation: Manufacturers are Applying High
Standards for Ingredient Quality Assurance
• More intensive supplier qualification by
finished product manufacturers
– Auditing of ingredient manufacturing sites
– Expectations for direct communication
between makers and user of ingredients
– More rigor in standards of quality for
ingredients
– More frequent user confirmatory testing
9
FDA API CGMP Inspections
• API - ingredient intended to furnish pharmacologic effect
• The law defines API as a drug because it is a component
of a drug
• The law requires all drugs to be manufactured in
conformance with CGMP
– API not manufactured in conformance with CGMP is
deemed adulterated
– An import alert can be issued when an API appears to
be adulterated as a result of inspection findings
• ICH Q7 is a standard for FDA inspection of API
establishment (see also CDER Compliance Program
10
Guidance Manual section 7356.002F)
FDA API Pre-approval and
CGMP Inspection Programs
• CGMP inspections
– Focused on six systems
• Quality management system is always inspected
• Facilities and equipment, Materials, Production,
Packaging and Labeling, Laboratory
• On a pre-approval inspection FDA will also be looking at
the control of the API manufacturing process with
greatest emphasis on critical process parameters and
quality attributes
• Biotechnologically derived APIs
– Are usually going to be produced as “Sterile API”
– Other more rigorous inspection programs which apply finished
dosage form CGMP will generally apply
11
Facilities and Equipment Systems
• Risks to address
– Cross contamination risk
– Contamination due to equipment or exposure of API
process
– Mix-ups
-----------------------------------------------------------------------------• Facility and equipment design
– Flow of materials, people, activity
– Cleaning during changeovers
– Compatibility of materials with process stream
– Identification of each piece of equipment and piping
systems
12
• Maintenance
Areas of High Contamination Risk
• Dry processing such as drying or particle
size reduction can generate airborne fine
particles
• Equipment which if not properly
maintained or taken out of service when in
irreversible disrepair can shed particles
• Areas in which there is potential for API to
accumulate and not be readily removed
during cleaning
13
Materials Systems
• Identification and purity specifications and
testing of critical starting materials
• Segregation in warehouse to avoid mix-ups
• Tracking of inventory and traceability
– traceability of API starting materials
– FDA is particularly concerned about agriculturally
derived starting materials
• Water quality
– Minimum standard is WHO drinking water quality
– Water purification systems should be validated
– Water quality should be monitored and controlled
using action limits and procedures to describe
actions taken when limits are exceeded
14
Suppliers of Critical Raw Materials
for API Manufacturing
•
•
•
•
System for technical evaluation of suitability
System for approval of suppliers by the QU
Agreed upon purchasing specification
Name and address of the manufacturer of the
critical raw material known
• Written agreement to be notified about
significant changes to manufacturing that might
impact critical material quality
15
API Guidance Which Cover Starting Materials
ICH Q7A: GMP Guidance for API
http://www.fda.gov/downloads/Drugs/GuidanceComplia
nceRegulatoryInformation/Guidances/UCM073497.pdf
ICH Q11: Draft Guidance on Development and
Manufacture of Drug Substances
http://www.fda.gov/downloads/Drugs/GuidanceComplia
nceRegulatoryInformation/Guidances/UCM261078.pdf
Draft Guidance on Heparin for Drug and Medical Device
Use: Monitoring Crude Heparin for Quality
http://www.fda.gov/downloads/Drugs/GuidanceComplia
nceRegulatoryInformation/Guidances/UCM291390.pdf
16
Date of data pull: Sept 19, 2011
ES
EAN
ING/
MAI.
20%
15%
10%
5%
All
Source: DIDQ CO reviews of EIRs as reported in CMS
Europe
India
China
INAD
EQU
ATE
OR G
AN IZ
A
C OM
ENV
S
PLAI
NT
IRON
ME N
TA L
NEL
I...
ATIO
N
CON
TRO
LS
TIO N
TION
/PER
SON
INAD
EQU
ATE
IFICA
STEM
VAL ID
QU A
L
UTE
R
TEM
CO M
P
SYS
QA S
Y
TS, IN
TER
PRO
MED
D UC
IATE
TION
S, R
/PRO
AW M
C ES
ATER
S CO
IALS
NTR
INAD
O LS
EQU
ATE
VALID
ATIO
N PR
OTO
C OL
PAC
KAG
ING/
LABE
L IN G
STAB
ILITY
PR O
GRA
HO L
M
DING
/DIS
TRIB
U TIO
N CO
...
INAD
EQU
ATE
LAB
C ON
TR O
LS
UN V
ALID
ATE
D LA
B TE
ST M
...
DEF
ICIEN
CIES
IN R
EC O
RD S
...
REP
ROC
ESS
IN G/R
EWO
RKS
CO N
TRO
L OF
WAT
ER S
YST.
..
DEF
ICIEN
CIES
IN M
EDIA
FILL
INAD
S
EQU
ATE
PRO
C ES
S VA
LIDA
LACK
TION
OF/IN
ADE
QU A
TE S
OPS
..
