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1 www.pharmaevolution.

com
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
1
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
8
Drug Regulatory Scrutiny & the
Pharmaceutical Industry
Summary of Market Predictions
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ANNUAL INDUSTRY REPORT
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PANEL MEMBER
Dilip Shah, CEO, Vision Consulting Group
www.cphi.com
1
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
9
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Table 1
Warning Letters by Office of Manufacturing & Product Quality, US FDA
No Issue 2010 2011 2012 2013* Total
A Active Pharmaceutical Ingredients (APIs)
1 Mfg facility inspection 2 8 5 1 16
2 Deviations from cGMP 5 5
3 Change notification - 1 1
Total APIs 7 9 5 1 22
B Finished Pharmaceuticals (Formulations)
1 Mfg facility inspection 2 2
2 Violations of cGMP 5 10 16 12
(a)
43
Total Formulations 7 10 16 12 45
Total API + Formulations 14 19 21 13 67
Source: www.fda.gov (a) Includes API Mfg Facility Inspection of one Unit
* To 30 June Only
Table 1 shows that during the last 3.5 years warning letters relating to APIs, which largely
concern manufacturing facility inspection, have decreased, whereas those relating to
formulations have increased. It is evident from these figures that the detection of cGMP
violations at formulation units is growing alarmingly. A further analysis of this data shows that
66 companies received a warning letter during the 42-month period, with one company, Apotex,
receiving two. Prominent names among those on the receiving end of warning letters highlight
both innovators and generics companies, including Boehringer Ingelheim, Hospira, Merck
KGaA, Novartis, Novo Nordisk, Sanofi Aventis, SmithKline Beecham, Teva and Wyeth Lederle.
Indian companies, which account for 40% of DMFs to date and 37% of ANDAs in 2012,
accounted for 12% of the warning letters.
________________________________________________________________________
Website: http//www.vision-india.com, Email: dgshah@vision-india.com
A similar analysis of warning letters issued by the Office of Drug Security, Integrity and Recalls
during the same period (Table 2) provides another useful insight, and suggests that internet
marketing is still eluding regulatory oversight.
Table 2
Warning Letters by Office of Drug Security, Integrity & Recalls, US FDA
No Issue 2010 2011 2012 2013* Total
1 Internet Marketing of Unapproved and
Misbranded Drugs
- 2 6 - 8
Source: www.fda.gov
* Up to 30 June Only
The study also examined Drug Recalls, Market Withdrawals & Safety Alerts during the 42-
month period, as shown in Table 3.
Table 1
Warning Letters by Office of Manufacturing & Product Quality, US FDA
No Issue 2010 2011 2012 2013* Total
A Active Pharmaceutical Ingredients (APIs)
1 Mfg facility inspection 2 8 5 1 16
2 Deviations fromcGMP 5 5
3 Change notification - 1 1
Total APIs 7 9 5 1 22
B Finished Pharmaceuticals (Formulations)
1 Mfg facility inspection 2 2
2 Violations of cGMP 5 10 16 12
(a)
43
Total Formulations 7 10 16 12 45
Total API + Formulations 14 19 21 13 67
Source: www.fda.gov (a) Includes API Mfg Facility Inspection of one Unit
* To 30 June Only
Table 1 shows that during the last 3.5 years warning letters relating to APIs, which largely
concern manufacturing facility inspection, have decreased, whereas those relating to
formulations have increased. It is evident from these figures that the detection of cGMP
violations at formulation units is growing alarmingly. A further analysis of this data shows that
66 companies received a warning letter during the 42-month period, with one company, Apotex,
receiving two. Prominent names among those on the receiving end of warning letters highlight
both innovators and generics companies, including Boehringer Ingelheim, Hospira, Merck
KGaA, Novartis, Novo Nordisk, Sanofi Aventis, SmithKline Beecham, Teva and Wyeth Lederle.
