Elemental Impurities

Advancing Development & Manufacturing

MARCH 2015 VOLUME 27 NUMBER 3

LYOPHILIZATION

Cycle Optimization for BiologicsPEER-REVIEWED

Real-Time Imaging for Particle Characterization

FORMULATION

Semi-Solid Dosage Forms

ElementalImpuritiesA closer look at the new ICH Q3D guidelines

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Cover: Rafe Swan/Getty ImagesArt direction: Dan Ward

March 2015

Features

COVER STORY

12 Implementation of ICH Q3D Elemental Impurities

Guideline: Challenges and Opportunities

Assessing risk factors is key to

implementing the new ICH Q3D guidelines.

LYOPHILIZATION

24 Lyophilization Cycle Optimization

of Cell-Derived Products

Viscosity and aggregation after product

reconstitution must be carefully managed.

FORMULATION

38 Semi-Solid Dosage Forms

While the skin offers an alternative route of

administration for local and systemic drug delivery,

developing semi-solid dosage forms can be a challenge.

PharmTech.com

Column and Regulars

6 Editor’s Comment

Lifting the Veil on Drug Pricing

8 European Regulatory Watch

Europe Strives for a More Efficient

Generic-Drug Approval Framework

29 API Synthesis & Manufacturing

Minimizing Risk during HPAPI Manufacture

41 Troubleshooting

Removing Aggregates in Monoclonal Antibody Purification

44 Product/Service Profiles

50 Ask the Expert

Managing Supplier Data Collection

50 Ad Index

Peer-Reviewed32 Monitoring Fluid-Bed Granulation and

Milling Processes In-Line with Real-Time Imaging

This study examines the efficacy of a particle

characterizing technology to capture particle images

under dynamic conditions and to calculate particle

size distribution data both in-line and at-line during

fluid-bed granulation and milling.

32 3824 12

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PharmTech EuropeEditorAdeline Siew, [email protected]

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EDITOR’S COMMENT

Lifting the Veil on Drug Pricing

Every now and then,

you will hear about

the rising costs of R&D,

which in turn, translate

into high prices for

new drugs entering the

market. Of course, with

the blockbuster model

becoming obsolete and

the pharmaceutical industry shifting focus

to personalized medicines, one can only

expect drug prices to hit the roof.

Cost is always a controversial matter that

sparks questions regarding affordability and

sustainability. Now if you’ve ever wondered

how drugmakers come up with a price

tag for their product, there is a possibility

that the veil may be lifted. The United

States could be leading the way in a push

for greater transparency in drug pricing

as assembly member and San Francisco

democrat David Chiu introduced a new

bill (AB 463) requiring pharmaceutical

companies to disclose information on how

they set the price tags for new drugs (1). If

this law is passed, the manufacturer of any

course of treatment costing $10,000 or more

per year must report the production costs

for the drug, which include R&D costs paid

by the manufacturer or by grants; clinical

trial and other regulatory costs; financial

assistance offered to patients through

various programmes; manufacturing costs;

acquisitions costs such as licensing fees

or the purchase of patents; total spend

on marketing and advertising; and profits

attributed to the drug.

A recent report by the Tufts Centre for

the Study of Drug Development estimates

that, on average, it costs $2.6 billion to

bring a drug to market (2). Whether or not

it is a myth or fact, this figure has caused

disputes with critics accusing the industry

of using R&D cost as an excuse to mark up

drug prices. Perhaps the new transparency

act on drug pricing will clear up some of the

confusion and serve as an eye opener as

to why our medicines cost so much. And

it would be interesting to see if Europe will

follow suit.

References1. AB 463 Pharmaceutical Cost Transparency

Act of 2015, http://leginfo.legislature.ca.gov/faces/billNavClient.xhtml?bill_id=201520160AB463, accessed 2 Mar. 2015.

2. Tufts CSDD, Cost to Develop and Win Marketing Approval for a New Drug is $2.6 Billion, Press Release, 18 Nov. 2015.

Adeline Siew, PhD

Editor of Pharmaceutical Technology Europe

[email protected]

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The European Union’s decentralized procedure (DCP) for drug

approval is regarded outside Europe as an effective system

for cross-border collaboration in the authorization of medicines,

such that it is being used as a model for a number of new global

initiatives in the harmonization of pharmaceutical regulatory

standards. Yet within the EU, both industry and regulators now

acknowledge that deficiencies with the procedure need to be

tackled before they start to undermine its benefits.

“The DCP has been a very successful procedure,” Stella

Koukaki, managing partner and scientific affairs director at

PharOS Ltd., a Greek-based developer of generic medicines,

told the annual regulatory and scientific affairs conference of

the European Generic Medicines Association (EGA) in London

in January 2015 (1). “But it is time to take the DCP to the next

stage [of its evolution] so that it is able to face a very

challenging environment,” she added.

Room for improvement

The EGA used the meeting as a platform to reveal publicly, for

the first time, a series of its own proposals for making the

procedure more efficient. Generic and hybrid medicines now

account for more than 90% of the activities of the DCP, which

is currently used by the 28 member states of the EU and three

non-EU European countries—Norway, Iceland, and

Liechtenstein. A key objective of the EGA is to make the

handling of information on the manufacturing processes for

generic drugs quicker and less cumbersome. Some of the

regulators from the 60 national and regional medicines

authorities from 27 countries attending the conference also

outlined their suggestions for improving the DCP, although

their ideas were not so radical as the EGA’s.

“It’s time to ask ourselves whether we are efficient enough,”

said Xavier De Cuyper, chief executive of the Belgian Federal

Agency for Medicines and Health Products (FAMHP), speaking

on behalf of the management board of the Heads of Medicines

Agencies (HMA) in Europe. “We can do better, especially in the

way we interact with other medicines agencies both inside

and outside Europe,” he said.

De Cuyper was referring in particular to the operations of

the European Medicines Regulatory Network (EMRN), which

includes 44 national competent authorities in medicines

control in the 31 countries involved in the DCP. It also

embraces the EU’s centralized procedure (CP) for

pharmaceuticals approval run by the European Medicines

Agency (EMA). “I am convinced that if we continually set higher

standards, we can improve how our network currently

operates,” De Cuyper continued.

The DCP was introduced 10 years ago to streamline a

system of multistate mutual recognition under which an

authorization of a medicine in one state could be automatically

accepted by other EU states. It was drawn up to help

companies wanting to market the same drug in only a limited

number of states rather than in all EU countries for which the

centralized procedure had been devised.

Under the decentralized procedure, a marketing application

for an individual medicine is assessed by a reference member

state (RMS). This evaluation is submitted to the other countries,

called concerned member states (CMSs), where the applicant

wants to market its drug. Disagreements about the RMS

evaluation among CMSs are normally resolved by the

Co-ordination Group for Mutual Recognition and Decentralized

Procedures—human (CMDh) that is responsible for the smooth

running of the DCP.

Speeding up generic-drug approvals

The DCP is seen to have been operating so well that it is

influencing the ways new international initiatives, such as the

International Coalition of Medicines Regulatory Authorities

(ICMRA) and the International Generic Drug Regulators Pilot

(IGDRP), are being organized. With the IGDRP, which aims to

provide a foundation for faster authorization across the world

on safe, effective, and high-quality generic-drug products, a

pilot information sharing system is based on that used in the

DCP. As part of the pilot, details of assessments of products

carried out by RMS countries are, with the agreement of the

companies applying for authorization, being sent to the states

participating in the IGDRP.

The pilot, which was due to be completed in 2014, is likely to

be extended for another two years to 2016 with the assessment

A key objective of the EGA is to make the handling of information on the

manufacturing processes for generic drugs quicker and less cumbersome.

Europe Strives for a More Efficient

Generic-Drug Approval FrameworkProposals to make the decentralized procedure more efficient were discussed at the January 2015 EGA conference.

Sean Milmo

is a freelance writer based in Essex,

UK, [email protected].




of generic medicines under the EU’s centralized procedure also

being included in the information sharing component of the

project. EMA agreed in January 2015 to share its CP

assessments in real time with regulatory agencies in the IGDRP.

“We should be proud of what we are doing in Europe in the

regulation of medicines,” commented Peter Bachmann, CMDh

chair and head of the European and international affairs

co-ordination group of the German Federal Institute for Drugs

and Medical Devices (BfArM) at the EGA conference (2). “One of

Europe’s strengths is the existence of a (cross-border) legal

framework. Also, after years of experience, we trust each other.”

“People inside Europe are thinking the CP and DCP are still

not working as well as they should be,” Bachmann added.

“It is always more difficult [to appreciate how well they are

working] when you are inside the box.”

In the eyes of the EGA, the shortcomings of the DCP now

need urgent attention to ensure that it operates efficiently and

reliably for generic-medicine producers. From the industry’s

viewpoint, there were two important prerequisites for a

successful authorization procedure.

“One absolute need is flexibility and we need a lot of it,”

said Caroline Kleinjan, chair of the EGA’s regulatory and

scientific committee and head of the European regulatory

competence centre of Sandoz, part of Novartis (3). “Our

association has many different types of companies with

difference needs—small and big ones and companies

developing medicines for licensing.”

“Another big need is speed,” Kleinjan continued. “Timelines

need to be as short as possible and as transparent and

predictable as possible.” Among the flaws pinpointed by the

EGA in the current DCP are delays in the granting of marketing

authorizations (MA) and approvals of process and other post-

authorization variations. Some applications for marketing

authorizations can take more than three years to be accepted

so that the MA is often too late to be used, according to the

association. These lengthy hold-ups are frequently caused by

duplication of examinations of dossiers and CMS

prevarications when evaluating RMS assessments.

Four types of DCP

The EGA has suggested the creation of four DCP types that will

help to deal with the present needs of generic medicine

producers. They would assist companies wanting to take quick

advantages of new manufacturing processes and to respond

rapidly to changes in market conditions within groups of

countries, according to Kleinjan.

A major change should be the introduction of what the EGA

called a “backbone” decentralized procedure, with similar

characteristics to the CP, with one application undergoing a

core assessment and approval by a rapporteur and

co-rapporteur, with the approval being confirmed by the

CMDh. The holder of this marketing authorization would be

able to choose in which state it wanted further approvals “in

any number and at any point of time within five years,”

Kleinjan told the meeting.

A “basket” DCP, another EGA proposal, would also comprise

one application containing all potential strengths, supply

arrangements, and pack sizes. “The MAH would be able

to choose the desired elements in each of the involved

member states,” Kleinjan said.

Another suggested change would be the introduction of a

“mini” DCP that would be applied to a minority of states when

the majority of countries have approved a product. It would

provide “almost immediate access” to these other states.

Finally, the EGA has put forward the idea of a DCP under

which several applications for a medicine could be assessed

under a work-sharing arrangement by different RMSs to make

better use of assessment resources in agencies.

“What we want to do with these proposals is start a dialogue

with regulators,” Kleinjan told Pharmaceutical Technology

Europe. “The response at the meeting from regulators was

very promising—much more so than we expected. One

national agency has said it will hold a special meeting to

discuss them while another has already come up with its own

alternative proposals.”

In addition, the association is pressing for a simplification of

data requirements in application dossiers, such as, for

example, details of GMP certification being dealt with

separately. The mandatory inclusion of some GMP information

in dossiers is seen as being a barrier to the fast approval of

post-authorization variations.

Reorganization of the DCP, however, will not be easy. Even if

eventually the regulators and industry reach agreement on a

modified, more efficiency procedure, it is likely to require

amendments to existing EU legislation that will have to be

approved by the European Parliament and EU governments. It

could, therefore, be a lengthy process.

References

1. S. Koukaki, “10 years’ Experience with the DCP—Does

DCP Need Refreshing,” presentation at the 14th EGA

Regulatory and Scientific Affairs Conference (London, 2015).

2. P. Bachmann, “Opportunities and Challenges of

Globalization,”presentation at the 14th EGA Regulatory and

Scientific Affairs Conference (London, 2015).

3. C.Kleinjan, “’Dream DCP’—The EGA’s Proposal for Improve-

ments,” presentation at the 14th EGA Regulatory and Scientific

Affairs Conference (London, 2015). PTE

The EGA has suggested the creation of four DCP

types that will help to deal with the present needs

of generic medicine producers.


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*Andrew Teasdale is a principal scientist at AstraZeneca, [email protected]; Cyrille

C. Chéry is a senior scientist, analytical sciences for biologicals, UCB Pharma SA; Graham Cook, PhD,

is a senior director, Pfizer Global Quality Intelligence and Compendial Affairs; John Glennon is a stability

laboratory team leader, GlaxoSmithKline; Laurence Harris and Carlos W. Lee are both associate

research fellows, analytical research and development, pharmatherapeutics pharmaceutical sciences, Pfizer,

Inc.; Nancy Lewen is a senior principal scientist, Bristol-Myers Squibb; Phil Nethercote is analytical

director, product quality, global functions at GlaxoSmithKline; Samuel Powell is a scientist, analytical

research and development, pharmatherapeutics pharmaceutical sciences, Pfizer, Inc.; Helmut Rockstroh

is head, pharmacopoeial affairs office, F. Hoffmann-La Roche Ltd.; Laura Rutter is SM manager, analytical

services at GlaxoSmithKline; Lance Smallshaw is worldwide analytical expert for biologics and strategies,

corporate analytical sciences, UCB; Sarah Thompson is an associate principal scientist and Vicki

Woodward is a technical services manager, both at AstraZeneca; Katherine Ulman is vice chair of

science and regulatory policy for IPEC-Americas and a global regulatory compliance manager at Dow Corning.

*To whom all correspondence should be addressed.

Implementation ofICH Q3D ElementalImpurities Guideline: Challenges and OpportunitiesAssessing risk factors is key to

implementing the new ICH Q3D guidelines.

New guidelines relating to

elemental impurities from

the International Conference on

Harmonization (ICH), Q3D Guideline

for Elemental Impurities (1) have

presented the pharmaceutical

industry with new challenges.

These challenges include the

complexity of introducing new

analytical technology—specifically

inductively coupled plasma (ICP)-

based techniques replacing the

wet chemical ‘heavy metals’ limit

test—along with new and specific

limits for individual elements.

Perhaps the most significant

challenges, however, are related

to the practical implementation of

the guideline.

ICH Q3D advocates the use

of a risk-based approach to

assessing the potential presence

of elemental impurities in drug

products. While such assessments

are common within other aspects

of pharmaceutical development,

application to elemental impurity

assessment presents new

challenges. Specific challenges

include determining how to

assess or quantify the risks

associated with factors such as

water, container-closure systems,

and excipients. Defining where

in the assessment process data

may be required and identifying

where risks can be determined

to be negligible through a

thorough scientific theoretical

risk assessment also present

significant questions. This article

seeks to review these questions by

looking at the various risk factors

and, where possible, weighting the

risk factors based on appropriate

and relevant considerations to

establish an effective framework

for the systematic assessment of

risk and final control strategy.

Introduction of ICH Q3DThe introduction of ICH Q3D

(1) is one of the most complex

changes in regulations pertaining

to impurities seen by the

pharmaceutical industry. While the

guideline is ultimately intended to

focus on final drug product quality,

the actual risk assessment will

touch all facets of the manufacture

of a drug product. The guideline



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Elemental Impurities

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permitted daily exposure (PDE) limits

to individual elements replacing non-

specific 19th century wet chemical

‘heavy metal’ limit tests. ICH Q3D

advocates the use of a risk-based

approach to assessing the potential

for presence of elemental impurities

in drug products. The process of

executing and documenting the risk

assessment is a major challenge,

primarily as a result of a limited global

understanding about how to assess

or quantify the risk associated with

factors such as water, container-

closure systems, and excipients.

