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
13
Implementing Health- and Science-
Based Risk Assessment for Multi-Product
Manufacturing
Summary of market predictions
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manufacture in dedicated facilities
Introduction
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ANNUAL INDUSTRY REPORT
|rJJs.y |xpo. |.ro| SJbn|ss|crs
PANEL MEMBER
Dr. Mark Carver, Senior Vice President Research & Development and Innovation
|J|||n ||csyr| b|coc|rc|cg|os
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
14
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Draft Guidelines Could Prevent Some Biologics from Entering Clinical Trials
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maintain patient and operator safety and assure product
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
15
,J.||y |o ||skV.|| |..no.c.k |.J |rpJ |.cn . .|Jo
..rgo c| ccnp.r|os .rJ ..s s|..oJ .|| n.c. .ogJ|.c.s
bo|c.o pJb||c.|cr |s cc.o .occnnorJ.|cr |s |o Jso
c| . rJnbo. c| .|skb.soJ .pp.c.c|os .rJ .Jcp|cr c|
|o |o.||b.soJ ccrcops c| cx|cc|cg|c.||y Joo.n|roJ
Accop.b|o |.||y |xpcsJ.o (A||) .rJ Opo..|cr.| |xpcsJ.o
||n|s (O||) c ccr.c| c.css ccr.n|r.|cr oxpcsJ.o c
p.|ors .rJ cpo..c.s, .ospoc|vo|y
|r |oconbo. 2012 |o J..| |VA gJ|Jo||ro (|VA, 2012)
.occnnorJoJ Jso c| |o.n|oJ |.||y |xpcsJ.o (|||) c. |o
|.os|c|J c| cx|cc|cg|c.| crco.r () p...noo.s .|or
ccrs|Jo.|rg |o p.cJJc|cr c| J||o.or noJ|c|r.| p.cJJcs
in shared facilities.
|o Jo|r||crs c| |o |o.||b.soJ ||n|s A|| .rJ |||
..o Josc.|boJ |r ||gJ.o 1 |oy ..o ossor|.||y s|n||.. .rJ
.|n c Jo|ro . J.||y Jcso c| . sJbs.rco bo|c. .||c| rc
adverse efects are anticipated if individuals are exposed to
|o nc|ocJ|o o.c| J.y |c. . |||o|no |oy ..o Jo.|voJ |.cn
cx|cc|cg|c.| sJJ|os .rJ .o,J|.o p.c|oss|cr.| cx|cc|cg|c.|
expertise to determine.
A g.o. .Jv.r.go c| Js|rg ||s .pp.c.c| |s |. | Jcos
rc .o,J|.o |np.oc|so Jo|r||cr c| . nc|ocJ|o .s ||g||y
pcor c. cx|c .|or Joo.n|r|rg .|o|o. co..|r ccr.c|
no.sJ.os ..o .o,J|.oJ |.|o., |oso |c. |.cn |o A||
c. ||| c.|cJ|.oJ .rJ .ry .sscc|.oJ p.cJJccp.cJJc
c...ycvo., og n.x|nJn .||c..b|o c...ycvo. (VAO)
c.|cJ|.|crs |oso .pp.c.c|os .c.k .o|| |c. |.Jrc|oJ
p.cJJcs .rJ |.o p|.so |V|s .|o.o |o cx|cc|cg|c.| J..
rooJoJ c or.b|o Jo.|v.|cr c| A|| c. ||| |s .v.||.b|o, .rJ
where likely doses of products are known.
||sc.|c.||y, n.rJ|.cJ.o.s n.k|rg b|c|cg|cs |r nJ||
p.cJJc |.c||||os |.vo rc JsoJ |o.||b.soJ c|o.r|rg ||n|s
.|or ccrs|Jo.|rg p.cJJccp.cJJc c|.rgocvo.
Acceptable Daily Exposure (ADE)
|.||y Jcso c| . sJbs.rco bo|c. .||c| no adverse efects
..o .r|c|p.oJ, by .ry .cJo, ovor || oxpcsJ.o cccJ.s |c. .
|||o|no
A|| |OA|| (b\)


(UF
c
) (V|) (||)
oxp.ossoJ .s ng (c. g) po. J.y \|o.o
NOAFL |c Obso.v.b|o AJvo.so ||oc |ovo| (ng A||/kg
bcJy .o|g|)
BW bcJy \o|g| (kg)
UF
c
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sJc| .s |ro. .rJ |r.. spoc|os J||o.orcos, sJbc|.cr|c c
c|.cr|c ox..pc|.|cr, |OA|| c |OA|| ox..pc|.|crs .rJ
J..b.so ccnp|ooross
MF VcJ||y|rg |.cc. b.soJ cr |o JJgonor c| .