Indian companies, which account for 40% of DMFs to date and 37% of ANDAs in 2012,
accounted for 12% of the warning letters.
________________________________________________________________________
Website: http//www.vision-india.com, Email: dgshah@vision-india.com
A similar analysis of warning letters issued by the Office of Drug Security, Integrity and Recalls
during the same period (Table 2) provides another useful insight, and suggests that internet
marketing is still eluding regulatory oversight.
Table 2
Warning Letters by Office of Drug Security, Integrity & Recalls, US FDA
No Issue 2010 2011 2012 2013* Total
1 Internet Marketing of Unapproved and
Misbranded Drugs
- 2 6 - 8
Source: www.fda.gov
* Up to 30 June Only
The study also examined Drug Recalls, Market Withdrawals & Safety Alerts during the 42-
month period, as shown in Table 3.
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1 www.pharmaevolution.com
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
ANNUAL INDUSTRY REPORT
How Many, and For What?
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www.cphi.com
1
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
10
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Table 3
Drug Recalls, Market Withdrawals & Safety Alerts by Reason, US FDA
No Reason/Problem 2010 2011 2012 2013* Total % of Total
1 Undeclared ingredient;
including sildenafil,
acetaminophen,
dexamethasone, diclofenac, etc.
17 14 8 9 48 27.0
2 Visible particulates;
including fungal microbial
contaminants,
precipitation/crystallization,
brass particulates, etc.
0 12 15 11 38 21.3
3 Unapproved drugs 1 2 7 4 14 7.9
4 Sterility 0 0 4 10 14 7.9
5 Deviations in fill volume,
Size/Thickness of Tabs, variations
in tablet strength, etc.
0 3 7 1 11 6.2
6 Packaging error; including
mislabeled/incorrectly labeled
bottles, and bottles containing
wrong drugs, etc.
0 6 3 1 10 5.6
7 Quality control and
manufacturing processes,
insufficiencies in the
development of the
manufacturing process or non-
compliance with drug
manufacturing requirements
1 1 0 1 3 1.7
8 Equipment cleaning, leading to
product containing trace
amounts of other drugs
0 1 0 1 2 1.1
9 Others; including contamination,
odour, impurity, leaking
container, difficulty in using
measure dosing system, etc.
0 18 13 7 38 21.3
Total 19 57 57 45 178 100.0
Source: www.fda.gov
* Up to 30 June 2013
Further analysis of Drug Recalls, Market Withdrawals & Safety Alerts, by company, is presented
in Table 4 below:
Table 4
Drug Recalls, Market Withdrawals & Safety Alerts by Company, US FDA
No Frequency 2010 2011 2012 2013* Total % of Total
1 1 Time 17 24 30 25 96 80
2 2 Times 1 4 3 6 14 12
3 3 Times 2 1 1 4 3
4 4 Times 1 1 2 2
5 5 Times 1 1 1
6 > 5 Times 2 1 3 2
Total 19 33 36 32 120 100
Table 3
Drug Recalls, Market Withdrawals & Safety Alerts by Reason, US FDA
No Reason/Problem 2010 2011 2012 2013* Total % of Total
1 Undeclared ingredient;
including sildenafil,
acetaminophen,
dexamethasone, diclofenac, etc.
17 14 8 9 48 27.0
2 Visible particulates;
including fungal microbial
contaminants,
precipitation/crystallization,
brass particulates, etc.
0 12 15 11 38 21.3
3 Unapproved drugs 1 2 7 4 14 7.9
4 Sterility 0 0 4 10 14 7.9
5 Deviations in fill volume,
Size/Thickness of Tabs, variations
in tablet strength, etc.
0 3 7 1 11 6.2
6 Packaging error; including
mislabeled/incorrectly labeled
bottles, and bottles containing
wrong drugs, etc.