Defining where in the assessment

process data may be required and

identifying where risks can be

determined to be negligible through

a thorough scientific theoretical risk

assessment also present a significant

challenge. Where the risk assessment

identifies the need for testing, the

level of the PDEs for the element(s) of

concern may also require the broader

introduction of new, more sensitive,

and specific analytical technology,

adding further to the complexity.

This article specifically seeks to

examine relevant risk factors and,

where possible, the weighting of

these risks based on appropriate

and relevant considerations. It also

seeks to specifically define where in

the assessment process data may be

required as well as seeking to identify

where risks can be determined to be

negligible simply through a thorough

scientific theoretical risk assessment.

The general principles outlined in

this article are believed to address

most scenarios or product types;

however, ultimately any drug-product

manufacturer needs to consider

potential sources of elemental

impurities appropriate for their

specific product.

Risk assessmentThe evaluation of the potential risk

posed by elemental impurities within

a formulated drug product requires a

holistic approach taking into account

all potential sources of elemental

impurities. Figure 1 illustrates

potential sources that should be

considered in such an evaluation.

Drug substance As presented in Figure 1, the drug

substance is a key component that

can contribute elemental impurities to

the finished drug product. The risk of

inclusion of elemental impurities from

a drug substance, therefore, needs

to be considered when conducting a

drug product risk assessment. Control

of the elemental impurity content

of a drug substance can be assured

through a thorough understanding

of the manufacturing process

including equipment selection,

equipment qualification, GMP

processes, packaging components,

and the selection and application of

appropriate control strategies.

A principal responsibility for any

drug-substance manufacturer is

to develop a strategy to ensure

effective control of the levels of

elemental impurities in the finished

drug substance. An approach

based on assessing and controlling

potential sources of elemental

impurities, coupled with focused,

limited testing, is preferable to

exhaustive testing on the finished

drug substance. A scientific, risk-

based approach combined with

knowledge and control of the key

sources of elemental impurities in

the drug-substance manufacturing

process such as catalysts, provides

an efficient and comprehensive

elemental impurity control strategy

for finished drug substances.

Figure 2 shows potential sources

of elemental impurities in the drug

substance manufacturing process.

Of the sources highlighted, the

Figure 1: Sources of elemental impurities in finished drug products.

Figure 2: Primary sources of elemental impurities in drug substances (DS).

Drugsubstance

Manufacturingequipment

Utilities(e.g., water)

Containerclosure system

Elementalimpurities indrug product

Excipients

Elementalimpurities

in DS

Primarycontainer

closure

Metalcatalysts

Manufacturingequipment

Processingaids

Inorganicreagents

Organicmaterials

Water

Solvents

All

figu

res

are

co

urt

esy

of

the a

uth

ors

.



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greatest risk comes from intentionally

added metals (e.g., metal catalysts

used in the process). Manufacturing

equipment, processing aids, inorganic

reagents, water, solvents, and other

organic materials are less likely

to serve as major contributors of

elemental impurities in the finished

drug substance, but do require

consideration.

Metal catalysts. Metal catalysts,

such as palladium and platinum, are

often used in the drug-substance

manufacturing process and can

therefore be present at low levels

in the finished drug substance. The

synthetic route should be reviewed

for intentionally added metals, and

data from purging studies, including

any supportive testing of appropriate

isolated intermediates, should be

used in the design of an appropriate

control strategy.

The ability to remove the catalyst

(purge capacity) will be influenced

by catalyst loading and the nature of

the catalyst used in the process (i.e.,

homogeneous vs. heterogeneous

catalysts). Heterogeneous catalysts,

such as palladium on carbon, are often

easily removed from reaction mixtures

by filtration, and therefore, the risk of

carryover of elemental impurities into

the drug substance is typically low.

Even in cases where metal catalysts

are used in the final stages of the

process, good historical data and/

or understanding of carry-over may

permit reduced testing schemes.

Biotech products do not normally

rely on the use of catalysts. As ICH

Q3D points out, typical purification

schemes in biotech drug substance

manufacturing are well capable of

clearing any elements introduced

either intentionally or inadvertently

“to negligible levels.” The principles

outlined previously may nonetheless

be relevant in some specific cases

(e.g., chemically modified biotech

drug substances).

When considering the other

potential sources highlighted in

Figure 2, it is recommended to

focus primarily on the manufacturing

steps that occur after the formation

of the final intermediate. Washes,

crystallizations, phase separations,

chromatography, distillations, and

processing aids/scavengers aid in

purging of elemental impurities and,

therefore, reduce the risk of carryover

into the finished drug substance from

stages earlier in the upstream process.

Areas for further consideration include

manufacturing equipment, processing

aids/inorganic reagents, solvents,

water, and packaging.

Manufacturing equipment. In

general, GMPs, including equipment

compatibility assessment and

qualification, are sufficient to ensure

that significant levels of elemental

impurities are not leached from

manufacturing equipment into

the drug substance. Hastelloy,

stainless steel, and glass are the

most commonly used materials of

construction for drug substance

manufacturing equipment, due to their

superior chemical resistance. Nickel,

cobalt, vanadium, molybdenum,

chromium, and copper are key

elements in some Hastelloy and

stainless-steel alloys. Under extreme/

corrosive reaction conditions, such

as high temperature and low/high

pH, these elements could have the

potential to leach from manufacturing

equipment. In such cases, it may be

necessary to supplement standard

GMP equipment compatibility

assessments with specific

studies to assess the elemental

impurity-leaching propensity from

manufacturing equipment due to

corrosive reaction conditions.

Other potential sources include

high-energy processes such as

milling/micronization equipment.

These are also generally considered

to be low risk, but should be

addressed via appropriate GMP

including cleaning records and visual

inspection. Particle size reduction

is discussed in the Drug Product

Manufacture section.

Processing aids/inorganic

reagents. Processing aids such as

charcoal, silica, celite, and darco, and

inorganic reagents such as sodium

chloride, magnesium sulfate, and

sodium sulfate, are often used in drug-

substance manufacturing processes

and may be used in significant

quantities. Depending on their specific

composition, inorganic reagents

should be considered within the risk

assessment, especially when ICH Q3D

elements are integral to the formula.

The levels used should also be

considered as some reagents may be

employed in higher relative amounts

(i.e., in stoichometric amounts). In

such instances not only the elements

(intentionally) present in the reagents,

but also reagent purity (or lack thereof)

need to be taken into account.

In general, the use of such reagents

presents a low risk. In studies

conducted within the organizations

associated with this article, there

is little evidence to support such

materials being a significant risk.

Therefore, the risk assessment should

primarily focus on processing aids

and inorganic reagents used late in

the drug substance manufacturing

process, and/or where aggressive

reaction conditions exist (e.g.,

extreme pH/high temperatures for

prolonged times).

Solvents. Most solvents used in

the manufacture of drug substances,

particularly those listed in ICH Q3C,

Impurities: Guideline for residual

Solvents (2) Class 3, are unlikely to

contribute elemental impurities to the

finished drug substance. The majority

of solvents are purified by distillation

and few involve the direct use of

metal catalysts in their manufacture;

hence, they are considered a low risk

source of elemental impurities. In the

event that solvents have not been

purified by distillation, especially if a

catalyst in used in their manufacture,

further evaluation in the risk

assessment should be considered.

Water. Refer to the environmental

factors discussion is the Drug Product

Manufacture section.

Packaging. Packaging is discussed

in the section Container-Closure

Systems (CSS) as a Potential Source

of Elemental Impurities in Finished

Drug Product.

Evaluation option limits. It

must be recognized that, from a

compliance perspective, the limits

for elemental impurities in ICH Q3D

One of the greatest challenges to performing an elemental impurity risk assessment for a drug product is to understand the potential contribution of elemental impurities from excipients.


ES582501_PTE0315_016.pgs 03.10.2015 22:55 ADV blackmagentacyan



apply only to the drug product. To

ensure effective control of the level

of elemental impurities in the drug

substance a number of options are

available:

• The ICH Q3D option 1 concentration

limits assume a maximum daily

drug product intake of 10 g/day.

Drug substances that meet option

1 concentration limits can be used

at any dose in the drug product.

• ICH Q3D option 2 concentration

limits are calculated specifically

based on the actual daily drug

product intake (and composition)

and may provide higher

concentration limits than option

1 (if the maximum daily intake of

drug product is < 10g).

The acceptable level of elemental

impurities in a drug substance may be

defined and agreed upon in a suitable

quality agreement between the drug

substance manufacturer and the drug

product manufacturer.

Conclusion for drug substancesWhile drug substance manufacturing

often involves a complex series of

processes, some simple scientific

principles can be applied to ensure

that elemental impurity levels in the

final drug substance are controlled

to appropriate levels. The application

of a risk-based control strategy,

involving an understanding of the

manufacturing process and key

sources of elemental impurities,

appropriate equipment selection/

qualification, adoption of suitable

GMP processes/procedures, and

the selection and application of

appropriate control options will

typically result in the manufacture

of drug substances with elemental

impurity levels well below ICH Q3D

option 1/option 2 concentration

limits. This overall low risk status

is supported by the emerging

dataset from ICP–optical emission

spectrometry (OES) and ICP–mass

spectrometry (MS) screening of a

wide range of drug substances plus

the significant body of historical

heavy-metals test data.

Excipients One of the greatest challenges to

performing an elemental impurity

risk assessment for a drug product

is to understand the potential

contribution of elemental impurities

from excipients. Elemental impurities

of concern for excipients would

typically be:

• Class 1 and Class 2a elements

potentially present at trace

levels in the excipient based on

environmental factors

• Intentionally added catalysts or

reagents for synthetic excipients

• Class 3 elements from excipients

that are targeted for a specific route

of administration (e.g., inhaled).

Unlike drug substances, there may

be less information available from

excipient vendors with respect to

the manufacturing equipment and

processes used (e.g., any high energy

steps, corrosive reagents, or added

catalysts), which may potentially

introduce elemental impurities.

While many vendors will supply, on

request, a compliance statement

with the European Medicines Agency

(EMA) metal catalyst guideline (3), the

elemental impurity testing reported

on the certificate of analysis is

typically based on a non-specific, wet

chemistry heavy-metals limit test

with the result reported as less than

the specification value in parts per

million. When considering the risk of

elemental impurities potentially being

introduced into the drug product via

excipients at levels greater than the

PDE, the following points should be

considered:

• Source of the excipient (mined,

plant, animal, synthetic, etc.)

• Excipient level in the formulation

(wt. %) (4)

• Drug-product daily dose.

Source of the excipient. The origin

of an excipient can have a significant

impact on the degree of risk

associated with elemental impurities.

Figure 3 provides a useful guide.

Mined excipients may exhibit a

natural variation depending on the

location of the mine and the natural

geology. The potential levels of

elemental impurities from mined

excipients may be more variable and

therefore pose a higher risk than

synthetic excipients manufactured

using metal reagents and/or catalyst

where the levels are less variable as a

result of well-defined manufacturing

processes and controls.

Excipients harvested from plants

also pose a potential risk as a result

of their uptake of metals from their

environment. Synthetic excipients

that are manufactured without

the use of metal catalysts and/or

reagents present the lowest risk of

introducing elemental impurities to

the drug product.

Proportion of formulation. An

essential consideration in determining

the risk contribution for elemental

impurities from an excipient is the

proportion of the excipient used in

the formulation. The risk contribution

from a mined excipient used as a filler

or diluent (typically >20 wt. % of the

blend), for example, will be greater

than the risk contribution of a mined

excipient used in a tablet film coat

(typically <5 wt. %).

Generally, low-weight percentage

components that are not mined

are regarded as low risk; however,

the daily product dosing and route

of administration also need to be

considered.

Dose/route of administration.

Dose and dosing regimens should

also be considered. A low, orally

administered, daily dose clearly

presents a lower risk than an inhaled

Figure 3: Potential sources of elemental impurities in excipients.

Elementalimpurities in

excipients

Mined(e.g., talc)

Synthesized with metal catalyst(e.g., mannitol)

Plant Origin(e.g., cellulose derivatives)

Animal origin(e.g., lactose & gelatin)

Synthesized without metal catalyst(e.g., colloidal SiO

2)

Increasing

potential risk of

contributing

elemental

impurities




product as shown by the lower PDE

limits for inhalation vs. oral found in

Table A.2.1 of the ICH Q3D guideline (1).

Conclusion for excipientsThe above principles can be used as

part of an excipient risk assessment

and are a useful guide in the absence

of data. In addition, manufacturers

should consider the principles for

controlling elemental impurity

generation from manufacturing

equipment, as described in the

Manufacturing Equipment section for

drug substances.

With the pending removal of United

States Pharmacopeia (USP) <231>

from the United States Pharmacopeial

Convention, however, uncertainty

exists as to whether excipient

manufacturers and vendors will test

for elemental impurity concentrations

and, if so, for what elements, to what

levels, and using what procedures/

equipment.

It must be recognized that, from a

compliance perspective, the limits for

elemental impurities in ICH Q3D only

apply to the drug product. Excipient

manufacturers may, however, be

requested to assist in assuring

compliance through awareness of the

level of elemental impurities within

the excipient itself. In addition, the

same general principles of evaluation

options for drug substances

described previously apply to

excipients.

In some instances, it may be

appropriate to define and agree on

the acceptable level of elemental

impurities in an excipient through a

suitable quality agreement between

the excipient manufacturer and the

drug product manufacturer.

Ultimately, it is the responsibility

of pharmaceutical manufacturers to

demonstrate, via risk assessment

and/or data, that the drug product

is compliant with ICH Q3D. To this

end, the development of a common

database for excipient elemental

impurity profiles will be a useful

activity to support risk assessments.

The International Pharmaceutical

Excipients Council of the Americas

(IPEC-Americas) and FDA have

performed an exercise examining

elemental impurity levels from

multiple excipients, which is planned

for publication. This information

indicates that the vast majority of

excipients (analyzed by ICP–MS)

contain elemental impurities at levels

unlikely to cause concerns at typical

usage levels in oral solid dosage forms.

Drug product manufactureThe drug-product risk assessment

needs to consider the potential

elemental impurity contribution

from the drug product

manufacturing equipment/process.

Manufacturing for solid products

encompasses a large variety of

processes, such as solid mixing

(blending), granulation, tableting

(compression), coating, and

particle size reduction. For liquid

product manufacture, dissolution

or suspension of solid excipients

and drug substance is often carried

out in metallic equipment. In

contemporary cGMP facilities, the

likelihood of additional contribution



of elemental impurities is negligible.

However, there is a theoretical risk

associated with Class 2A metals such

as vanadium, nickel, etc., because

these elements are commonly

found in manufacturing equipment;

for example, 316L stainless steel

contains approximately 10% w/w

nickel. Therefore, understanding the

drug product equipment in terms

of materials of construction will be

a key factor in completing the risk

assessment. The risk assessment

should focus on any steps involving

high kinetic energy (solids) or

corrosive liquids that may facilitate

the transfer of elements from the

equipment into the product.

A consideration of typical drug

product manufacturing steps and

conditions is provided in Table I.