cx|cc|cg|s
PK ||..n.cck|ro|c AJJsnors

Permitted Daily Exposure (PDE)
|o ||| .op.osors . sJbs.rcospoc||c Jcso |. |s Jr||ko|y
to cause an adverse efect if an individual is exposed at or
bo|c. ||s Jcso ovo.yJ.y |c. . |||o|no
||| |OA|| (b\)

|1x|2x|3x|4x|5
F1 A |.cc. (v.|Jos bo.oor 2 .rJ 12) c .cccJr |c.
ox..pc|.|cr bo.oor spoc|os
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F3 A |.cc. c| 10 c .cccJr |c. .opo.Jcso cx|c|y sJJ|os
c| s|c. JJ..|cr, |o, |oss |.r 4.ooks
F4 A |.cc. (110) |. n.y bo .pp||oJ |r c.sos c| sovo.o
cx|c|y, og rcrgorccx|c c..c|rcgor|c|y, roJ.ccx|c|y c.
o..cgor|c|y
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|ovo| ..s rc os.b||s|oJ \|or cr|y .r |O|| |s .v.||.b|o, .
|.cc. c| Jp c 10 ccJ|J bo JsoJ JoporJ|rg cr |o sovo.|y
of the toxicity.
Figure 1: Health-Based Limits

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
|c. p.cJJc A c p.cJJc b ccrs|Jo..|crs V.x|nJn A||c..b|o ...y Ovo. (VAO) c.|cJ|.|crs |or Jso A|| c. ||| .s
|o ccrs..|r|rg .||c..b|o c...ycvo.
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
16
.c .pp.c.c|os |.vo boor ncs ccnncr|y JsoJ
| |o.r|rg c |rJJs.y .occgr|soJ Jo|roJ ||n|s (og
v|sJ.||y c|o.r .rJ <20Jg O/25cn2, 1ppn O)
(|O| c. |O) oc
|| |o.r|rg c <1/1000 Jcso c. 10ppn c| p.cJJc A
c...y|rg cvo. c p.cJJc b
|o p.cpcsoJ |o.||b.soJ oxpcsJ.o ||n| no|cJ c| .|sk
.ssossnor |.s n.ry .Jv.r.gos cvo. |o .pp.c.c|os
nor|croJ .bcvo, .rJ cJ. ccnp.ry |.s boor J|||s|rg
A||b.soJ .ssossnor |c. sovo..| yo..s .|or ccrs|Jo.|rg
p.cJJccp.cJJc c|.rgocvo.
So Why is a Health-Based Limits Approach Problematic for Some IMPs?
|o |VA J..| gJ|Jo||ro (|VA, 2012) ccrc|JJos |. |r
cases where scientifc data does not support threshold
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scno o..|y p|.so |V|s, p..|cJ|..|y b|c|cg|cs, .s . rJnbo.
of parameters are frequently not known when decisions
to proceed to manufacture are taken. Important examples
|rc|JJo
| |c. scno o..|y p|.so |V|s |o.o n.y bo rc c. |||o
cx|cc|cg|c.| |r|c.n.|cr .v.||.b|o c or.b|o |o
c.|cJ|.|cr c| .r A|| cnp.r|os Jovo|cp|rg sJc|
molecules often require the manufacture of early
CV| b.c|os bo|c.o cx|cc|cg|c.| sJJ|os |.vo boor
ccnp|ooJ, .s |oy c|or Jso |o s.no o..|y b.c|os
c| CV| p.cJJc |c. cx|cc|cg|c.| .rJ o..|y c||r|c.|
studies.
|| |c. n.ry o..|y p|.so |V|s |o |rorJoJ Jcs.gos c|
|o p.cJJc (p.cJJc A) .rJ sJbso,Jor p.cJJc
(p.cJJc b) n.y rc bo krc.r . |o pc|r c|
n.rJ|.cJ.o, |Js p.ovor|rg no.r|rg|J| VAO
calculations.
||| |oc|s|crs c n.rJ|.cJ.o |V|s ..o c|or n.Jo bo|c.o
|r|c.n.|cr .o|.|rg c |o |Jor|y c| sJbso,Jor
p.cJJcs |r |o n.rJ|.cJ.|rg .ssos |s krc.r
|v ||g||y sors||vo p.cJJcspoc||c .ss.ys (nc.o
sors||vo |.r Ob.soJ .ss.ys) ..o |.o,Jor|y rc
.v.||.b|o . |o o..|y p|.sos c| p.cJJc Jovo|cpnor
.rJ |r p..c|co ..o c|or rc .v.||.b|o Jr|| |.o
clinical phase.
|oso |.cc.s n.y n.ko | |npcss|b|o c c.|cJ|.o .r A||
c. ||| |c. .r o..|y p|.so |V| boc.Jso |o J.. .o,J|.oJ
..o s|np|y rc .v.||.b|o | .cJ|J |or bo |npcss|b|o c
po.|c.n VAO c.|cJ|.|crs boc.Jso |o Jcsos c| p.cJJcs
A .rJ b n.y rc bo krc.r |cos ||s no.r |. . rcvo| |V|
s|cJ|J bo n.rJ|.cJ.oJ |r . JoJ|c.oJ |.c|||y` || sc, n.ry
developmental products will never make it to clinical trials.