0 6 3 1 10 5.6
7 Quality control and
manufacturing processes,
insufficiencies in the
development of the
manufacturing process or non-
compliance with drug
manufacturing requirements
1 1 0 1 3 1.7
8 Equipment cleaning, leading to
product containing trace
amounts of other drugs
0 1 0 1 2 1.1
9 Others; including contamination,
odour, impurity, leaking
container, difficulty in using
measure dosing system, etc.
0 18 13 7 38 21.3
Total 19 57 57 45 178 100.0
Source: www.fda.gov
* Up to 30 June 2013
Further analysis of Drug Recalls, Market Withdrawals & Safety Alerts, by company, is presented
in Table 4 below:
Table 4
Drug Recalls, Market Withdrawals & Safety Alerts by Company, US FDA
No Frequency 2010 2011 2012 2013* Total % of Total
1 1 Time 17 24 30 25 96 80
2 2 Times 1 4 3 6 14 12
3 3 Times 2 1 1 4 3
4 4 Times 1 1 2 2
5 5 Times 1 1 1
6 > 5 Times 2 1 3 2
Total 19 33 36 32 120 100
1 www.pharmaevolution.com
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
ANNUAL INDUSTRY REPORT
www.cphi.com
1
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
11
Not Learning from Mistakes
|o 18 |rc|Jors .opc.oJ |r .b|o 3 .o|.o c 120
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J.Jg .oc.||, n..ko .||J....| c. s.|oy .|o. bJ, .s s|c.r
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|rc|JJo Ano.|c.r |ogor (13 |rs.rcos), |csp|.. (10) .rJ
boJ|c.J (6) |.oo n.c. |rJ|.r ccnp.r|os, C|orn..k, SJr
.rJ |.rb.xy, .o.o .ncrg |cso ccnp.r|os |. o.c| |.J
one violation.
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.||J....|s, c. s.|oy .|o.s .|ncs JcJb|oJ |.cn 19 |r
2010, c 36 |r 2012, .rJ |o.o |.vo boor 32 |r Js |o
|.s s|x ncr|s c| 2013 ||s .|so |s |rJ|c.|vo c| ||As
.|Jo. .o.c| .rJ J.|vo c |Jor||y |ssJos c| v|c|.|cr \o||
.occgr|.oJ ccnp.r|os |rc|JJ|rg Apcox, b.Jsc| |cnb,
b.yo., bVS, op|.|cr, Cororoc|, C||o.J, CS|, C.oorscro,
'', Vy|.r, S.rJc., Sn|| |op|o., ov., \.scr .rJ \os
c.s, |.vo .|| boor c|oJ by ||A Ag.|r, ||s ||s |rJ|c.os
bc| |rrcv.c. .rJ goro.|c ccnp.r|os
Ar |rc.o.s|rg rJnbo. c| ccnp.r|os ..o ...coJ c
.rJ |.vo . p.osorco |r |o |S n..ko, bJ ||s no.rs
|o rJnbo.s c| |rspoc|crs .rJ Jo|.J|s ..o .|sc .|s|rg
|c.ovo., .|. n.y bo c| g.o.o. ccrco.r, bc| c |o
J.Jg .ogJ|.c.s .rJ |o pJb||c |o.|| .Jn|r|s..c.s, |s
|. |o ||s c| Jo|.J|o.s ccr.|rs os.b||s|oJ ccnp.r|os
Also of concern is the types of default that are on the rise.