Manufacture of liquid dosage

forms. Processing a liquid product

containing a drug substance,

excipients, and solvent (typically

water-based buffer) in metallic

vessels can potentially facilitate the

transfer of elements into the liquid

drug product, particularly at high/low

pH. An assessment of material

compatibility should be completed,

taking into account factors such as

ionic content, pH, temperature,

hyrdophilicity/hydrophobicity,

terminal sterilization conditions, and

contact time. Testing should only be

required if this assessment identifies

a substantive risk.

Conclusion for drug product manufactureIn general, the risk for elemental

impurity contribution due to processing

of solid drug product components

in cGMP facilities is low, as stated

explicitly in ICH Q3D. Although much

equipment used to process drug

product is metallic (e.g., stainless steel

vessel), the majority of the processes

used in drug product manufacture

can be discounted as a source of risk.

Even areas highlighted as needing

consideration (Table I) are expected to

only result in controls outside routine

cGMP in extreme cases.

Environmental factors As part of the holistic risk assessment

of elemental impurities described in

ICH Q3D, there is a need to consider

the potential contribution resulting

from environmental factors such as

water and air.

Table I: cGMP controls for selected operating conditions in drug product manufacture.

Unit operationKinetic

energy

Aggressive

conditions

Recommended routine

cGMP controlsRemarks

Mixing/ granulation

Low Dry = no NAe.g., Low equipment rotation/translation

speed

High (Shear) Wet = yes

Periodic visual inspection of

the equipment for abrasion

and/or corrosion.

Although the likelihood of a potential

elemental impurity contribution is increased

when moving from low shear mixing to high

shear mixing, the overall risk of a significant

elemental impurity

contribution remains low.

Tableting High NAPeriodic visual inspection, as

above.

Normal wear on dyes/punches is unlikely to

release any appreciable amount of elemental

impurities into the product.

Encapsulation High NAPeriodic visual inspection as

above.–

(Liquid) filling, lyophilization

LowProduct

specific

For aggressive, e.g.,high pH

conditions, regular visual

inspection of the equipment

for corrosion.

Effect of actual corrosion, as with tablet punch

erosion, unlikely to result in

substantive release of elemental impurities at

levels of concern into the product.

Coating Low LowCovered by routine cGMPs,

e.g., for maintenance, cleaning.–

Particle size reduction

High Very high

Despite the high energy it is

not expected that the particle

size reduction process will lead

to the need for routine drug

product testing requirements

for elemental impurities

associated with the materials

of construction of the mill. In

the vast majority of cases,

routine cGMP will be sufficient.

Although the possibility of metal transfer

during this process is high due to abrasion,

the risk of levels approaching the limits defined

in ICH Q3D is extremely low. Such a risk may be

evaluated through a mathematical

assessment, evaluating the theoretical

maximum level of metal possibly transferred

during the process, comparing this to the

permitted limits. Practical evaluation through

comparison of the elemental impurity profile

of the ingoing material to that of the outgoing

material may also be performed. Such an

assessment may also take into consideration

historical knowledge of similar processes and

substances. Such approaches may be used to

determine if further controls other than cGMP

are required.


ES582516_PTE0315_020.pgs 03.10.2015 22:55 ADV blackmagentacyan


Water. Water used in the manufacture of both drug

substances and formulated drug products is a potential

source of elemental impurities. The level of risk, however,

may be strongly related to the quality of water. This risk

was examined in detail in a USP stimuli article on water

for pharmaceutical use (5). The following position was

articulated:

• The source water used in drug product manufacturing

must meet the World Health Organization (WHO)

standard for drinking water. When this source water

is further purified in a contemporary plant to generate

purified water (PW) and/or water-for-injection (WFI), the

elemental impurity levels should be below acceptable

concentrations allowed for drug roducts using option 1

control strategy defined in ICH Q3D.

• As part of standard GMP, water quality should be routinely

monitored and the purification system and storage of the

water should not re-introduce elemental impurities.

Based on this position, the risk of elevated elemental

impurity levels within aqueous-based formulations—even

large-volume parenterals—is considered negligible. The

risk associated with the use of water in the manufacture

of the drug substance can also be effectively eliminated

through the appropriate use of WHO-standard potable

water combined with the use of USP purified water for

the final stage in the manufacture of the drug substance,

including its isolation.

Air. Air is not likely to present a substantive risk;

furthermore, air quality can also be managed through

proper GMPs via use of HEPA filtered air, etc. No specific

assessment is therefore generally required.

Container-closure systems as a potential source of elemental impurities in finished drug productOne of the potential sources of elemental impurities is

product packaging, often referred to as container-closure

system (CCS). In determining the risk posed by the CCS,

there are a number of factors that need to be taken into

consideration including:

• Nature of formulation—mechanism for contamination

• Level of metals present in the CCS

• Nature of risk: safety vs. quality risk

• Duration of storage (liquids).

In terms of the type of formulation, it is inconceivable that

substantive or even trace-level contamination would occur

where physical contact is limited to solid-to-solid contact.

This is entirely consistent with the FDA Guidance for

Industry, container closure Systems for Packaging human

Drugs & Biologics (6), which in relation to extractables and

leachables considers solid-to-solid contact of low risk. It

is, therefore, reasonable to conclude that any assessment

of risk associated with CCSs should be limited to those

associated with either liquid or semi-solid formulations.

The second aspect of any risk assessment of the CCS

involves an understanding of the potential levels of metals

present within the material concerned. A major review

of materials in manufacturing and packaging systems as

sources of elemental impurities in packaged drug products

was published in 2013 (7). The publication summarized

literature data for a number of common packaging

materials, including levels of elemental impurities within

the component material (determined by digestion), as well

as elemental impurities extracted from the component

materials. The data, while fragmentary, are nevertheless

comprehensive, and several key conclusions were drawn.

While certain materials were found to contain elemental

impurities, the presence of the elemental impurity was

Figure 4: Illustration of risk factors associated with packaging.

Limited solubility in

drug product

Limited interaction, buthigh metal content in

packaging

Good solubility in drug

product

Intimate contact, but low

metal content in packaging

Metal solubility in product

Meta

l co

nte

nt

in p

ack

ag

ing

Highest risk

High concentration of

metals in packagingHigh degree of interaction

between packaging and

drug product

Lowest risk

Low concentration of

metals in packagingLimited interaction

between drug product and

packaging

Elemental

impurities

from

packaging




predominantly associated with

deliberate use of metal catalysts,

for example the use of antimony in

the manufacture of polyethylene

terephthalate (PET). In the case of PET,

levels of antimony of approximately

50 ppm are typical (full digestion).

Focusing particularly on those

elements of high concern (Class 1 and

Class 2), only fragmentary data exist

to suggest even trace levels present

within the component material, for

example cadmium and lead levels up

to 100 ppm were reported in polyvinyl

chloride. Even when low levels of

elemental impurities are present in the

material itself, the effective ‘availability’

of the elemental impurity needs to be

considered. What is consistently clear

from the extraction data presented

is that extracted elemental impurity

levels (under relevant conditions)

are a minute fraction of the total

elemental impurity levels present in

the component materials, typically

<0.1% of that observed following

digestion. Therefore, even when trace

levels of certain elements are found in

the component material, the available

elemental impurity concentration may

represent an extremely low safety risk

(Figure 4).

There may, however, be potential

quality-related risks. Such risk

may result from potential metal-

catalyzed degradation of the product

in question. While the interaction

between packaging material and solid

dosage forms is negligible (ICH Q3D),

this may not always be the case for

non-solid drug products. Reported

examples include iron (8), nickel (9),

and tungsten oxide. In the case of

tungsten, this related to leaching from

the syringe barrel, causing protein

aggregation (10). As a consequence,

many biopharmaceuticals include

ethylenediaminetetraacetic acid to

“mop up” metals. Assessments of

such risks should be addressed on a

case-by-case basis.

Evaluations should thus focus on

liquid and semi-solid formulations.

Detailed leachable studies should only

be required where there is a lack of

elemental impurity extractives data for

the packaging components in question.

Analytical testingAnalytical testing for elemental

impurities is clearly an important

aspect of the assessment of elemental

impurities. It is not, however, within

the scope of ICH Q3D. The guideline

states that “Pharmacopoeial

procedures or suitable validated

alternative procedures for determining

levels of elemental impurities should

be used, where feasible.”

USP has developed General

Chapter <233> “Elemental

Impurities—Procedures” (11), and

the European Pharmacopoeia (Ph.

Eur.) has recently published general

chapter 2.4.20 “Determination of

Metal Catalyst or Metal Reagent

Residues” covering analytical testing

(12). USP <233> describes two

specific procedures for the evaluation

of the levels of metal impurities.

Importantly, it also describes criteria

Figure 5: Elemental impurity control strategy.

Yes

Yes

Yes

Yes

Yes

Is source of EIknown?

Has a risk beenidentifed?

Document:

Existing controls are adequate

and/or

rationale for not requiring EI testing

Justifcation for

higher PDE

Higher PDE

justifed?

Open discussions with

regulatory bodies

Defned control strategy

Risk assessment

Replace source

of EI?

Change control:

Justifcation for

replacement

Establish appropriate limit

for EI in the product

Identify source of

elemental impurity

Identify how EI level

will be controlled

Use engineering controls

Choose suitable

approach

Use specifcation

Monitor EI level with testing

Is the control

successful?

Is the control

successful?

Justifcation for

engineering controls

Justifcation for

periodic controls

Yes No

No

No

NoNo

No No




for the use of alternative procedures. Thus,

a flexible approach may be adopted in

terms of the analytical procedure, provided

the method concerned meets the required

acceptance criteria.

Control strategyA drug-product risk assessment can use

prior knowledge of the input materials to

demonstrate that the risk of significant

elemental impurity levels is low across

multiple batches. When the risk

assessment concludes that elemental

impurities are below 30% PDE, it should be

acceptable to rely on the quality system to

maintain the control of the process and the

existing use of standard cGMPs as a control

strategy of the drug product, without

requiring any additional element-specific

testing on each batch of product.

Other factors to consider could include:

• Security of external supply chain along

with a quality history (e.g., audit history,

levels of complaints, recalls, etc.) for

each vendor

• Control of vendor elemental impurity

specifications and elemental impurity

reporting on ingredient certificates of

analysis

• Security of internal supply chain.

It is anticipated that a properly executed

and documented elemental impurity

risk assessment for the majority of drug

products may justify the use of standard

cGMP as being a sufficient control strategy

to ensure levels of elemental impurities

meet the levels defined in ICH Q3D, without

the need for additional testing.

Where the drug product elemental

impurity risk assessment identifies the

need for additional elemental impurity

control, it is crucial to first understand

the potential source of the elemental

impurity(s). Once the source is known,

appropriate controls, in addition to cGMP,

can be applied. The flow chart in Figure 5

can be followed to help determine when

additional controls are required and what

those controls may look like.

Lifecycle managementProduct and/or process changes have

the potential to change the elemental

impurity content of the final drug product.

Therefore, their impact on the overall risk

assessment, including established controls

should be evaluated. Such changes could

include, but are not limited to, changes in

synthetic routes, excipient suppliers, raw

materials, processes, equipment, container

closure systems, or facilities. All changes

are subject to internal change management

process ICH Q10 Pharmaceutical Quality

System (13) and, if needed, appropriate

regional regulatory requirements.

ConclusionThe implementation of the ICH Q3D guideline

can be adequately achieved through

using an appropriate risk-based process

combined with existing GMP standards. A

risk assessment should be performed to

identify any elemental impurities that may

potentially be present at significant levels

in the drug product. Such an assessment is

then used to define an appropriate control

strategy. ICH Q3D allows the option that the

scope and extent of quality control testing

may be reduced, or even eliminated provided

there is adequate control. In many cases,

this can be successfully achieved through

the use of appropriate GMP controls both in

terms of input materials and manufacturing

processes, limiting testing to those areas

clearly identified as a substantive risk.

AcknowledgementsThe authors would like to thank Patrick

Drumm, Mark Schweitzer, and Darragh

Norton of Novartis, who also contributed to

the article.

References1. ICH, Q3D Guideline for Elemental Impurities

(2014).

2. ICH, Q3C Impurities: Guideline for residual

Solvents (2011).

3. EMEA, Guideline on the Specification Limits for

residues of Metal catalysts or Metal reagents,

EMEA/CHMP/SWP/4446/2000 (2008).

4. IPEC Americas, PDE Calculator, http://

ipecamericas.org/content/pde-calculator,

accessed 17 Feb. 2015.

5. T.S.A. Bevilacqua, “Stimuli to the

Revision Process: Elemental Impurities in

Pharmaceutical Waters,” Pharmacopoeial

Forum 39 (1) (2013).

6. FDA, Guidance for Industry: container

closure Systems for Packaging human Drugs

and Biologics (Rockville, MD, May 1999).

7. D. Jenke et al., PDa J Pharm Sci and Tech, 67,

354-375 (2013).

8. I. Beck-Speier et al., Particle and Fibre

Toxicology, 6, 34-36 (2009).

9. M. Schmidt et al., Nature Immunology, 11,

814-820 (2010).

10. J. Bee et al., J Pharm Sci, 98, 3290-3301, (2009).

11. USP General Chapter <233> ”Elemental

Impurities–Procedures” http://www.usp.org/

sites/default/files/usp_pdf/EN/USPNF/key-

issues/2013-12-27_233_pf40-2.pdf.

12. Ph.Eur. General Chapter 2.4.20, EDQM,

Strasbourg, France).

13. ICH, Q10 Pharmaceutical Quality System

(2008). PTE

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The ability of a biological formulation to maintain its physical,

chemical, and therapeutic properties is often put to the test during

transportation and storage. Because many cell-derived therapeutics

are administered by infusion or injection, lyophilization is a common

method used to keep the product viable. There are, however, many

factors that can influence the behaviour of a drug within a batch of

vials, and issues with maintaining biological activity and stability during

formulation. This article provides an overview of the factors that can

influence protein behaviour during lyophilization of a pharmaceutical

product and the ways in which manufacturers can reduce processing

costs and timelines.

Special considerations for cell-derived productsBecause proteins are prone to chemical and physical degradation,

aggregation events and potency loss of the product are common

challenges associated with the lyophilization of biologics. “While

lyophilization is done to achieve long-term stability, the process

itself can be quite destabilizing for the molecule,” says Mathew

Cherian, PhD, director and senior fellow, pharmaceutical development

Randi Hernandez

While the optimization of a lyophilization cycle for a biologic relies

on a well-characterized formulation, viscosity and aggregation after

product reconstitution must also be carefully managed.

Lyophilization Cycle Optimization ofCell-Derived Products

at Hospira. “Finding the optimal

cryoprotectant levels; the optimal

rate and extent of freezing; the

optimal pressure during primary and

secondary drying; and measuring

the extent of primary and secondary

drying” are crucial to ensuring a

good-quality final product. Changes

to the product, such as freezing,

concentration and pH shifts,

decreasing temperatures, and

desorption can cause irreversible

denaturation, adds Edward H.

Trappler, president of Lyophilization

Technology.

Protein stress. Although primary

freezing is believed to cause the

most stress to a biologic product,

degradation and the formation

of aggregates can occur at any

stage in the lyophilization process.

According to Martin Gonzalez, senior

group leader, One-2-One R&D at

Hospira, primary freezing can cause

pH shifts, super-concentration

of protein species, and exclusion

of solvents, which can result in

problems in protein thermodynamic

stability. This instability can cause

protein unfolding, denaturation,

or aggregation. Specifically, says

Cherian, the formation of a solid-

liquid interface due to the advancing

freezing front can generate

aggregates.

Dehydration stresses during

drying can also cause problems.

