qbd in api manufacturing

Advancing Development & Manufacturing

PharmTech.com

PLUS:

PEER-REVIEWED

Investigation of Various Impurities in Febuxostat

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Quality by Design in API Manufacturing

API SYNTHESIS & MANUFACTURING Asymmetric Synthesis Advances

TECHNICAL Q&A Flexible Manufacturing

DRUG DELIVERY SAFETY Vial Withdrawal Practices

SEPTEMBER 2014 Volume 38 Number 9Healthcare Reform in China

Ultrasonic Cleaning

Testing pMDIs with Add-On Devices

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4 Pharmaceutical Technology September 2014 PharmTech .com

EDITORIALEditorial Director Rita Peters [email protected]

Managing Editor Susan Haigney [email protected]

Scientific Editor Adeline Siew, PhD [email protected]

Manufacturing Editor Jennifer Markarian [email protected]

Art Director Dan Ward

Contributing Editors Jill Wechsler [email protected]; Jim Miller info@

pharmsource.com; Hallie Forcinio [email protected]; Susan J. Schniepp sue.schniepp@

mac.com; Eric Langer [email protected]; and Cynthia A. Challener, PhD

[email protected]

Correspondents Hellen Berger (Latin/South America, [email protected]),

Sean Milmo (Europe, [email protected]), and Jane Wan (Asia, [email protected])

485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA

Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com

EDITORIAL ADVISORY BOARDPharmaceutical Technology publishes contributed technical articles that undergo a

rigorous, double-blind peer-review process involving members of our distinguished

Editorial Advisory Board. Manuscripts should be sent directly to the managing editor. Below is a partial list

of the Pharmaceutical Technology brand editorial advisory members. The full board, which includes advisory

members from Pharmaceutical Technology Europe, can be found online at PharmTech.com/EAB.

James P. AgallocoPresident, Agalloco & Associates

Larry L. Augsburger, PhDProfessor Emeritus University of Maryland

David H. Bergstrom, PhDSenior Vice-President, Pharmaceutical Development & Corporate Quality Assurance Antares Pharma, Inc.

Phil BormanQbD Lead & Data Management & Analysis Manager GlaxoSmithKline

Rory BudihandojoDirector, Quality and EHS Audit, Boehringer Ingelheim Shanghai Pharmaceuticals Co. (China)

Todd L. CecilVice-PresidentCompendial ScienceUnited States Pharmacopeia

Metin Çelik, PhDPresident, Pharmaceutical Technologies International (PTI)

Zak T. Chowhan, PhDConsultant, Pharmaceutical Development

Suggy S. Chrai, PhDPresident and CEO,Chrai Associates, Inc.

Roger Dabbah, PhDPrincipal Consultant, Tri-Intersect Solutions

Tim FreemanManaging Director, FreemanTechnology

Sanjay Garg, PhDProfessor, Pharmaceutical Sciences, University of South Australia

R. Gary Hollenbeck, PhDChief Scientific Officer, UPM Pharmaceuticals

Ruey-ching (Richard) Hwang, PhDSenior Director, Pharmaceutical Sciences,Pfizer Global R&D

Mansoor A. Khan, PhDDirector, FDA/CDER/DPQR

Russell E. MadsenPresident, The Williamsburg Group, LLC

Heidi M. Mansour, PhDProfessor, College of Pharmacy, University of Arizona–Tucson

Jim MillerPresident, PharmSource Information Services Bio/Pharmaceutical Outsourcing Report

Colin Minchom, PhDVice-President, Particle DesignHovione

Christine Moore, PhDDeputy Director for Science and Policy, Office of New Drug Quality Assessment, CDER, FDA

R. Christian Moreton, PhDVice-President, Pharmaceutical Sciences, Finnbrit Consulting

Fernando J. Muzzio, PhDDirector, NSF Engineering Research Center on Structured Organic Particulate Systems, Dept. of Chemical and Biochemical Engineering, Rutgers University

Moheb M. Nasr, PhDVice-President, CMC Regulatory Strategy, Global Regulatory Affairs, GlaxoSmithKline

Garnet E. Peck, PhDProfessor Emeritus of Industrial Pharmacy, Purdue University

Wendy Saffell-ClemmerDirector, ResearchBioPharma Solutions

Gurvinder Singh Rekhi, PhDDepartment of Pharmaceutical and Biomedical Sciences,The University of Georgia College of Pharmacy

Susan J. SchnieppVice-President, Quality and Regulatory Affairs, Allergy Laboratories, Inc

David R. SchonekerDirector of Global Regulatory Affairs, Colorcon

Eric B. Sheinin, PhDPresident, Sheinin and Associates

Aloka SrinivasanPrincipal Consultant, PAREXEL International

Heinz Sucker, PhDProfessor Emeritus,Pharmaceutical Institute, University of Bern

Scott Sutton, PhDMicrobiology Network

Read board members’

biographies online at

PharmTech.com/eab.