\|c|.|crs c| cCV| n.y bo .o|.oJ c p.ck.g|rg o..c.s,
o,J|pnor c|o.r|rg .rJ so.|||y |ssJos, bJ nc.o |.r
cro||.J c| .opc.oJ |rc|Jors .o|.o c JrJoc|..oJ
|rg.oJ|ors .rJ Jr.pp.cvoJ J.Jgs ||s sJggoss . .||||J|
.onp c byp.ss .ogJ|.c.y cvo.s|g|, .rJ |r |oso c.sos
|o .ospcrs|b|||y .oss s,J..o|y .|| |o p|..n.coJ|c.|
industry. It is noteworthy that these incidents declined
scno.|. bo.oor 2010 .rJ 2012, bJ |.vo .|sor .g.|r
JJ.|rg |o |.s |.|| c| 2013
A ||.J n.c. ccrco.r .o|.os c |o ..p|J |rc.o.so |r |o
Jooc|cr c| |c.o|gr p..|c|os |r J.Jgs A ccnncr p.cb|on,
||s |sr . Jo||bo..o v|c|.|cr, bJ rooJs c bo .JJ.ossoJ,
.|| |o |o|p c| gJ|J.rco |.cn |o .ogJ|.c.s .rJ oxpo.s
V.ry c|o. |ssJos ccJ|J bo s|n||..|y .osc|voJ, bJ | .|||
.o,J|.o . c|.rgo |r |c. |o .c|o c| J.Jg |rspocc.s |s
po.co|voJ |oss .s . |c.ors|c .JJ|c., .rJ nc.o .s . gJ|Jo,
c |o|p orsJ.o |o ccnncr gc.| c| orsJ.|rg s.|o, o|oc|vo
and quality medicines.
Attempts to Beat the System
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.b|o c koop p.co .|| |o |.o,Jor .ogJ|.c.y c|.rgos
|. gcvo.r J.Jg ,J.||y .rJ cCV|, |o.o |s rc .o.scr c
bo||ovo |. ro. or..rs c |o |S n..ko .||| bo .ry
boo. p|.coJ c cvo.ccno |oso c|.||orgos |.cn .|.
|o |.s |o. yo..s c| J.. s|c., scno c| |o sn.||o. .rJ
.o|.|vo|y |osso. krc.r ccnp.r|os soon c bo |rJJ|g|rg
|r .||||J| Jo|.J|, .rJ | |s ||ko|y |. . |..go rJnbo. c|
ro. ccnp.r|os |. ..o ...coJ c |o |S n..ko ccJ|J
po.co|vo ||s .s .r cppc.Jr|y, .||c| .||| .osJ| |r |J.|o.
.onps . Jo||bo..o Jo|.J|
oc|rc|cgy .||| p|.y . koy .c|o |r n.k|rg sJ.o |. .r
|rc.o.s|rg rJnbo. c| v|c|.|crs, .|o|o. Jo||bo..o c. rc,
..o |Jor||oJ, |c. ox.np|o, by or.b||rg |o nc.o .ccJ..o
Jooc|cr c| |c.o|gr sJbs.rcos |r n.rJ|.cJ.oJ p.cJJcs
|o Jps|c |s |. .o n.y |o.. nc.o c| .|o.s, .oc.||s .rJ
n..ko .||J....|s, Jr|oss |o |rJJs.y .Jcps . ro.