Towards a Solution: Potency Toxicity and Banding
|o.o |.s boor . goro..| v|o. |. b|c|cg|cs, bo|rg |..go|y
p.co|rb.soJ ..o rc, .s . c|.ss, cx|c ||s v|o. |s sJppc.oJ
by sJJ|os Joncrs..|rg |. b|c|cg|cs |.vo . s|gr||c.r|y
lower failure rate than small molecule pharmaceuticals in
s.|oy |rJ|c.|rg c||r|c.| .|.|s (||V.s| o .|, 2010) b|c|cg|cs
..o yp|c.||y p.co|rs c| ~5100k|. nc|ocJ|.. .o|g|, .rJ
|oy ..o goro..||y ..o.sc|Jb|o |o|. b|c|cg|c.| .c|v|y |s
Joo.n|roJ by |o|. |.ooJ|nors|cr.| s|.pos, .||c| | |s
.ssJnoJ ..o o.s||y Jog..JoJ by |o c|o.r|rg c|on|s.|os
JsoJ |r |rJJs.y SJc| nc|ocJ|os ..o JsJ.||y ,J|o spoc||c |r
b|c|cg|c.| o|oc .rJ ..o |.o,Jor|y c| |c. goro..| cx|c|y
Scno b|c|cg|cs ..o ||g||y cx|c boc.Jso c| |o|. b|c|cg|c.|
|Jrc|cr (og bcJ||rJn cx|r), bJ ||s |s ...o
|o Jso c| |o.||b.soJ oxpcsJ.o ||n|s, |c.ovo., Jcos
rc J||o.or|.o bo.oor ccrcops c| cx|c|y .rJ pcorcy,
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
1
.rJ |o .occgr||cr |., .|||s p.co|rs n.y rc bo cx|c
n.ry c| |on ..o ||g||y pcor, |s |o.J|rg c...Js . c|.rgo
c| v|o. .bcJ |c. sJc| nc|ocJ|os ..o n.rJ|.cJ.oJ .rJ
handled.
b|c|cg|cs .s . c|.ss c| nc|ocJ|o ox||b| . .|Jo ..rgo c|
pcorc|os, .rJ . rJnbo. c| |on ..o ||g||y pcor |o
..rgo c| pcorc|os J|sp|.yoJ by b|c|cg|cs oxp.ossoJ .s A||s
|s s|c.r |r ||gJ.o 2
|.cn ||s | c.r bo soor |. co..|r sJbc|.ssos c| b|c|cg|c
nc|ocJ|os, og ncrcc|cr.| .r|bcJ|os .rJ cyck|ros, orJ
c ||o |r J||o.or p..s c| |o pcorcy spoc.Jn Sc, |c.
|rs.rco, ncs |ro.|o.crs |.vo s|n||.. A|| v.|Jos, .rJ
|oso ..o J|s.r |.cn ncs ncrcc|cr.| .r|bcJy A||
v.|Jos ||s g.cJp|rg |s Jso|J| .s | n.y .||c. oxpo.|orcoJ
cx|cc|cg|ss .rJ sc|or|ss c n.ko scno .ssossnor c|
the potential potency of molecules even when there is
|rsJ|c|or |r|c.n.|cr c or.b|o |J|| c.|cJ|.|cr c| .r A||
c. |||
|J|||n ||csyr| b|coc|rc|cg|os |.s Jovo|cpoJ . |..no.c.k
|. .||c.s |o Jso c| |o.||b.soJ .ssossnor |c. o..|y p|.so
|V|s .|or .o|ov.r J.. n.y bo Jr.v.||.b|o c. |rccnp|oo
\o .cJ|J p.cpcso |. |o .pp.c.c| .o,J|.oJ by |o J..|
|VA gJ|Jo||ro |s .pp||oJ .|o.o |o.o |s sJ|c|or J.. c Jo.|vo
. ||| c. A|| .rJ po.|c.n VAO c. s|n||.. c.|cJ|.|crs, bJ
|c. o..|y cx|cc|cgy/||.so | n.o.|.|s .|o.o sJc| J.. |s rc
.v.||.b|o, . b.rJ|rg .pp.c.c| bo ccrs|Jo.oJ, s|n||.. c |.