E, L O
CAT
ION
, SIZ
ROL
C OM
PON
EN
CO N
T
NT C
L
SIGN
IL ITI
0%
EQU
IPME
NT D
E
/FAC
DA...
AMIN
ATIO
N
FRO
M DM
F/N
BUIL
DING
S
TION
EQU
IPME
DEV
IA
CO N
T
Total – deficiencies seen on API
inspections 2007-2010, by region
25%
20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
360 API Inspection Observations 2007 – 2010
18%
16%
53 API Inspections China 2007 - 2010
14%
12%
10%
8%
6%
4%
2%
0%
25%
80 API Inspection India 2007 - 2010
20%
15%
10%
5%
0%
25%
171 API Inspection European Sites 2007 - 2010
20%
15%
10%
5%
0%
Lab Systems - Data Integrity
• Accurate and reliable data and information
• Ensuring data trustworthiness and reliability, as
related to the security of the information/data
• Quality
– the degree to which a collection of data is
complete, consistent, and accurate.
• Attributable, Legible, Contemporaneous,
Original, and Accurate (ALCOA)
– FDA may look to see that the process of data
creation at the site can be reconstructed and
that it matches the information submitted to
the agency. If problems are discovered, the
integrity of the data is questionable.
22
Data Integrity – What We See
• Not recording activities contemporaneously
– Backdating
• Fabricating data
– Copying existing data as new data
• Discarding data
– Not saving electronic or hard copy data
• Discarding data to release failing product
– Repeat sampling or testing until compliance can be
documented
23
Loss of Data Integrity - Observations
• Batch production record
– 7 instances involving 2 employees signing as having
completed manufacturing steps; neither employee
was on the premises at the time the steps were
completed
• Stability
– Testing conducted late but recorded as having been
tested on time
– Testing data was generated without samples having
been taken
• Analytical Method Validation
– Results from the method validation of one drug were
used for the method validation of another drug
24
Loss of Data Integrity - Observations
• Test Data for Batch Release
– Test results for one batch were used to
release other batches
• Occurred for at least 3 batches
• Happened at two unrelated firms
– Employee used same sample for identity
testing of multiple batches
– Firm repackaged and released failing batch
without performing an investigation
25
Data Integrity - References
• FDA’s Guidance to Industry: Part 11, Electronic
Records; Electronic Signatures — Scope and
Application, available at
http://www.fda.gov/downloads/Drugs/GuidanceC
omplianceRegulatoryInformation/Guidances/UC
M070295.pdf
• Glossary of Computer Systems Software
Development Terminology (8/95),
available at
http://www.fda.gov/ICECI/Inspections/Insp
ectionGuides/ucm074875.htm
26
Nine FDA Warning Letters Were Issued to
Foreign API Manufacturers in 2011
•
•
•
•
•
•
•
•
•
Failure to conduct adequate release testing
Failure to investigate failing lab results
Failure to validate analytical methods
Lab control issues and falsification of lab data
Failure to review data before release and failure to
evaluate suppliers
Failure to implement procedures to prevent crosscontamination with penicillin products
Failure to document manufacturing operation records
and inadequate facilities
Inadequate production records and laboratory controls
Failure to investigate deviations and inadequate
maintenance
27
Validation
• All API manufacturing processes should be
validated
– FDA recommends a lifecycle approach to validation
• All test methods for release of API should be
validated
• All test methods should be suitable and
scientifically sound for intended purpose
– In process testing
– Testing of starting materials, reagents, solvents,
catalysts, etc.
28
Residual Solvents and Metallic Impurities
• API manufacturers should be prepared to
provide identity of potential residual solvents and
metallic impurities to finished dosage form
manufacturers
– Requirements apply to finished drug products
– See ICH Q3C for residual solvents (Option 2)
– ICH Q3D (soon to be a Step 2 draft) and draft USP
chapters <231> and <232> express impending
expectations for metallic impurities
• Instrumental methods to replace heavy metals test
• Calculation of metallic impurities in drug products will usually
be based on levels in APIs and excipients
29
Expect To See More…
• Inspections of foreign API sites
– Heightened focus on inspections related to
generic drug manufacturing
– More focus on management of suppliers
• Consistent raw materials fit for purpose
• Integrity of API supply chains
• Sharing of information with trusted regulatory
counterparts under confidentiality agreements
• 3rd party involvement, especially in supplier
audits normally conducted by finished drug
manufacturers
30
References
• Validation
–FDA Guidance on Process Validation: General
Principles and Practices
http://www.fda.gov/downloads/drugs/guidancecomplianceregulat
oryinformation/guidances/ucm070336.pdf
• Residual Solvents
–ICH Q3C
http://www.fda.gov/downloads/Drugs/GuidanceCom
plianceRegulatoryInformation/Guidances/UCM07339
4.pdf
–USP <467>
• Elemental (Metallic) Impurities USP <232>
–USP-PF 37(3)
31
Acknowledgements
•
•
•
•
•
Karan Takahashi
Grace McNally
Raphael Brykman
Steven Wolfgang
Elizabeth Philpy
32