An emerging theory is that drying

increases surface area, and as a

result, the protein molecules on

the surface of the dried solute (i.e.,

those that are under mechanical

stress within the solid matrix) are

at a “greater risk for aggregation

or other negative consequences

upon reconstitution,” notes Jim

Searles, PhD, technical fellow,

global manufacturing science and

technology, Hospira. Proteins in

dried products, therefore, are not

as protected by the amorphous

environment of the inner matrix.

According to Kevin Ward, PhD,

director of R&D, Biopharma

Technology, the risks of protein

instability can be minimized by

“intelligent formulation design

and the use of excipients with

specific cryo- and lyo-protective

qualities.” Searles of Hospira points



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Editorial Director

Pharm Tech


Lyophilization

out that the “addition of a surfactant to

the formulation can mitigate interfacial

damage, and emerging science is showing

that post-drying, super-Tg [glass-transition

temperature] annealing can allow structural

relaxations in the lyophilized matrix that

result in stability improvements.”

To ensure optimal storage conditions

and preservation of structure for a freeze-

dried biologic, molecular mobility must be

minimized and suitable excipients selected,

according to Trappler. A sound formulation

is the first step, and then the formulation

must be protected from temperature

cycling, light, and oxygen. Vials should

be stored upright, packed with vibration-

absorbent secondary packaging, and

handled with care during shipping, notes

Cherian.

Other concerns lie in the post-

reconstitution risks that exist with

biologics. “Aside from the all-important

retention of activity, as clinical demand

for high-concentration formulations (>

100 mg/mL) continues, the formulation

scientist must be cognizant of increased

aggregation propensity as well as managing

viscosity after reconstitution,” says John

G. Augustine, PhD, principal development

scientist, analytical and formulation

development at CMC Biologics.

The most important step to control

instability during storage is to carry out

thorough preformulation work as early

as possible during the drug-development

process. This information can help inform

the downstream processing cycle, aid

future purification efforts, and help ensure

that the proper excipients to minimize

degradation and aggregation have been

selected, says Augustine.

Scale-up: Moving from the laboratory to a commercial facilityOne of the common mistakes in

lyophilization scale-up is to assume

that a laboratory-scale freeze dryer

containing a few hundred vials behaves

the same way as a production-scale freeze

dryer containing thousands of vials (1).

Commercial equipment capabilities can

vary widely depending on their design

specifications and their age. Equipment

differences and batch uniformity under new

temperature profiles must be considered

during processing when switching from lab

lyophilization experiments to commercial

lyophilization systems, says Trappler.

Equipment differences can create drying

rate differences and variations in the final

water content in the products. “Industrial

freeze dryers have larger chambers with

larger shelf dimensions,” says Ward. “This

leads to a reduction in radiative heating and

often an increase in intra-shelf temperature

profiles.”

As a result, sublimation rate capability of

the production equipment should be carefully

tested, note representatives from Hospira.

Product quality testing on at least one full

shelf of vials should be done on products

sampled from the edge as well as the interior

of the shelf on the drying unit, they note.

Additionally, vial handling, washing, and

depyrogenation characteristic of full-scale

manufacturing can weaken glass, making

vials susceptible to potential vial breakage.

Cost-saving effortsShortened lyophilization times.

Shortening lyophilization times is

economical and reduces cost-per-unit.

“Reducing the cycle time reduces the

energy costs per run, and also increases

the potential throughput of a facility by

maximizing the number of runs that can

be processed in a similar timeframe,”

comments Ward.

Oftentimes, altering the design space

can facilitate shorter drying times and help

with product output. This type of process

alteration, however, should occur while the

product is still in the lab, observes Hospira’s

Gonzalez. “It’s better to achieve cycle time

reduction before going into full commercial

operation, perhaps by spending a little bit

more time developing a robust cycle that

yields more in the long run,” he says.

The design space influences shelf

temperature, chamber pressure, and hold

time for each step of the lyophilization

cycle, notes Mark Nachtigall, PhD,

scientist, global manufacturing science

and technology, Hospira. The ideal

design space—one that will generate

optimal primary drying times—will allow

a product to remain as warm as possible

without collapsing. A shorter drying time

will also rely on the sublimation rate

capability of the lyophilizer, says Nachtigall.

To ensure optimal storage conditions and preservation of structure for a freeze-dried biologic, molecular mobility must be minimized and suitable excipients selected.

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Lyophilization

“Experimental exploration of these

parameters in combination with

statistical evaluation of the effects

of changes in the parameters will

help determine the optimal process

conditions,” he says.

According to Ward, the single

biggest influence on drying time

is the critical temperature of the

formulation itself. As a result,

designing a formulation with a high

critical temperature is the best way

to obtain better lyophilization cycle

times. Ping Ma, PhD, senior group

leader, global pharmaceutical R&D at

Hospira, however, says that increasing

shelf temperature would be the most

efficient way to reduce cycle time.

Robert Stoner, associate research

scientist, Global Pharmaceutical R&D

at Hospira agrees, saying, “Designing

cycles that run at warmer shelf

temperatures and higher pressures

reduces equipment stress with

greater facility/utilities savings.”

Another option would be to

lyophilize a more concentrated

solution (i.e., increasing API

concentration to reduce the amount

of solvent), because less water to

sublimate is correlated with shorter

lyophilization cycle times, note Stoner

and Ma. Manufacturers can also

reduce lyophilization cycle time by

reducing freezing hold time, says Ma.

Related cost-saving measures.

Other ways to create shorter

lyophilization cycle times include

increasing the vial size. Using taller

vials will allow more vials to fit into the

lyophilization chamber per batch, notes

Stoner. This method, however, may

have to be coupled with longer drying

times, as there would be smaller shelf

contact area and taller lyophilization

cakes. Lastly, reformulating with fewer

excipients can reduce cost as well,

suggests Gonzalez.

Influences on drying timeForm and function. The physical

properties set during the freezing

phase can influence drying time

greatly, says Nachtigall. These

properties include the size of the

crystals in the matrix and crystal form

of the frozen product. In general,

slower cooling produces larger, better

networked crystals, says Ward, and

the larger pores and more “open

structure” that is produced present

less of an impedance to vapor

migration during drying. Primary

drying and sublimation is accelerated

with larger crystal sizes. Ward warns,

however, that control is needed to

balance safety and efficacy, as some

biologic products are sensitive to slow

cooling. Additionally, total process

time may be adversely affected

because of larger crystal sizes, notes

Trappler. Larger crystals represent

a reduction in the surface area and

a decreased desorption rate, which

could mean the product would require

longer secondary drying times.

A primary drying rate can be

significantly influenced by an

additional annealing step, which

can improve the appearance and

homogeneity of the cake of the final

drug product and ameliorate the non-

uniform nature of freezing and drying.

A post-freezing annealing process has

been shown to increase the rate of

primary drying (1). “This is because

annealing eliminates the smallest ice

crystals through Ostwald ripening,”

asserts Nachtigall. “These ice crystals

leave channels as they dry that water

vapor lower in the cake will travel

through; larger channels equal less

resistance, and therefore, faster

drying times.” Crystal forms matter

as well, and annealing can promote

crystallization for those products

predispositioned to crystallize, he

adds. “A crystalline product matrix

typically has a higher collapse

temperature than an amorphous

one,” which allows for higher drying

temperatures, and subsequently,

faster drying times.

Controlled nucleation. While

obtaining larger ice crystals and a

reduced surface area through the

use of controlled nucleation has been

shown to improve reconstitution

times and reduce the primary drying

time for concentrated proteins

and antibodies, there is still some

uncertainty as to whether controlled

nucleation is truly a benefit to

biologics, according to Trappler. He

says, “Preliminary data show there

is no detrimental effect in the initial

critical quality attributes (CQA) of

the protein preparation,” but that

the “complete impact on CQA can

only be confirmed from the results

of long-term stability tests.” Even

though controlled nucleation offers

some process benefits, investigators

may be able to better control for

differences in freezing and drying

with better glass vial “bottom

geometry,” says Trappler. “Even

with controlled nucleation, there are

differences in ice crystal growth as

well as consistency during drying due

to vial bottom contour.”

With controlled ice nucleation-

formed cakes, the rate of sublimation

is greater than in cakes formed as

a result of uncontrolled freezing.

“From a clinical standpoint, for highly

concentrated protein formulations,

a reduction in reconstitution times

can be observed in cakes produced

under controlled nucleation,” says

Augustine.

Regardless of what methods

are used to control for differences

in freezing behaviour and prevent

non-uniform drying of batches of

biologics, there will always be some

variation in product heterogeneity,

says Ward. These differences can be

due to differences in temperature

control across a shelf or variations

in vapor flow across a chamber, he

points out.

Know your characters. Process

engineering for lyophilization relies

on adequate characterization

of a formulation. To figure out

the parameters for adequate

solidification and the threshold

temperature required to maintain

product structure, a suite of tests and

preformulation tests, such as studies

of solubility, pH effect, stability

in solution, and low-temperature

analysis should be conducted, says

Trappler. “Use of freeze-drying

microscopy—an insightful method—

coupled with low-temperature

differential scanning calorimetry and

electrokinetic or electrical resistance

measurement” is essential to the

The single biggest influence on drying time is the critical temperature of the formulation itself.



Lyophilization

formulation characterization process, he adds. Ward echoes

these sentiments, saying that freeze-drying microscopy is the

only method for determining collapse temperature, and thermal

analysis can identify glass transitions and other events such as

eutectic melting and crystallization. “Without this information,”

he says, “cycle development is very much a trial-and-error

process.”

Hospira’s Ma points out that characterization tools “enable

[drug developers] to better understand each composition

and its physicochemical interactions in formulation,

optimize formulation process parameters, evaluate overall

risk assessment, and establish in-process and final release

specifications” for each formulation.

Future focus: Intelligent formulation designQuality by design (QbD) is built into a well-characterized

formulation. Thus, a product in development must be tested

for collapse temperatures, sensitivity to freezing rates, and

stability against excess moisture, among other factors, says

Gonzalez. “For lyophilization, this [the QbD approach] usually

means the designation of freezing rates, temperatures,

pressures, and hold times as critical process parameters,”

he says. “With so many parameters, one must fully leverage

process understanding to decide which combinations of these

to test in laboratory runs. It is also important to make use

of process analytical technology, such as instruments that

indicate completion of primary and secondary drying.”

Advances in protein characterization methods may allow

greater assessment and insight in the development of

formulations and processes for biologicals, says Trappler.

He lists light scattering, size-exclusion high-performance

liquid chromatography, dynamic light scattering, right-angle

light scattering, infrared, and nuclear magnetic resonance as

important analytical tools of the trade.

For biologics, the development of standard platform

technologies may help companies optimize formulations

and processing procedures. Companies are now developing

such platforms for evaluating molecules with a risk-based

approach, says Lisa Cherry, senior group leader, global

pharmaceutical R&D at Hospira. Molecule formulation

development and manufacturability are increasingly being

driven by prior knowledge gleaned from similar molecules. “For

formulation development of lyophilized biologics, there are

relatively few combinations of excipients in currently licensed

products,” notes Cherry. Starting within this formulation

design space will offer a high probability of success, she says.

“While formulations are being screened, one should use a

conservative (and therefore long) lyophilization cycle, which

can then be optimized once the final formulation candidate(s)

are selected.”

Reference1. B.S. Chang and S.Y. Patro, “Freeze-drying Process Development for

Protein Pharmaceuticals,” in Lyophilization of Biopharmaceuticals,

H.R. Constantino and M.J. Pikal, Eds. (2004), pp. 113-138. PTE

The development of standard platform technologies may help companies optimize formulations and processing procedures.

Frankfurt am Main · 15 – 19 June 2015

Be informed. Be inspired. Be there.

➢ World Forum and Leading Show for the Process Industries

➢ 3,800 Exhibitors from 50 Countries

➢ 170,000 Attendees from 100 Countries

www.achema.de


API SyntheSIS & MAnufActurIngM

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The market for formulated drugs based on highly

potent active pharmaceutical ingredients

(HPAPIs) is growing at a rapid pace, largely due

to the development of highly targeted therapies

based on antibody-drug conjugates, which can

include cytotoxic small-molecule components. The

manufacture of this expanding field of HPAPIs is

challenging and requires specific know-how, facilities,

equipment, and procedures designed to mitigate

the risk associated with producing and handling

potent compounds. Standards and technologies

are continually changing, and HPAPI manufacturers

must remain vigilant and prepared to adopt and

implement the latest designs, equipment, training,

and procedures to reduce the risks posed by HPAPIs.

Dealing with uncertaintyAlthough many challenges exist for high-containment

API manufacturing, the variability and uncertainty

associated with each compound present the greatest

risks, according to Waldo Mossi, general manager

of Helsinn Advanced Synthesis. “The importance of

occupational exposure limits (OELs) is widely neglected

in discovery research and early development,” he

states. He explains that many companies use a one-

size-fits-all approach to handling and managing the

containment of bulk drug substances. Each individual

process, however, offers different challenges, and

no two new chemical entities (NCEs) are alike. The

situation is aggravated by the lack of universally

accepted definitions for various compound types,

such as highly active, highly potent, and cytotoxic

agents, which can lead to confusion between sponsor

companies and custom-manufacturing organizations

(CMOs), according to Mossi.

To manage the variation and address the

uncertainty associated with new substances,

Helsinn continues to strive for design of toxicology

testing and safety evaluation from the early stages

of process development. The company also uses

a comprehensive, science-based OEL evaluation

approach from the start of an HPAPI project, and

works with experienced industrial hygienists to assign

initially conservative OELs to each potent compound

that will enter its facility. “Since a certain level of

risk will always exist when working with HPAPIs, it

is important to foster a strong company culture of

excellence in protecting employees, products, and

the environment. Our comprehensive approach to

process and compound evaluation helps to clearly

define the needs and objectives in handling each

process step,” Mossi observes.

Fortunately, as an HPAPI project proceeds through

the development lifecycle and into clinical trials, the

understanding of the risks associated with the potent

compound increases and risk mitigation generally

becomes less difficult, according to Patrick Klipstine,

director of SAFC’s Madison, WI site. “During the

development process, SAFC pursues ongoing internal

evaluations and works with third parties to bolster

this process. As the definition of potency becomes

better defined during the development cycle, our

process engineers and environmental, health, and

safety (EHS) representatives can make appropriate

modifications to the manufacturing engineering

controls,” he notes.

Manufacturing and process continuity are also

crucial during scale up to ensure that risks are

minimized, according to Mossi. “Laboratories and

small-scale GMP equipment should be designed so

that they are aligned with the large-scale equipment

used for commercial production in order to ease the

transition and reduce uncertainty and risk during

scale up,” he says. At Helsinn, the risk associated

with scale up is reduced through facility design and

investigated during early design-of-experiment (DOE)

analyses.

More than chemistryIn any chemical manufacturing plant, the protection

of operators is a top priority. In facilities producing

HPAPIs, providing operator protection is absolutely

critical and the top priority, according to Klipstine,

which means that appropriate engineering controls

are in place and personal protective equipment is

available. In addition, every unit operation must be

considered with regard to both the chemistry and

potential occupational exposure. “Chemical

processing steps are evaluated on their merits with

regard to sound chemical process hazard criteria, and

Protecting workers, patients, and the environment requires advanced technologies.

Minimizing Risk during HPAPI Manufacture

cynthia A. challener, PhD,

is a contributing editor to

Pharmaceutical Technology.