cJ|J.o .rJ p|.ys .r .c|vo p.. |r .oJJc|rg sJc| |rc|Jors
Cultural Change And Communication
A rJnbo. c| ,Jos|crs ..o ..|soJ, |c.ovo. \||c| ..o |o
..o.s |. .||| p.osor |o g.o.os |JJ.o .ogJ|.c.y .|sks
.rJ |o.J c |o |..gos rJnbo.s c| ...r|rgs, .rJ |c. c.r
.o scp c. n|r|n|.o |on .s ro. ccnp.r|os .Js| |rc |o
|S n..ko .||cJ .Jo,J.o p.op...|cr` |o g.c.|rg
.orJ c...Js .o.c c|o..rco .||| rocoss|.o c|.rgos |r
.|JJo .rJ cJ|J.o .c.css .r c.g.r|..|cr |o |rJJs.y
rooJs c boccno nc.o |r.cspoc|vo .rJ |cck |c. ..ys c
cvo.ccno |oso |ssJos |o.vo | Jp c |o .ogJ|.c., .rJ
|o sc|J|cr n.y |rvc|vo sc.||rg Jp |o por.|y |c. .||||J|
Jo|.J| cnp.r|os |.cn .|| gocg..p||os nJs onb..co
|oso c|.rgos, bc| |c.|.cr.||y .rJ vo.|c.||y, oro.p.|so
wide. It is a slow process that will require patience and
po.sovo..rco, .s n.ry c.g.r|s.|crs p.y .or|cr c
1 www.pharmaevolution.com
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
ANNUAL INDUSTRY REPORT
www.cphi.com
1
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
12
n.rJ|.cJ.|rg, bJ Jovco |||o o|c. c p.op..o |o pocp|o
|c. c|.rgo
|ogJ|.c.y .J|c.||os .rJ ccnp.r|os .||| .|sc rooJ c
make more efort to communicate the rationale of the
p.osc.|boJ p.ccossos |. ..o pJ |r p|.co |xpoc|rg
ccnp||.rco .||cJ JrJo.s.rJ|rg |s |J||o |o n||g.|cr
c| .|sks .o,J|.os nJc| boo. .pp.oc|.|cr c| |o J.Jg s.|oy
.J|os .rJ . c|o..o. JrJo.s.rJ|rg c| |o p.ccossos
Barriers to Market Entry
\o .|sc rooJ c ccrs|Jo. |o ypos c| .ogJ|.c.y c|.rgos
|. n.y .ko p|.co, .rJ |o|. o|ocs cr |o n..ko J..or
cJccnos .rJ p..c|sos |rJ|c.o |. |o n.c.|y c|
...r|rgs .||| son |.cn |o |c.| (|S, |J.cpo .rJ ||r.)
Scno c| |o p.s c|.rgos ..o .|.o.Jy po.co|voJ .s bo|rg
J|.ocoJ c...Js ..|s|rg oc|r|c.| b...|o.s c ccnpo||cr
|.cn |o |c. ccs, o|c|or p.cJJco.s, .rJ |o .ogJ|.c.s
.rJ oc|r|c.| oxpo.s ccrs|J|rg |o |ro.r.|cr.|
cr|o.orco cr |..ncr|..|cr (||) n.y ccr|rJo c
s.|vo |c. po.|oc|cr . |o .|sk c| |grc.|rg |o ccsboro|
.r.|ys|s ||s ccJ|J Jo|.y or.y c| |c||c.cr b|c|cg|cs, .rJ
n.y |o.J c scno n..g|r.| p|.yo.s g|v|rg Jp |o |S n..ko,
which will ultimately reduce competition.
Another point to consider is the need for and likelihood of
|rc.o.soJ .ogJ|.c.y |rog..|cr, .rJ |o ccrso,Jorcos c|
| rc |.ppor|rg Vcs ccnp.r|os, |..ospoc|vo c| |o|. s|.o,
socc. (c.|g|r.c. c. goro.|c) .rJ Jcn|c||o .cJ|J ||ko c soo
g.o.o. |rog..|cr c| .ogJ|.c.y p.ccossos c .oJJco Jo|.ys
.rJ |o .sscc|.oJ ccss c| .pp.cv.| |c.ovo., .|||o scno
cccpo..|cr bo.oor J.Jg .ogJ|.c.s |r J||o.or n..kos
|s ||ko|y cvo. |o rox |o. yo..s, ccnp|oo |rog..|cr |s
Jr||ko|y |r |o ro.. |JJ.o Scno .ogJ|.c.s n.y rc bo
.||||rg c g|vo Jp |o|. .J|c.|y, .rJ . pJs| c...Js
|rog..|cr ccJ|J .|sc bo no by b...|o.s c| scvo.o|gry | |s
thus likely that the industry will have to continue to have to
rogc|.o .ogJ|.c.y Jo|.ys .rJ |o ccs c| JJp||c.|cr
.ko .|| |oso pc|rs |rc ccrs|Jo..|cr, .rJ |s .|sc ||ko|y
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will push up the price of medicines as companies face
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1 www.pharmaevolution.com
PHARMA I NSI GHTS:
FORMULATI ON AND I NGREDI ENTS
Few would dispute the fact that pharmaceutical formulation has
become increasingly challenging. The difculties all start with
the ingredients used to make nished drugs. As more Active
Pharmaceutical Ingredient (API) and excipient manufacturing
moves offshore, particularly to India and China, there have been
increasing complaints of variable quality and tightening supply.