.|Jo|y JsoJ |r |o |o.|| .rJ S.|oy orv|.crnor |c. Jo.|v|rg
OccJp.|cr.| |xpcsJ.o b.rJs (O|bs)
Figure 2: Potency of Biologics (Recombinant Proteins)
Lethal Toxins
0.00001
0.0001
0.001
ADE
Indicative
n.b. ADE values and banding boundaries are indicative and are only presented for illustrative purposes.
0.01
0.1
10
100
1,000
10,000
1
Toxins
Apoptosis signals
Cytokines
growth factors etc
Antibodies,
atibody fragments
Insulins
B
C
D
Botulinum Toxins
e.g TNFa
Interferons
Interleukins
Growth factors
Insulins
mAbs
Antibody Fragments
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
Lethal Toxins
0.00001
0.0001
0.001
ADE
Indicative
Cleaning acceptance criteria
increasingly stringent
at each banding boundary
n.b. ADE values and banding boundaries are indicative and are only presented for illustrative purposes.
0.01
0.1
10
100
1,000
10,000
1
Toxins
Apoptosis signals
Cytokines
growth factors etc
Antibodies,
atibody fragments
Insulins
A
B
C
D
Botulinum Toxins
e.g TNFa
Interferons
Interleukins
Growth factors
Insulins
mAbs
Antibody Fragments
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
18
|o v.|Jo c| c|.ss||y|rg c|on|c.|s |rc O|bs .ccc.J|rg
c |o|. |....Js |.s boor .occgr|soJ |c. n.ry yo..s
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ccnp.r|os |r |o |.o 1980s c|.ss||oJ ccnpcJrJs b.soJ cr
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|rJJs.|.| |yg|oro Asscc|.|cr (A||A') ..|c|o (|.Jn.rr
o .|, 1996) A.cJrJ |o s.no |no |. b.rJ|rg sc|onos
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. Jso.|.|orJ|y b.rJ|rg sc|ono c.||oJ OS|| |ssor|.|s
(b.ccko, 1998, C..Joro. .rJ O|Jo.s|.., 1991, |S|, 1999,
V.|Jnor, 1998) |o |ro.r.|cr.| |.bc. O.g.r|..|cr |s
.|sc sJppc.|rg |o Jso c| ccr.c| b.rJ|rg |.cJg|cJ |o
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bo po.n|oJ c .ss|gr . b.rJ b.soJ cr |o .v.||.b|o
s.|oy J.. |c. |o p.cJJc |so|| .rJ/c. |r|c.n.|cr
cr p.cJJcs .|| . s|n||.. ncJo c| .c|cr |o |ovo| c|
Jrco..|ry |r |o .ssossnor .cJ|J bo |.cc.oJ |rc |o
b.rJ .ss|grnor, .|| |cso .|| |o ||g|os |ovo| c|
Jrco..|ry Jo|.J||rg c . ||g|o. .|sk b.rJ
A so.|os c| 45 b.rJs |s .occnnorJoJ, o.c| .|| .r oxpocoJ
A|| c. ||| ..rgo |o |c.o. orJ c| ||s ..rgo |c. . g|vor
b.rJ (|o .c.s c.so) ccJ|J bo JsoJ c c.|cJ|.o po.n|oJ
c...ycvo. ||n|s |c. o,J|pnor .os|JJos |o b.rJ .ss|groJ
.cJ|J .|sc Jo|ro |o sccpo c| |o .|sk n||g.|cr .o,J|.oJ,
|c. ox.np|o, .|o.o o,J|pnor s|cJ|J bo JoJ|c.oJ,
s|rg|oJso o,J|pnor s|cJ|J bo sJbs|JoJ |c. .oJs.b|o
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|rJ|c.|vo b.rJ|rg .pp.c.c| |c. |||Js..|vo pJ.pcsos
Figure 3 : Potency of biologics possible banding scheme
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
19
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out as part of each new product introduction to confrm
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vo.||oJ .os|JJo |ovo|s pcs c|o.r|rg |r |o ovor |oy .o.o
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Towards a Solution: Potency Toxicity and Banding
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are put in place to minimise the risk to personnel and patients
c| c...ycvo. |ob.o .rJ J|scJss|cr .ncrg .ogJ|.c.s .rJ |o
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n.rJ|.cJ.o |r |J||y JoJ|c.oJ .ssos JJo c |.ck c| sJ|c|or
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Even when there is only partial data on early phase
Jovo|cpnor.| p.cJJcs .rJ |o ||ko|y Jcsos |oy .||| bo
JsoJ . c sJppc. |J|| ||| .rJ VAO ypo c.|cJ|.|crs, |o.o
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interested parties is required.
| .cJ|J ||ko c |.rk . rJnbo. c| cc||o.gJos p..|cJ|..|y Arr
A|vos, c||r C.|| .rJ || |.|ob.c| |c. |o|. ccr.|bJ|crs c |o
||rk|rg |. JrJo.p|rs ||s ..|c|o
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