API Synthesis & Manufacturing

30 Pharmaceutical Technology Europe March 2015 Pharmtech.com

considerations for personal protective equipment when handling cytotoxic drugs

Cytotoxic drugs are widely used in the healthcare industry. However,

whilst effective in treating diseases, the toxicity of these drugs can

present a significant health risk to the manufacturers, pharmacists,

and other healthcare professionals who handle them. Occupational

exposure can occur in many ways; staff are at most risk when

preparing the cytotoxic drugs. The greatest hazards arise through

the formation of dusts (e.g., in the event of defective injection vials

containing dry solids), liquids (e.g., on transfer and dispensing of

the dissolved substance), aerosol formation (e.g., when dissolving

the dry solids), or when containers containing cytostatics are

inadvertently dropped. Once exposed, a wide range of potential side

effects could occur, including abdominal pain, vomiting, and allergic

reactions. To mitigate the risk of exposure, it is vital that companies

involved in the manufacturing and handling of cytotoxic drugs

ensure that staff are given the highest possible levels of protection.

Cytotoxic drugs are hazardous substances as defined by the

Control of Substances Hazardous to Health Regulations 2002

(COSHH) [www.hse.gov.uk/healthservices/safe-use-cytotoxic-drugs.

htm]. Under COSHH regulations, employers must assess the risks

from handling cytotoxic drugs for employees and take suitable

precautions to protect them. This includes carrying out a full risk

assessment that will identify any potential hazards, define who may

be harmed and how, as well as flag up if existing precautions are

adequate or whether more could be done. Risk assessments should

continue to be carried out periodically to ensure that the protective

measures are still suitable.

controlling exposure It is important that all possibilities of removing the hazard

altogether are exhausted before considering ways of limiting staff

exposure. The following hazard-control hierarchy can be used as

a guide to good practice:

• Eliminate—remove the risk altogether if possible.

• Substitute—find a safer substitute (e.g., a less toxic material or a

different working method).

• Safeguard—put technical solutions in place that protects the

worker (e.g., mechanical ventilation, machinery guards, and

remote controls).

• Warn and educate—implement worker training and install

suitable alarm and warning systems.

It is the responsibility of management to implement safe working

methods and to reassess procedures in response to changing

conditions such as the emergence of new hazards. However,

employees must also be trained and educated to accept responsibility

for identifying risk situations and for taking the necessary safety

precautions. This includes a responsibility for using the personal

protective equipment (PPE) provided in the correct manner and being

aware of its use, its limitations, and its correct disposal.

choosing the optimum PPe PPE is the final line of defence when it comes to protecting

personnel from toxic substances. PPE, whilst primarily intended

to prevent the body from coming into contact with hazardous

chemicals and dusts, also plays a vital part in protecting the

manufacturing process from human contamination, including hair,

shedding skin, and clothing fibres. As such, it is a crucial safety

measure that cannot be compromised. The following factors should

be considered when choosing coveralls and protective garments.

Protection from particle intrusion. Barrier efficiency against

migrating particles, such as those from clothing or human skin,

is a crucial performance feature when working with cytostatics.

When determining the level of protection from particle intrusion,

it is important to look at the Type 5 test results. The Type 5 test

specifies the minimum requirements for chemical protective

clothing resistant to penetration by airborne solid particles. To test

particle intrusion, the Type 5 test method uses sodium chloride

particles at 0.6 micron sizes suspended in a fine spray in a test

chamber. The 9-minute test (3 minutes standing, 3 minutes walking,

and 3 minutes squatting) is repeated on 10 suits. To pass the test,

eight out of the 10 suits tested must have on average less than 15%

inward leakage into the suits. This means that coveralls that have

passed the Type 5 test offer a certain level of protection against

fine particulates. It is important to choose a coverall that offers

the lowest level of inward leakage for the best possible protection

when working with cytostatic drugs.

Material. While most coveralls look similar, the material used

makes a difference in determining the end protection level. There

are three common types of material: microporous film (MPF),

spun bond–melt blown–spun bond (SMS) and Tyvek (DuPont),

which is a synthetic material made out of flashspun high-density

polyethylene fibres. When tested against BS 6909, these materials

perform differently. MPF (sometimes known as LMPF) is made

using a spunbond polypropylene and a film of polyethylene. Due

to the structure of the material, it is not breathable and has a

high particle shed count. SMS is a breathable material but has

poor liquid repellency. Due to the short fibres in the material, it

sheds fibres quickly and is, therefore, unsuitable for cleanroom

environments. Tyvek, manufactured only by DuPont, is made up

of ultrafine endless high-density polyethylene fibres using specific

spinning and bonding technology. Because of the endless fibres, it

has a low particle shed count.

comfort. Whilst protecting both the worker and the process

is crucial, a further, important issue is having coveralls that are

comfortable. If workers are comfortable, they are more willing

to wear the protective garments and protection is, therefore,

heightened. The garments should ideally be designed to be durable

enough to allow for a range of movement and flexibility, without

compromising safety through ripped seams. At the same time, the

fabric should offer sufficiently high levels of permeability to both air

and water vapour to allow it to “breathe.”

The German Apothekenbetriebsordnung (ApBetrO, regulation on

the operation of pharmacies), which has been in force since June

2012, has also set out specific hygiene conditions for working with

cytostatics. According to the regulation, protective clothing must

also comply with the following requirements:

• Liquid-tight at arms and front

• Long sleeves

• Closed at the front

• Tight seal at cuffs

• Low-linting

• Barrier against pure and dilute cytostatics as well as fine particles

• Smooth surface (prevents particles from adhering to the surface)

• Optional: comfortable to wear, antistatic treatment, sterilizable.

Ian Samson, DuPont consultant for the EMEa and russia

regions, www.chemicalprotection.dupont.co.uk.

ES582366_PTE0315_030.pgs 03.10.2015 22:26 ADV blackyellowmagenta

API Synthesis & Manufacturing

then each process is developed to

allow for the safest execution of the

process within the identified

equipment train, taking into

consideration compatibility with

materials of construction, thermal

output, gas evolution, waste stream

management, etc.,” Klipstine notes.

With these considerations taken into

account, SAFC then applies

engineering controls for containment

to mitigate the risk for occupational

exposure. Specifically, the company

has adopted a risk-minimization

strategy that is systematically

constant, but allows for different

outcomes depending on the

chemistry and potency of each API.

“Each opportunity that turns into

a project goes through a defined risk

assessment process, with experts

in our process development, EHS,

and process engineering groups

closely collaborating to provide a

robust process from both a chemical

engineering and process engineering

standpoint. One of SAFC’s first

principles is that all processing of

powders and liquids are conducted

in closed systems that have been

verified to be effective for the

prevention of occupational exposure.

Second tier to these systems are

robust training programs that have

been designed for specific unit

operations,” he adds.

Helsinn also emphasizes the use

of fully closed systems and isolation

to avoid or mitigate areas of greatest

risk. The company fosters the

approach of contained chemistry,

which means that equipment for each

individual process (e.g., balances,

rotary dryers, pressure filter dryers,

and slurry vessels) is installed inside

an isolator that has been qualified

for occupational exposure levels

down to nanogram levels according

to the International Society for

Pharmaceutical Engineering’s

(ISPE) Standardized Measurement

of Equipment Particulate

Airborne Concentration (SMEPAC)

methodology. The use of such an

approach, according to Mossi, was

made possible by a clean atmosphere

design supported by accurate general

ventilation using double-pass, high-

efficiency particulate arrestance

(HEPA) filtration.

It should also be noted, according

to Mossi, that in addition to variable

chemistry, operational risk depends

greatly on several factors, including

the company culture, personnel

training, proper operational

execution, and the design and

engineering of the facility. In general,

the greatest challenges are typically

associated with operations such

as sampling, loading/unloading

of the reactor, and transfer of the

material. “Powder handling presents

the highest probability for potential

worker exposure, and it is important

to carefully study optimal methods for

minimizing and, wherever possible,

removing powder handling operations

from an HPAPI process,” he states.

At Helsinn, if powder handling is

necessary, effective and consistent

safeguards are factored in with

redundancies to mitigate the risk

even further.

SAFC handles both liquid and

powder HPAPIs under a defined set

of unit operations to minimize the

potential for occupational exposure.

“By using one common system

defined appropriately for scale to

ensure containment, our chemists

can be assured that the processes

they are executing are appropriately

identified for the defined potency,”

Klipstine explains. To reduce risk, all

large-scale isolation of powders is

conducted in jacketed filter dryers

where solids can be filtered and dried

without the necessity for discharge

from the drying unit operation.

Once dry, the HPAPI is discharged

using glove-box containment

techniques directly into predefined

drug-substance packaging using ILC

Dover continuous liner technologies,

according to Klipstine. As a best

practice, Helsinn investigates each

manufacturing process step for

hazard and safety together with the

aid of an outside industry expert as

part of its DOE analysis.

cross-contamination preventionOf significace to HPAPI producers

is having a thorough understanding

of the cleaning procedures required

to meet allowable carryover limits

for multipurpose equipment,

according to Klipstine. “Controlling

cross-over contamination mitigates

any potential risk to patients,” he

asserts. Mossi agrees that safety

cleaning verification at each stage of

a manufacturing process and GMP

cleaning validation is crucial. SAFC’s

philosophy is to apply a continuous

improvement mentality so that its

systems will exceed current industry

standards. Even so, one challenge the

company faces regularly as a CMO

with a multipurpose facility relates

to servicing customers ranging from

virtual biotechnology firms to large

pharmaceutical manufacturers that

have a wide range of expectations

regarding handling and cleaning

verification.

constant evolutionAnother challenge for CMOs that

offer HPAPI manufacturing services

is the continual evolution of industry

standards and technologies.

“Companies that want to participate

in this market must adopt these

newer technologies,” Klipstine

asserts. SAFC, for example, had to

transition to more robust analytical

technologies with improved

sensitivity and detection levels

that allow for the determination of

potential API carryover at part-per-

billion levels.

On the other hand, as the industry

continues to mature, consultants and

innovative equipment manufacturers

can help design state-of-the-art

engineering controls to better

suit specific facility containment

requirements, according to Mossi.

He notes that Helsinn’s recent facility

expansion was custom-designed

to support workflow, ergonomics,

and safety, while containing several

unit operations within only a few

isolators. Pte

In addition to variable chemistry, operational risk depends greatly on several factors, including the company culture, personnel training, proper operational execution, and the design and engineering of the facility.


ES582369_PTE0315_031.pgs 03.10.2015 22:26 ADV blackyellowmagenta


PEER-REVIEWED

I. Jones is founder and CEO of Innopharma Labs, jonesi@

innopharmalabs.com; Matti-Antero Okkonen is research team

leader, VTT Research Centre of Finland; A. Greene is senior

lecturer, School of Chemical and Pharmaceutical Sciences,

Dublin Institute of Technology, Kevin Street, Dublin 2, Ireland; and

P.J. Cullen is senior lecturer, School of Chemical Engineering,

UNSW Australia, Sydney NSW 2052 Australia.

Submitted: Feb. 18, 2014. Accepted: May 2, 2014.

Monitoring Fluid-Bed

Granulation and Milling Processes

In-Line with Real-Time ImagingI. Jones, Matti-Antero Okkonen, A. Greene, and P.J. Cullen

The pharmaceutical manufacturing platforms of

fluid-bed granulation and milling are widely used

to modify particle size. However, the adoption of

process analytical technology to monitor and control

these processes is difficult because of their dynamic

nature. This study examines the efficacy of a particle

characterizing technology to capture particle images

under dynamic conditions and to calculate particle

size distribution data both in-line and at-line during

fluid-bed granulation and milling.

Granulation methods are used in the pharmaceutical

sector to enlarge and densify small powder particles

into larger ones, typically to improve powder flow so that

the material can be processed effectively and efficiently

into solid dosage forms. In addition, granulation methods

are important for “locking in” the API within the formulation,

thereby reducing the risk of segregation. Granulated material

is attained by direct size enlargement of primary particles or

size reduction from dry compacted material (1).

Granule properties play a pivotal role in the f inal

performance of the tablet; for example, granule size can affect

the flowability and hence the average tablet weight and weight

variation. The effect of granule size and size distribution on

final blend properties and tablet characteristics is dependent

on formulation ingredients, their concentration, and the type

of granulating equipment and processing conditions employed.

Granulation and sizing of granulation are therefore critical unit

operations in the manufacture of oral solid dosage forms (2).

Granulation methods can be divided into two types—wet

methods, which use some form of liquid to bind particles

together, and dry methods, which do not use liquid (1).

The objectives of this study were to assess the ability to

measure particle size distributions under static (offline) and

Figure 1: Image of Eyecon particle characterizer

on a Glatt fluidized-bed granulator.S

UN

NY

/D

IGIT

AL

VIS

ION

/GE

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GE

S

CITATION: When referring to this article, please cite it as I. Jones et

al., “Monitoring Fluid-Bed Granulation and Milling Processes In-Line

with Real-Time Imaging,” Pharmaceutical Technology 39 (3) 2015.



Real-Time Imaging

dynamic (on-line) conditions for milled and fluidized particles

as well as to determine the following:

• A correlation with known particle size ranges for certified

ceramic spheroids for at-line benchtop analysis

• Acquisition of high resolution images during a dynamic

manufacturing environment

• The tracking of a fluidized bed process within a fluid-

bed granulator and the ability to monitor the wetting,

agglomeration, and drying phases of granulation

• A correlation between mesh size reductions and particle

size distribution for polyvinylpyrrolidone (PVP) during cone

milling.

Materials and methods

For the off-line analysis, aluminium oxide (Al2O

3) ceramic

microspheres (Brace GMBH) of size ranges 212–250 µm,

500–560 µm and 900–1120 µm were tested to determine

the precision of the instrument. For in-line evaluation within

0.05

0.045

0.04

0.035

0.03

0.025

0.02

0.015

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0.005

0

0.004

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1600

1400

1200

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0

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0

0 200 400 600 800 1000 1200 1400 1600

100 200 300 400 500 600 700 800 900 1000

50 100 150 200 250 300 400 500

Eyecon Data

Normal Distribution ofSpecifcation

Eyecon DataNormal Distribution ofSpecifcation

Eyecon Data

Normal Distribution ofSpecifcation

Al2O

3 sintered spheres 212µm and 250µm

(a)

(b)

(c)

Al2O


Chart Al2O


350 450

Figure 2: Particle size distribution and images of Al2O

3-sintered spheres, (a) 212 µm–250 µm, (b) 500 µm–560 µm,

(c) 900 µm–1120 µm.

AL

L F

IGU

RE

S A

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UR

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OF

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E A

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Real-Time Imaging

a fluidized-bed chamber, a

placebo of microcrystalline

cellulose (Avicel) and lactose

was granulated. Four granu-

lation experiments were car-

ried out in a laboratory scale

f luid-bed granulator (Glatt,

model GPCG15). The formu-

lation comprised of 33.33%

Avicel 101 (BASF), 66.66% lac-

tose 200 (Meggle). The spray

solution comprised of water

and 5.5% PVP 90 (supplier

BASF) with an addition rate

of 220 g/min using a Watson

Marlow 505S peristaltic pump.

Measurements were taken in

real-time and the granulate

growth per batch was evalu-

ated. For the in-line evaluation

of the rotary milling process,

granulate that was processed

by twin-screw granulation and

fluid-bed drying was meas-

ured during rotary milling.