Ingredients have never ofcially been covered by existing
pharmaceutical good manufacturing practices (GMPs),
although different countries follow guidelines set by WHO,
as well as ICH Q7.
Supply chain disasters of 2008, the heparin recalls and
tainted glycerin tragedies, focused attention on the lack of
systematic and harmonized global quality control standards for
pharmaceutical ingredients.
Sweeping regulations in Europe and the US, namely the Falsied
Medicines Directive and the FDA Safety and Innovation Act, aim
to address this need, and improve the safety and quality of APIs
and ingredients.
Globalization of the market has also heightened awareness
that the worlds regulators couldnt possibly inspect every
pharmaceutical ingredients plant or all the new API and
ingredient manufacturing facilities coming online. Regulatory
authorities, including EMA and FDA, collaborated on some API
plant inspections, and have recognized a role for independent
third-party auditors for API and ingredients facilities.
This has led to the development of formal cGMP guidelines for
excipients and new options such as third-party supplier auditing
and qualication programs.
But formulation challenges continue, all along the
pharmaceutical value chain. The unit operations that precede
formulation can be extremely difcult to control.
In addition, many developmental products now in the pipeline
are insoluble or difcult to work with. The Venus de Milo is 10
times more soluble in water than many APIs, noted Shaukat
Ali, technical sales manager of BASFs Pharma Ingredients and
Services at a Catalent Applied Drug Delivery Institute training
event on June 12.
He said that most APIs now commercially available are insoluble,
as well as the growing number of t in the pipeline. What
cannot be dissolved cannot be absorbed, and cannot cure.
Click here for an article on absorption modeling.
CPhI and CPhI PharmaEvolution.com surveyed readers on their
experiences and challenges in formulation and ingredients
sourcing and management. Responses from 123 industry
professionals suggest main areas of concern and overall trends.
Brian Carlin, Director, Open Innovation, at FMC BioPolymer,
an expert in excipients; Girish Malhotra, President of Epcot
International, an API expert, and Emil Ciurczak, independent
NIR spectroscopist and PAT expert; all on CPhIs Advisory Board;
and Irwin Silverstein, VP and COO of IPEA, commented on the
overall results, which are summarized in this brief report. IPEA
was the rst third-party excipient auditing organization, which,
together with the Pharmaceutical Quality Group, drafted the
cGMP requirements for excipient suppliers.
India The Main Source Of APIs And Ingredients
On the ingredients sourcing side, survey respondents say they
are getting most of their APIs and ingredients from India,
and, when they partner or outsource any activities, they are
Survey Suggests a Need for Greater Control
of Formulation & Ingredient Management
CPhIs rst survey on formulation suggests that drugmakers
communicate more closely with suppliers, and better
understand and control their processes
Introduction
ANNUAL INDUSTRY REPORT
www.cphi.com
CPhI drives growth and innovation at every step of the global pharmaceutical supply
chain from drug discovery to finished dosage. Through exhibitions, conferences and
online communities, CPhI brings together more than 100,000 pharmaceutical
professionals each year to network, identify business opportunities and expand the global
market. CPhI hosts events in Europe, China, India, Japan, Korea, Southeast Asia, Istanbul,
Russia and South America and co-locates with ICSE for contract services, P-MEC for
machinery, equipment & technology, InnoPack for pharmaceutical packaging and BioPh
for biopharma. CPhI provides an online buyer & supplier directory at CPhI-Online.com.
For more information visit: www.cphi.com