During this study, granules

of PVP (Kollidon 30, supplier

BASF) were milled through

mesh sizes of 2000, 1575, 1397,

and 991 µm.

The imaging technology (the

Eyecon particle characterizer)

employed in this study is

based on high-speed machine

vision. It enables the capture

of both size and shape of

par t icles between 50 and

3000 microns. A continuous

i m a g e s e q u e n c e o f t h e

particles is captured using

il lumination pulses with a

length of one microsecond

for freezing the movement of

particles that are moving at

a speed up to several meters

per second. The illumination

is arranged according to the

p r inc ip le o f photomet r ic

stereo for capturing the 3-D

features of the particles in

addit ion to a regular 2-D

image. The particle size is

calculated from the images

u s i n g t h e 2 - D a n d 3 - D

information, applying novel

image ana l y s i s metho ds

145

140

135

130

125

120

115

110

(a)

(b)

(c)

480

460

440

420

400

380

360

340

320

300

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170

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150

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Batch 1

Batch 2

Batch 3

Batch 4

Batch 1

Batch 2

Batch 3

Batch 4

Batch 1

Batch 2

Batch 3

Batch 4

End point

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97

Part

icle

siz

e (

µm

)Pa

rtic

le s

ize (

µm

)Pa

rtic

le s

ize (

µm

)

Measurement points

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97

Measurement points

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97

Measurement points

D10 granule size for four repeat batches

D90 granule size for four repeat batches

Mean granule size for four repeat batches

Figure 3: Particle size results from fluid-bed granulation platform. Green

bars indicate the commencement phase of granulation, completion phase of

granulation, and the end point of granulation.


Pharma Supply Chain Security:Are You in Control?

Who Should Attend:

n Chemist, Scientist, Researcher

n Vice President, Director, Manager,

and Group Leader for Research,

Development, Discovery, Quality

n Vice President, Director, Manager,

Buyer of Purchasing, Sourcing,

Supply, Outsourcing


Register for free at www.pharmtech.com/security

EVENT OVERVIEW:

Recent regulations, including the U.S. Drug Supply Chain

Security Act, the FDA Safety and Innovation Act and the EU’s

Falsifed Medicines Directive, require that drug manufacturers

have more control than ever over their supply chains and

the quality and safety of APIs, and contractors that make

them. New requirements require a change in thinking,

from the broadest supply chain management concepts, to

the most granular, including audits, quality agreements and

maintaining supplier records.

Control assumes close communication and awareness, from

the time a supplier or services provider is selected. n Can you ensure compliance and prevent legal

liability?

n How strong are your auditing and communication

practices?

n How closely do you monitor practice and

performance?

n How efective are your legal agreements?

In this webcast, an expert on pharma and biopharma

supply chain management and security will look at new

regulations and enforcement, and what it means for you and

your business.

You Will Learn:

n The major factors that can compromise your chemical

ingredient supply chain.n What you can do to minimize these risks.

n How to identify and select a reliable and trustworthy

supply chain partner.

BONUS

CONTENT:

Attend to receivea FREE executive

summary of the webcast

For questions,

contact Sara Barschdorf at

[email protected]

Presenter

HEDLEY REES Managing ConsultantPharmafow Ltd

Moderator

AGNES SHANLEYSenior EditorPharm Technology

ON-DEMAND WEBCAST (Originally aired 25 February, 2015)



Real-Time Imaging

and direct geometrical measurement. As the approach is

based on direct measurement instead of indirect, such

as laser diffraction, there is no need for material based

calibration. In addition, the method is non-contact and

can be applied, for example, behind a view glass on a

granulator without physical modification of the process

equipment. Direct imaging technologies may be considered

more accurate methods of measurement compared with

laser and sieve analysis techniques because of the two

dimensional method of measurement. These advantages

of non-product contact and more accurate size estimation

for in-line measurement are considered beneficial to the

pharmaceutical development

and manufacturing sector

where reduct ion of cross

cont aminat ion r i sks and

accuracy of measurement are

paramount. Figure 1 provides

an example of an integrated

technology on a Glatt fluidized

bed granulator.

Results and discussion

Summar y of data f rom

benchtop, fluidized bed and

milling platforms

Experiment 1: Benchtop

evaluation. Figures 2a, b,

and c show the size distri-

butions from Al2O

3-sintered

spheres plotted against their

certified size ranges. The red

line indicates a normal distri-

bution of the sample based

on defined lower and upper

range specif ications to 3σ.

Representative images for

each distribution are also pre-

sented. During experiment 1,

the at-line benchtop analysis

using certified Al2O

3-sintered

spheres of known size distri-

butions indicates a signif i-

cant level of accuracy of the

imaging technology. Figures

2a, b, and c indicate that a

minimum of 91% of spheres

were calculated as being

within the pre-defined sup-

plier certified specifications.

The number of Al2O

3-sintered

spheres measured were 4572

(212 µm–250 µm), 440 (500

µm–560 µm), and 314 (900

µm–1120 µm). Because of

the tight certif ied distribu-

tion range for these samples, it was deemed that a low

sample population was acceptable. A larger data set may be

required if greater variability is present within the sample set,

for example, when evaluating granulates or milled materials.

Experiment 2: Fluidized bed evaluation. Figures 3a, b,

and c show the D10 and D90 (i.e., the diameters at which

10% and 90% of the samples mass is comprised of smaller

particles and mean particle distributions during fluid-bed

granulation trials. All fluid-bed granulation trials were circa

40 minutes in duration. Graphs illustrating the D10, D90,

and mean indicate the wetting, agglomeration, and drying

phases that are typical of a fluid-bed granulation process.

120010008006004002000

(a)

(b)

(c)

(d)

00:00 00:17 00:35 00:52 01:09 01:26 01:44 02:01

dia

mete

r (µ

)d

iam

ete

r (µ

)d

iam

ete

r (µ

)d

iam

ete

r (µ

)

120010008006004002000

120010008006004002000

Time

00:00 00:17 00:35 00:52 01:09 01:26 01:44 02:01

Time

00:00 00:17 00:35 00:52 01:09 01:26 01:44 02:01

Time

120010008006004002000

00:00 00:17 00:35 00:52 01:09 01:26 01:44 02:01

Time

D90 Run 1 2000 µm mesh




Figure 4: A summary of results from rotary milling platform. D10 and D90 are the

diameters at which 10% and 90% of the samples mass is comprised of smaller particles.



Real-Time Imaging

Other D values (D25, D50, and D75) were also tracked

and similar profiles were identified. During the process,

the technology successfully captured images, measured

granulate size, and tracked a typical fluid-bed granulation

process. The granulate size for all four batches reflected the

typical granulate growth profile for a fluid-bed granulation

process, including the wetting, agglomeration, and drying

phases. The granulation growth trajectory (3) and end points

(as illustrated in Figure 3a) could be monitored with this

data. The variability between batches 1 and 4 versus 2 and

3 is most likely linked to variability in humidity levels during

the trials as the dew point was not a controlled parameter

and all other parameters remained fixed. These changes

were confirmed through off line sieve analysis.

It can be seen from the particle size data illustrated in

Figures 3a–3c that the dried granulate is of a smaller size

compared to wet granulates earlier in the agglomeration

process. This observation is to be expected when

considering the removal of moisture and granule-granule

attrition during the fluidized bed drying phase. All of the

information presented in Figures 3a–3c could be used to

develop, model, and control fluid-bed granulation processes.

Experiment 3: Rotary cone milling evaluation. Figures

4a, b, c, and d show the results achieved with the imaging

technology during a rotary cone milling evaluation. The

technology was capable of detecting the reduction in particle

size of the milled material as the mesh size was reduced

from 2000 µm to 991 µm as measured with D90 values. A

positive correlation (weighted R2 = 0.8696) was calculated.

The reduction in particle size was also evident in the

images that were captured during each milling run. A

sample of images are included in Figures 4a–4d. There

is a visible reduction of larger

particles as the mesh size was

reduced.

It can be seen in Figure 5

that the level of particle size

variability reduces with the

reduction in mesh sizes. Run

1 with a mesh size of 2000 µm

mesh generated a D90 particle

size range from 385 µm to

1196 µm (standard deviation

= 199 µm). Run 4 with a mesh

size of 991 µm generated a

D90 particle size range from

427 µm to 707 µm (standard

deviation = 69 µm).

T h e s a m p l e s i z e w a s

c o n s i d e r a b l e w i t h o v e r

46,000 particles measured

during each run, which was

between 90 and 120 seconds

in duration. The number of

particles analyzed will vary

depending on the speed of

material flow, the volume of material transferred to the

interface window for analysis, and the particle size range

being analyzed. The density, hardness, and moisture content

of particles were also considered during the development

of the integration device to ensure a repeatable and

representative sample for analysis.

Conclusion

The imaging technology (the Eyecon particle characterizer)

successfully captured images and subsequently calculated

particle size distributions for the sample materials in a rapid

and accurate manner. As expected, there will be a degree

of modification required as part of integration on new

equipment types to ensure a representative and consistent

sample presentation—which is critical to enabling accurate

sample measurement. It can be concluded that the Eyecon

particle characterizer can be successfully integrated within

typical pharmaceutical fluid-bed granulators and milling

environments in addition to accurately measuring samples

in an at-line benchtop set-up.

References

1. D.M. Parikh, Chapter 1 “Introduction,” in handbook of Pharmaceutical

Granulation Technology, pp. 1–3 (Tailor and Francis Group, 2005).

2. G. Singh Rekhi and R. Sidwell, Chapter 17 “Sizing of Granulation,” in

handbook of Pharmaceutical Granulation Technology (Tailor and Francis

Group, 2005).

3. J. Huang and M. Moshgbar, “Platform Technologies for Manufacturing

Process Optimization through Integration of PAT and Control System,”

www.intellicentic.com/wp-content/uploads/2014/08/Platform-

technologies-for-manufacturing-process-optimization-through-

integration.pdf, accessed 18 Dec. 2014. PTE

900

800

700

600

500

400

300

200

100

0

900 1400 1900

mean

median

D10

D50

D90

Part

icu

le s

ize (

µm

)

MESH size (µm)

Figure 5: An evaluation of correlation for mesh size versus size parameters. Bars

represent standard errors.


Yu

ji S

aka

i/G

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ag

es

Matthias Springfelter, senior formulation scientist at Recipharm

Pharmaceutical Development AB, Solna, Sweden, spoke to

Pharmaceutical Technology Europe about the advantages and the key

considerations in developing topical formulations.

AdvantagesPTE: What advantages do topical formulations offer compared to

other dosage forms?

Springfelter: Perhaps the most obvious advantage is that topical

formulations allow for local treatment of a number of dermatological

conditions with very little systemic exposure. A high drug load can be

applied on the actual site where the drug is required, with a reduced

risk of unwanted side effects. Topical products are easy for the

patient to apply, and the moisturizing effect of topical formulations,

such as creams and ointments, may also be beneficial for several skin

conditions.

Transdermal delivery systems offer an alternative route for systemic

administration of various drugs with the benefit of a reduced risk of

loss of potency or unwanted variability due to first-pass metabolism.

Transdermal delivery systems can be designed to offer prolonged

and controlled-release absorption of certain drugs, which can be

convenient for pain relief drugs, nicotine, and hormone products.

Drug absorptionPTE: Can you tell us more about the mechanisms of drug absorption

across the skin barrier and how they affect the development of topical

drug products?

Springfelter: The human skin functions as an efficient barrier

against the outside environment. Achieving sufficient drug absorption

can, therefore, prove challenging for many molecules. For a drug

to reach its target site or to be absorbed into the blood stream, a

sufficient amount has to pass through the outer part of the epidermis,

the stratum corneum, and the epidermis. Even though there are

some passages, such as the hair follicles, sweat glands, and active

transportation mechanisms, the most important mechanism for drug

A Q&A by

Adeline Siew, PhD

absorption is by passive diffusion. The

rate of diffusion will, to a large extent,

depend on the properties of the drug

molecule itself. However, formulators

can use a number of methods to

optimize drug absorption.

In general, small-sized and

relatively lipophilic molecules are

most likely to be readily absorbed

through the skin, and this aspect

must be considered when selecting

a drug candidate. Sometimes,

it is possible to modify the drug

properties or alternatively, choose a

pro-drug that is delivered in inactive

form and that better matches

these criteria. The choice of vehicle

depends on the properties of the

drug substance, such as the solubility

profile and partition coefficient, so

that the chemical potential of the

drug is maximized. The permeability

of the skin is also an important

factor—the penetration rate could

be increased by an increase in skin

hydration, for example, by choosing

an occlusive vehicle or patch. A

number of penetration enhancers

that increase the absorption of a

drug by temporarily increasing the

permeability of the skin have been

evaluated, but there are limitations

because of skin irritation or toxicity

concerns.

PTE: What are the main

components of a topical formulation?

Springfelter: The components

of a topical product will depend on

the type of formulation. It could be

as simple as an active ingredient

dissolved in a solvent with suitable

additives such as pH-buffers,

co-solvent, and preservatives to

achieve adequate solubility and

stability for the formulation. In a

topical gel, viscosity modifiers such as

cellulose-based or synthetic polymers

are added to achieve the desired

rheological properties. Ointments

are semi-solid preparations of a drug

substance dissolved or dispersed

in a semi-solid ointment base made

of paraffin or other hydrocarbons.

Emulsions are somewhat more

complex because they consist of

two liquid phases, one of which is

dispersed within the other, usually oil

droplets dispersed in water. A number

of excipients are often necessary to

achieve a physically and chemically

stable emulsion. Water and one or

Semi-Solid Dosage FormsWhile the skin offers an alternative route of administration for local and

systemic drug delivery, developing semi-solid dosage forms can be a challenge.



Applying Water Activityto Pharmaceutical Products

Who Should Attend:

n Directors, group leaders, and managers

of quality, QA/QC, and compliance


of development


of manufacturing/production

n Scientists


Register for free at www.pharmtech.com/water

EVENT OVERVIEW:

An understanding of water activity—or the measure

of the free water in a substance—is crucial to the

development of pharmaceutical products to achieve

optimal stability, shelf life, and physical properties. Water

activity measurement also is a useful quality and safety

measurement tool to assess the potential for microbial

growth in pharmaceutical products.

In this 60-minute educational webcast, two experts on

water activity applications in pharmaceutical product

development will explain the basics of water activity and

the role it plays in pharmaceutical products, compendial

and regulatory requirements for water-activity

determination, and practical applications of water activity

to assess chemical stability, microbial content, physical

properties, and other pharmaceutical characteristics.

Key Learning Objectives:

n Learn how water activity is defned and regulatory

implications

n Understand how water activity measurement can be

used to assess the stability and physical properties of

pharmaceutical products

n Review applications for water activity in

pharmaceutical products

For questions,

contact Sara Barschdorf at

[email protected]

Presenters

Tony Cundell, PhDConsulting Microbiologist

Linda K. SkowronskySenior Development MicrobiologistGlaxoSmithKline Consumer Healthcare

Moderator

Rita PetersEditorial DirectorPharmaceutical Technology

LIVE WEBCAST: Wednesday, March 25, 2015 at 11:00 am EDT


Formulation

more organic compounds, such as

mineral or vegetable oils, make up

the two liquid phases, and one or

more emulsifying agents will be

needed to keep the phases apart.

The stability of the emulsion can be

further improved by the addition of

polymers to increase the viscosity

of the water phase. Additional

excipients such as pH-buffers,

antioxidants, and preservatives are

usually added as well.

Considerations in formulation developmentPTE: What are the key considerations

when designing a formulation for

topical drug delivery?

Springfelter: First of all, the

choice of formulation must be made

based on the disease or condition

to be treated, the type of skin upon

which it is to be applied, and the

properties of the drug substance.

After that, one has to ensure that

sufficient amount of the drug

reaches its site of action, whether it

is on the skin layer, or systemically.

The drug absorption may have to be

optimized, for example by adjusting

the vehicle or adding penetration

enhancers. It is also important

to ensure that skin irritation and

toxicity are minimized.

As always in formulation

development, the physicochemical

properties of the drug product must

be well controlled. The stability of

the active ingredients and other

functional excipients, such as

preservatives or antioxidants, will

have to be monitored.

Phase changes, such as

separation or bleeding, must

be prevented in emulsions and

ointments. The microbial quality

control of the drug product needs

to be considered, especially in

water-rich formulations; in this

case, it is often necessary to add

preservatives. The viscosity and

rheological behaviour should

be adjusted to fit the type of

application and the overall cosmetic

properties should be acceptable.

Vehicle selectionPTE: Can you elaborate more on

the selection of a vehicle for topical

formulations and how drug properties

will affect the choice of a vehicle?

Springfelter: The selection of a

vehicle for a topical formulation is

based on several factors, ranging

from stability and compatibility,

the type of disease and skin to be

applied on, to biopharmaceutical

considerations.

In general, the lipophilic type of

vehicles, such as ointments and

emulsions, are preferred for conditions

that involve dry skin. Ointment

vehicles are commonly used as they

provide a moisturizing effect on dry

and flaky skin due to their occlusive

properties. In addition, the increase in

hydration of the skin can also improve

the absorption of the drug. Ointments

are also less irritating to sensitive skin

than water-based formulations, but

they have a greasy feel that patients

tend to dislike.

Emulsion-type vehicles, such as oil-

in-water creams, are often preferred

for their improved cosmetic properties

because they are easy to apply and

are less viscous and greasy. Achieving

a stable emulsion, however, can prove

to be challenging in some cases.

Liquid vehicles such as solutions or

gels are convenient for application on

hairy skin areas such as the scalp and

are sometimes preferred in dermal

conditions for which a drying effect is

desired. For transdermal applications,

a suitable patch or other device would

have to be evaluated together with the

formulation.

Testing drug release and drug absorption PTE: How do you test drug release

and drug absorption?

Springfelter: A number of

methods are available for the

evaluation of the drug release and

absorption of dermal and transdermal

products. There is, however, no gold

standard, and the method used will

vary from case to case.

Some in-vitro methods are

particularly useful for early studies

and screening purposes. For

transdermal patches, the paddle-

over-disc method described in the

United States Pharmacopeia and

the European Pharmacopoeia is

a reliable test to determine the

in-vitro dissolution rate. For semi-

solids, no compendial methods

are available, but the diffusion cell

systems, such as Franz or In-Line

cells, are widely used and may

be fitted with various artificial or

animal skin membranes, or even

excised human skin. Diffusion

cell systems can provide useful

information and guidance, for

example, when choosing the vehicle

for a topical product, but as always,

caution should be taken when

extrapolating into more complex

in-vivo conditions. New in-vitro

models and methods are also being

developed, and are becoming more

useful in the characterization of

topical products. In-vivo studies

in different species of animals are

often performed, but as animal skin

differs from human skin, results

should be extrapolated with caution.

PTE: As the pharmaceutical

landscape becomes increasingly

competitive, drug developers are

now focusing more on patient

centricity and formulation for specific

populations. In your opinion, what

is the future outlook for semi-solid

drug products and do you expect

demand for this type of dosage form

to increase?

Springfelter: We have seen

increased interest in semi-solid

products in recent years and there

may be several reasons for this

trend. Where, several years ago, the

focus was on blockbuster products,

today there is a move toward more

niche applications. As demand for

personalized products increases,

topical administration is gaining

popularity. Another key driver is the

increasing interest in new products

that use existing drug substances.

New topical formulations using drugs

that were previously administered

in another dosage form can offer

significant benefits, not only

therapeutic benefits, but financial

ones, as they reduce development

cost and risk. PTE

The choice of formulation must be made based on the disease or condition to be treated, the type of skin upon which it is to be applied, and the properties of the drug substance.



TROUBLESHOOTINGD

AN

le

AP

/ge

tt

y i

MA

ge

s

William Evans

is technical service

specialist at Tosoh

Bioscience, 800.366.4875,

[email protected].

Several chromatographic resins are available for downstream purification.

Removing Aggregates in Monoclonal Antibody Purification

Monoclonal antibodies (mAbs) are a successful

class of therapeutic products used increasingly

in the past 15–20 years, but the manufacture of safe

and effective mAb drug products provides many

challenges to downstream molecule purification.

One of these challenges is the tendency of

mAb molecules to aggregate during processing.

Aggregates in the final drug product are undesirable

for two major reasons. First, aggregates may cause

a decrease in product efficacy due to lowering the

effective concentration of the drug product. Second,

aggregates increase the risk of an immunogenic

response in patients, including anaphylaxis. For

these reasons, the removal of aggregates is a focus

of downstream processing. The mAb purification

procedure must effectively reduce aggregate

concentration in the drug product, and processes

are usually optimized to target an aggregate

concentration of less than 1% for the final mAb drug

product. Additionally, processes must be optimized

to prevent the additional aggregation of the drug

molecule during processing.

Aggregate removal Removal of aggregates, especially soluble aggregates,

presents a challenge due to the physical and chemical

similarity of the aggregates to the drug product itself,

which is usually a monomer. Chromatography steps

can effectively remove aggregates, and typically,

one or more chromatography steps in a process will

be optimized for aggregate removal. The need for

aggregate removal, however, must be balanced by the

productivity of the process, the step yield, and the

overall purity of the product through the removal of

host-cell proteins and other contaminants.

For mAb products, nearly all processes begin with

an initial Protein A affinity chromatography step to

remove the bulk of impurities present in the clarified

harvest. This initial step provides a product that is

typically >90% pure and the subsequent processing

steps focus on the removal of the remaining

minor impurities. Due to the chemical similarity of

aggregates to the monomer molecule, however,

Protein A chromatography does not effectively

remove aggregates already present in the feedstock.

Additionally, Protein A elution conditions must be

optimized to prevent the further aggregation of

molecules due to denaturation at the acidic pHs

typically used. Finally, Protein A eluate is usually

maintained at a low pH for 30–60 minutes as a viral

inactivation measure. This hold has the potential to

exacerbate aggregate formation.

Secondary purification steps are often used

to remove aggregates following Protein A

chromatography and low pH treatment. Because

aggregate molecules are, chemically, multiples

of the monomer, aggregate molecules will have

proportionately greater surface charge or surface

hydrophobicity. Ion (anion or cation) exchange and

hydrophobic interaction chromatography modes may

be employed to take advantage of this increased

charge and hydrophobicity of the aggregates to

separate them from the monomer molecule. Figure

1 shows the strategy for aggregate removal with

ion exchange (IEX), hydrophobic interaction (HIC),

and mixed-mode chromatography. IEX methods

will separate based on molecule charge, while HIC

methods separate based on hydrophobicity. Mixed-

mode methods separate based on both charge and

hydrophobicity. Merits of the various chromatography

modes are discussed as follows.

Ion-exchange chromatographyCation-exchange chromatography. In cation exchange

chromatography (CEX), a positively-charged molecule

is adsorbed by the column resin and then displaced

with a high concentration of a positively-charged ion

such as Na+. As they require a positively-charged

molecule, CEX steps are performed at a pH below the

isoelectric point of the target molecule; for mAbs, this

is often in the range of 7.5–9. To determine elution

conditions during process development, separations

of aggregate-containing product may be done in

which material is bound at low conductivity and

eluted with a conductivity (salt) gradient (Figure 2) at

a constant pH.

The strength of the binding of the mAb to a CEX

resin is determined by the pH and the type of CEX



Troubleshooting

ligand used. Alteration of the pH will

affect the charge of the molecule and

increase or decrease the binding to a

given resin. The chemical properties of

the ligand will also affect the binding

affinity of the molecule. For instance,

carboxylic-type (CM) resins often

show a stronger binding then sulfonic

acid-type, thus requiring a higher

solution conductivity to cause elution.

For this reason, the CM-type resins

may be said to be “salt-tolerant”.

During process development, it is

common to screen multiple resins

at various pH points to optimize

the resolution between monomer

and aggregate peaks. In the final

processes, elution conditions are set

to collect primarily monomer. Species

that bind more weakly than the mAb

are washed off the column prior to

elution, while those that bind more

strongly, including aggregates, remain

bound and are cleaned off prior to

the processing of the next batch.

Theoretically, it is also possible to

adjust solution conductivity to allow

the monomer to flow through and the

aggregate to be retained, although this

method is not typically employed.

Anion exchange

chromatography. Anion exchange

(AEX) chromatography may also be

employed to remove aggregates.

Often, anion exchange is employed

in mAb processes in a product

flow-through mode to remove DNA

and some viruses that are highly

negatively charged at neutral pHs.

Salt-tolerant anion exchange resins,

though, may be used in bind-and-

elute mode, because significant

antibody binding can be achieved at

neutral to slightly-basic pHs. In this

mode, the salt-tolerant AEX resin

would be used in a manner similar to

CEX described previously.

Hydrophobic interaction chromatographyHIC may be used in much the

same manner as IEX to remove

aggregates. In this case, the

aggregates will show increased

surface hydrophobicity relative to

the monomer. HIC steps present

more variables for optimization

during process development, as the

hydrophobicity of the protein, the

type and concentration of salt in the

feedstock, and the hydrophobicity

of the resin come into play. Protein

hydrophobicity may be modulated by

change in pH to increase or decrease

the net charge of the molecule.

Different types of salts may be

used to modulate the strength of

the hydrophobic interaction of the

mAb with the resin. Different resin

ligands will also have varying levels of

hydrophobicity. For instance, a butyl

ligand will be more hydrophobic than

a phenyl ligand, which will, in turn,

be more hydrophobic than an ether

ligand.

Usually, HIC is performed in bind-

and-elute mode. The product is

bound under high-salt conditions

to strengthen hydrophobic effect

with the resin. To determine

elution conditions, a reverse-salt

gradient is then used to elute the

protein (Figure 3). Analogous to

cation exchange, the aggregate will

remain bound following monomer

elution due to greater surface

hydrophobicity. During process

development, various salt/resin

combinations may be screened

to provide the greatest aggregate

removal. Use of HIC in bind-and-

elute mode, however, provides

additional challenges, especially at a

manufacturing scale. The HIC eluate

may contain substantial amounts of

salt, which then must be removed

by diafiltration, or reduced in

concentration by the dilution of the

eluate prior to further processing.

This has led to the development of

low-salt or salt-free flow-through

HIC steps in some processes. For

these, a highly hydrophobic ligand

(such as hexyl) is used, and the

hydrophobicity of the mAb molecule

is modulated by pH change to allow

the monomer to flow through the

column, while aggregate and other

contaminants remain bound.

Other chromatographic modesMixed-mode chromatography.

Mixed chromatographic modes

allow separation based on both

charge and hydrophobicity in a single

step. Mixed-mode chromatography

(MMC) can provide a different

Figure 1: Strategies for aggregate removal with ion exchange (IEX), mixed-mode, and hydrophobic interaction (HIC) chromatography; mAb is monoclonal antibody.

Figure 2: Aggregate gradient elution profile with cation exchange chromatography (CEX).

Figure 3: Aggregate gradient elution profile with hydrophobic interaction (HIC) chromatography.

Hydrophobicity

HIC

IEX

mAb

monomer

dimer

trimer

tetramer

Mixed-Mode

Bound

Eluted

Bound

Eluted

BoundEluted

Charge

Volume

Aggregate

Monomer

Salt c

oncentr

atio

n

UV

Ab

sorb

an

ce

Volume

Aggregate

Monomer

Salt concentration

UV

Ab

sorb

an

ce

All f

igu

re

s A

re

co

ur

te

sy

of t

he

Au

th

or

.

During process development, it is common to screen multiple resins at various pH points to optimize the resolution between monomer and aggregate peaks.



Troubleshooting

selectivity than either IEX or HIC

alone. One drawback of mixed-mode

chromatography, however, is that

because of the increased binding

due to hydrophobic interactions, a

higher salt concentration is usually

needed to elute molecules bound

to an MMC resin than a simple IEX;

in effect, mixed-mode resins may

be employed as highly salt-tolerant

IEX resins (Figure 4). An alternate

strategy for separation by MMC

is to use both a conductivity and

pH change for elution; this may

provide the needed selectivity for

separation, as well as reducing the

salt concentration of the eluate.

Optimum elution conditions may

be determined by using combined

salt and pH gradients for elution, as

shown in Figure 5.

Why not size exclusion? A

special mention should be given

to size-exclusion chromatography

(SEC) for the purposes of aggregate

removal. As aggregates would

be proportionally sized relative

to the monomer (e.g., a dimer

would occupy twice the volume

of the monomer), molecule size

should provide a basis to separate

out aggregates. In analytical

chromatography (HPLC, UHPLC),

SEC is often used to determine the

amount of aggregate in a sample,

as monomer will be more highly

retained due to pore access, and

elute later than aggregates (Figure

6). For purification, however, it is

difficult to conduct SEC on the scale

necessary to perform industrial mAb

manufacture, and, therefore, it is not

used in practice. SEC is useful though

on a laboratory scale, especially as

a final purification step for material

that must be very pure (e.g., for

crystallography).

ConclusionThe removal of aggregates present in

a mAb purification process presents

a challenge to process development.

However, several chromatographic

tools are available to reduce the

concentration of aggregates to maintain

drug product efficacy and safety. Ion

exchange, HIC, and MMC may be used

for aggregate removal. PTE

Figure 4: Comparison of elution pro-files for S-type cation exchange chro-matography (CEX), CM-type CEX, and cationic mixed-mode chromatogra-phy (MMC) at a constant pH.

Figure 5: Mixed-mode chromatography (MMC) elution profile with combined salt and pH gradient.

Figure 6: Elution profile for aggregate separation by size-exclusion chromatography (SEC).

Volume

MMC

Salt co

nc.

CEX, CM-type

CEX, S-type

UV

Ab

sorb

an

ce

Volume

UV

Ab

sorb

an

ceAggregate

pH

Monomer

Salt co

ncentr

ation

Volume

Aggregate

Monomer

UV

Ab

sorb

an

ce

Molecule size should provide a basis to separate out aggregates.



Product/Service ProfileS

High Potency Solid dosage

capacity and expertise

Alkermes Contract Pharma Services,

has proven expertise in the handling of

highly potent drug substances. We have

over 500M annual solid oral dosage unit

capacity in our high potency suites. We

are capable of handling APIs to OEL 0.1μg/

m3 to commercial high-volume scale. Our

experience and expertise in manufacturing

is committed to providing you with your

exact production needs, delivered to the

highest quality standards and at a fair price.

Key Benefts of working with us

•45+ year history in contract pharma

manufacturing business with a proven

track record

•Experience and expertise handling at

commercial scale high potency

products

•FDA/EMA-licensed sites in both Europe

and U.S. – most recent FDA audits

resulted in no 483s

•Authorized to supply to all other major

territories including supply of product

to Brazil, China and India.

Alkermes contract Pharma Services

www.alkermes.com/contract

[email protected]

complex Sterile contract

Manufacturing

Parenteral manufacturing is a complicated

process. Cytotoxics, antibody-drug

conjugates (ADCs), highly potent

compounds, biologics, and lyophilized

products present many challenges and

require specialized understanding and

expertise. Baxter’s BioPharma Solutions

business brings more than sixty (60)

years of experience in handling complex

sterile manufacturing cytotoxics for global

markets. In 2013, Baxter announced a

third expansion of its fll/fnish cytotoxic

contract manufacturing facility in Halle

(Westfalen), Germany (following previous

expansions in 2007 and 2011) to meet

clients’ growing needs for cytotoxic

manufacturing. The expansion includes

the installation of a new commercial flling

line with two freeze dryers, and a clinical

flling line with an additional freeze dryer.

Both the new commercial and clinical

lines will be equipped with an automated

loading/unloading, capping and inspection

infrastructure. This expansion is expected

to be complete in late 2015, and has

been designed to support international

manufacturing and regulatory requirements

serving the needs of clients globally.

Baxter BioPharma Solutions

www.baxterbiopharmasolutions.com

[email protected]

Pft Powder flow tester

Brookfeld Powder Flow Tester (PFT)

delivers quick and affordable scientifc

testing for powder fow characterization

during gravity discharge in industrial

processing equipment.

The Brookfeld PFT is ideal for

manufacturers who process powders daily

and want to minimize or eliminate the

downtime and expense that occur when

hoppers/silos fail to discharge. With the

PFT customers can perform QC checks on

incoming materials, quickly characterize

new formulations for fowability and

adjust composition to match the fow

behavior of established products.

Powder Flow Pro Software and all

accessories for handling powder samples

are included with the instrument. Test

options including: Flow Function, Time

Consolidation, Wall Friction and Bulk

Density. The operator also has a choice

of graphical or tabular Data Output

Format for each test plus calculations

for arching dimension, rathole

diameter, hopper half-angle, gravity

chute angle and bulk density curve.

Brookfeld engineering laboratories, inc.

www.belusa.com

[email protected]



The new platform excipient for tablets, sachets and more

• first rate filler-binder properties due to excellent compressibility

• fast and slow disintegrating tablets (chewables, effervescents,

suckables, FDDTs…)

• ideal in sachets for direct oral application

or dry suspensions

• outstanding flow and mixing properties

• high dilution potential and high content uniformity

• very low hygroscopicity and excellent stability

• GMO-free and non-animal origin

BENEO-Palatinit GmbH · Phone: +49 621 421-150 · [email protected] · www.galenIQ.com

The Smart Bulk Excipient


Product/Service ProfileSProduct/Service ProfileS

catalent Pharma Solutions

Catalent Pharma Solutions, the leading

global provider of advanced delivery

technologies and development solutions

for drugs, biologics and consumer health

products, has invested in its Somerset, NJ

facility to create a Centre of Excellence

for potent handling across the company’s

portfolio of oral solid dose forms.

The investment included an expansion

of facility and engineering controls for

high potency tableting to supplement

existing capabilities, giving additional

capabilities to handle potent compounds

for large scale blending, fuid bed

processing and high shear granulation.

Catalent’s acquisition of Micron

Technologies allows the company to

undertake particle size engineering of potent

compounds, complementing handling and

manufacturing facilities at Somerset.

Investment was announced in 2014

at Catalent’s Kansas City, MO facility

to increase highly potent and cytotoxic

clinical drug packaging capabilities.

Catalent offers end-to-end solutions

for development, analysis and clinical

and commercial manufacturing for oral

solid doses and potent compounds.

catalent Pharma Solutions

www.catalent.com

[email protected]

etQ compliance

Management Software

EtQ is the leading FDA Compliance, Quality,

EHS and Operational Risk Management

software provider for identifying, mitigating

and preventing high-risk events through

integration, automation and collaboration.

Founded in 1992, EtQ has always had a

unique knowledge of FDA Compliance,

Quality, EHS and Operational Risk processes,

and strives to make overall compliance

operations and management systems better

for businesses. EtQ is headquartered in

Farmingdale, NY, with main offces located

in the U.S. and Europe. EtQ has been

providing software solutions to a variety

of markets for more than 20 years. For

more information, please visit http://www.

etq.com or contact us at 800.354.4476.

etQ

www.etq.com

[email protected]

dioSNA ccS 10 in isolator

The advantages of the compact design and

ease of use of Diosna´s pharmaceutical mixer

P1-6 and fuid bed processor Midilab XP are

the main reasons for integrating them in

isolators when granulation equipment for

high potent products at laboratory scale

(approx.. 0.1 kg - 5 kg) is needed. Mixing and

granulating of high potent powders with

an occupational exposure limit (OEL) under

0.1 µg/m³ is then possible. The isolators

are airtight and operate under negative

pressure. The transfer of the high potent

products is performed with rapid transfer

ports or endless liner systems. After

production the decontamination is achieved

by WIP (washing in place) to avoid cross-

contamination and hazards for the operators.

For the integration of granulation equipment

in an isolator the entire process must be

considered for the design of the system.

For this reason a mock-up study in which all

process steps are “played out” is necessary.

dioSNA dierks & Söhne GmbH

www.diosna.com

[email protected]

Product/Service ProfileS




flavor Bases for companion

Animal Health Products

Pet Flavors Inc. (PF, Inc.) is the world leading

developer and manufacturer of quality

f avor bases for both pharmaceutical drugs

and nutritional supplements in the animal

health industry. PF Inc. sells several types of

f avor bases for use in formulating palatable

canine, feline, and equine dosage forms

that are sold on a worldwide basis. PF Inc’s

Artif cial Powdered Beef Flavor; PC-0125

is sold to 9 of the top 10 largest animal

health pharmaceutical companies in the

world and has been successfully formulated

in over 20 New Animal Drug Approvals

(NADAs). Our company has over 30 years

of experience with formulation and product

development. With an active ingredient

and our f avor bases we can create

highly palatable chewable tablets, soft

chews or granules. Our services include

improving the palatability of an existing

product, creating product line extensions

or developing entirely new products.

Pet flavors inc.

www.Petflavors.com

[email protected]

oPtiMA pharma for

uncompromising

pharmaceutical applications

Optima Pharma develops and manufactures

f lling, sealing and process technology for

pharmaceuticals. Highly sophisticated,

fully automated systems from Optima

Pharma are used to process blood plasma

products, vaccines, oncology and biotech

products in pref lled syringes, vials, IV

bottles and cartridges. In addition to f lling

and sealing, complementary functions

and process equipment are integrated,

including washing machines, sterilization

tunnels and containment systems.

Pharmaceutical freeze drying and robotic

product handling complete the company’s

extensive portfolio. The division guarantees

quick, professional service with 13

international locations. Optima Pharma is

a member of the OPTIMA packaging group

GmbH (Schwäbisch Hall), which employs

a workforce of 1,900 around the globe.

oPtiMA pharma GmbH

www.optima-pharma.com

[email protected]

Bio/Pharmaceutical GMP

Product testing

Eurof ns BioPharma Product Testing offers

the most complete range of testing

services, harmonized quality systems and

LIMS to more than 800 virtual and large

pharmaceutical, biopharmaceutical and

medical device companies worldwide.

We offer complete CMC Testing Services

for the Bio/Pharmaceutical industry,

including all starting material, process

intermediates, drug substance, drug

product and manufacturing support, as well

as broad technical expertise in

Biochemistry, Molecular & Cell Biology,

Virology, Chemistry and Microbiology.

With a global capacity of more than

50,000 square meters and 14 facilities

located in Belgium, Denmark, France,

Germany, Ireland, Italy, Spain, Sweden and

the U.S., our network of GMP laboratories

and vast experience allow us to support

projects of any size from conception to

market. Further, we have teams of

scientists placed at more than 40 client

facilities throughout Europe and the U.S.

through our award-winning Professional

Scientif c Services (PSS) insourcing program.

eurof ns BioPharma Product testing

www.eurof ns.com/Biopharma

pharma@eurof ns.com




i-series - the new driver of

i-volution in HPlc analysis

Shimadzu has introduced the i-series of

integrated HPLC and UHPLC systems. The

analyzers meet the needs of any analytical

environment with high speed, outstanding

performance, maintainability and economic

effciency. The i-series concept combines

innovation, intuition and intelligence for

applications in the food, environmental,

chemical and pharmaceutical industry:

• Innovation, e.g. through higher

efficiency and remote monitoring

• Intuition, e.g. by utilizing a unified

graphical user interface

• Intelligence, e.g. realized in the

automation of routine procedures.

The i-series fts small labs with

limited space, as well as large labs

requiring high-throughput operation. Even

inexperienced operators easily obtain

high quality data and beneft from the

improved and automated workfow.

Shimadzu europa GmbH

www.shimadzu.eu

e-mail: [email protected]

flip-off® Plusru

West’s high-quality, sterile Flip-Off® PlusRU

seals are designed for capping under

Grade A air supply as mentioned in the

European Medicines Agency (EMA) Annex

1 “Manufacture of Sterile Medicinal

Products” guideline. Flip-Off® PlusRU seals are

manufactured using the TrueEdge® technology

production process providing precise and

reproducible seals, and are assembled in a

CNC (Controlled, not Classifed) environment.

A certifed bioburden prior to sterilization

allows cGMP compliant sterilization

validation, enabling clean crimping processes

in accordance with the latest regulations

described in EMA Annex 1. Flip-Off® PlusRU seals

are gamma sterilized and compliant with ISO

11137. They have full validation of sterilization

and packaging, including a comprehensive

certifcation package. When considering clean

crimping and capping process in non-aseptic

environments under Grade A air supply,

West’s vision-controlled Flip-Off® PlusRU

seals are intended to meet operational and

regulatory challenges to achieve consistently

reproducible, safe container integrity for the

drug product and ensure patient safety.

West Pharmaceutical Services, inc.

www.westpharma.com

[email protected]

Sterile Wipes

VAI features a complete range of dry &

saturated, sterile wipers for use in any

cleanroom environment. Our wipers are

knitted with continuous monoflament

polyester and are cut using “FocusEdge”

cutting technology. Every wipe that VAI

produces is available with the same material

for consistency and inexpensive validation.

The wipers are packaged into bags

suitable for use in an ISO Class 4 area and

labeled with lot number and expiration. All

sterile wipers are sterilized via gamma

irradiation at a 10-6 SAL, quality assurance

tested and released to specifcations

defned by IEST and ASTM. All shipments are

delivered with lot specifc documentation.

VAI’s high quality sterile wipers are

available in WipeDown® dry wipes,

Process2Wipe® (USP IPA and WFI Quality

Water), HYPO-CHLOR® WFI Formula in

0.25%, 0.52%, 5.25%, STERI-PEROX® WFI

Formula in 3% and 6%, DECON-CLEAN® RTU

reside remover, individually packaged

ALCOH-WIPES®, ALCOH-GLOVES®, and

STEEL-BRIGHT® Wipes.

veltek Associates, inc.

Sterile.com

[email protected]



PharmTech.com

NOVEMBER 2014 Volume 26 Number 11

MARKET REPORT

Germany Post AMNOG

TECHNICAL Q&A

Continuous Manufacturing

PEER-REVIEWED

Sublingual Formulations

QbD in

Parenterals

Addressing

Particulate

Contamination


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ASK THE EXPERT

Siegfried Schmitt, Principal Consultant, PAREXEL

International, discusses good engineering practices.

Q.Our engineering department is managed by a small team of

professionals who supervise and manage a large number of

service suppliers that perform the majority of engineering tasks.

We find that it typically takes more than a month before these

suppliers provide us with necessary documents, such as

calibration reports or updated piping and installation diagrams

(P&IDs). The engineering manager explained that this process

cannot be expedited. We are concerned that this long delay

may lead to a negative observation during our next inspection.

How can we change this pattern?

A.Outsourcing services is a common industry practice in the

pharmaceutical business. The regulatory agencies are well

aware of this fact and have issued rules and regulations governing

outsourced activities (1, 2). These regulations and guidance

documents, however, do not provide information that would define

an acceptable period of time for providing data and records to the

contract giver. In this specific case, the engineering department is

the contract giver, but there are no specific regulations you can cite

to ensure timely documentation. It is important to fix this challenge,

due to the possible impact on operations and quality this

document delay may create.

You mention two examples: calibration and engineering drawings.

There can be major impacts on each of these due to slow response

service suppliers. Let us first look at the calibration data and

records. For both manufacturing operations and process validation,

it is crucial to know the current calibration status of your equipment

and instrumentation. If that information is unavailable, then you

simply cannot proceed, seriously impacting your ability to operate.

Also, in the case of deviations, such missing information can

impede on the root cause investigation. Most companies attempt

to complete this type of investigation within 30 days, which may be

difficult if you must wait even longer for the relevant engineering

information and documents. It is important to note that the

validation in not confirmed until the engineering department verifies

and approves the third party’s report and conclusion.

In the case of the P&IDs, it will be difficult, if not impossible,

to present the as-is build of your facility in case of an inspection.

Without current drawings, making changes to the facility will be

challenging at best. Not having a picture of the as-is situation

may also hinder investigations if and when deviations occur.

In either case, the slow response time of your suppliers can have

critical impact on your engineering department and will need to

be addressed.

The time span from having the activity performed until you

receive the data and reports from your suppliers seems excessively

long, from both a compliance and a business perspective. If

possible, work with your engineering department to review the

quality/technical agreements in place with their suppliers (3). These

should detail defined timeframes and modes of delivery. The

agreement, for example, may specify that sending a scanned copy,

instead of a paper copy, of a report is acceptable. You will find

that a scanned copy may save time. Where suppliers are unable

to deliver within a reasonable amount of time (e.g., days), your

company may need to consider bringing the services back in-house.

Should you find it difficult convincing your engineering

department of the need to improve timelines, you should escalate

this issue to your senior management. After all, senior management

has the ultimate responsibility for quality and compliance. It is in

the best interest off all involved parties to assure your compliance

status reflects current good manufacturing practices.

References1. EC, EudraLex, Vol 4, Chapter 7 “Outsourced Activities,” http://

ec.europa.eu/health/files/eudralex/vol-4/vol4-chap7_2012-06_en.pdf, accessed 19 Jan. 2015.

2. FDA, FDASIA Title VII Drug Supply Chain Provisions, www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm365919.htm, accessed 17 Feb. 2015.

3. Quality-Technical Agreements, Pharm. Tech. 38 (5) 70 (2014). PTE

Managing Supplier Data Collection

Alkermes ............................................................................................... 13

Baxter Healthcare Corp ....................................................................... 11

Bend Research ..................................................................................... 25

BENEO GmbH ....................................................................................... 45

Brookfield Engineering ........................................................................43

Butterworth Laboratories ..................................................................... 6

Catalent Pharma Solutions ...........................................................23, 52

DECAGON.............................................................................................. 39

DECHEMA ............................................................................................. 28

Diosna Dierks & Sohne GmbH ............................................................ 19

Dow Europe GmbH .............................................................................. 51

ETQ Inc..................................................................................................... 9

Optima Packaging GmbH ...................................................................... 5

Panreac Quimica SA ............................................................................ 21

Pet Flavors Inc ...................................................................................... 17

Shimadzu Europe ................................................................................... 2

Spectrum Chemical Mfg Corp ............................................................ 35

Starna Scientific .................................................................................... 26

Veltek Associates Inc ............................................................................. 7

West Pharmaceutical Services ........................................................... 15

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