Pharmaceutical Technology’s eNewsletter Team:

• ePT, Editor Rita Peters, [email protected]

• Sourcing and Management, Editor Rita Peters, [email protected]

• Equipment & Processing Report, Editor Jennifer Markarian, [email protected]

• Send product releases to [email protected]

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PharmTech.com

On

th

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ov

er

Pharmaceutical Technology is the authoritative source of peer-reviewed research

and expert analyses for scientists, engineers, and managers engaged in process

development, manufacturing, formulation and drug delivery, Api synthesis, analytical

technology and testing, packaging, it, outsourcing, and regulatory compliance in the

pharmaceutical and biotechnology industries.

Continued on page 10

september 2014 volume 38 number 9

FeAtuRes

aPi synThesis & manuFacTurinG

30 Asymmetric Synthesis Continues to Advance

A survey of the recent literature

reveals numerous advances in

asymmetric chemocatalysis.

Pmdi TesTinG

34 Exploring Newly Introduced Methods for Testing MDIs with Add-On Devices

the role of add-on devices and

how they affect drug delivery with

a pressurized metered dose inhaler.

Technical Q&a: FleXible manuFacTurinG

66 Modularity Creates Flex-ible Manufacturing Systems

A roundtable discussion on modular bio/

pharmaceutical manufacturing systems

to enhance flexibility in facility design.

druG delivery saFeTy

68 Minimizing Variation in Vial Withdrawal Practices

Vial adapters can reduce variation of

volume withdrawn from injectable drug vials.

imPuriTies

38 Investigation of Various Impurities in Febuxostat

this article describes the identification and control of all isomeric,

carryover, and byproduct impurities of febuxostat and its intermediates.

QualiTy by desiGn

48 Using Quality by Design to Develop RobustChromatographic Methods

the authors use real-life examples from drug development projects to outline how an

understanding of chromatographic measurement system variability might be achieved.

peeR-ReVieweD ReseARCH

cover sTory

26 QbD in API Manufacturingwith a quality-by-design approach, robust

processes consistently deliver quality products.

Art Direction by Dan wardimages: Huchen lu/getty images

ON pHARMteCH.COM

Free enewsletters

Visit PharmTech.com/enews for:

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keeps you current with

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business notes.

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Report: Monthly reports on

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suppleMeNtBe sure to check

out this month’s Apis,

excipients, and

Manufacturing special

issue for articles on ele-

mental impurities, novel

excipients, and more.


2014

APIs, ExcIPIEnts, & MAnufActurIng

Supplement to the September 2014 ISSue of


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Continued from page 8

News & ANAlysis

GuesT ediTorial

12 The Relevance of Industry Techni-cal Associations

industry associations play a

strong role in helping the pharma-

ceutical industry meet challenges.

TroubleshooTinG

72 Using Ultrasonic Cleaning for Equipment and Tooling

An ultrasonic method cleans hard-to-reach

surfaces of solid-dosage equipment tooling.

ouTsourcinG ouTlook

74 Targeting Different Off-Shore Destinations

Annual study shows geographic

proximity not a factor in CMO selection.

conversaTion & communiTy

82 Taking the Pulse of the Industry

RegulAtiON & COMpliANCe

us reGulaTory waTch

16 Data Integ-rity Key to GMP Compliance

FDA demands accurate manufacturing and

test information to ensure product quality.

euroPean

reGulaTory waTch

20 Extending the Scope of Pharmacovigi-

lance Comes at a Price

As the pharmacovigilance infrastructure

becomes more entrenched in europe,

drug manufacturers are beginning to

feel the burden of its high cost.

emerGinG markeT rePorT

24 Healthcare Reform in China

Chinese healthcare reforms may be a

double-edged sword for foreign companies.

DepARtMeNts/pRODuCts

14 Product Spotlight

78 Pharma Capsules

79 Ad Index

80 Showcase/Marketplace

Pharmaceutical Technology is selectively abstracted or indexed in:

» Biological sciences Database (Cambridge scientific Abstracts)

» Biotechnology and Bioengineering Database (Cambridge scientific Abstracts)

» Business and Management practices (RDsi)

» Chemical Abstracts (CAs)

» Current packaging Abstracts

» DeCHeMA

» Derwent Biotechnology Abstracts (Derwent information, ltd.)

» excerpta Medica (elsevier)

» international pharmaceutical Abstracts (AsHp)

» science Citation index (thomson)

Pharmaceutical Technology is proud to be a member of DCAt, ipeC, and pDA.

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It takes horsepower and brainpower. It takes AmerisourceBergen. ItTakesAmerisourceBergen.com


12 Pharmaceutical Technology SEPTEMBER 2014 PharmTech .com

GUEST EDITORIAL

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PharmTech.com/forum

The objective of our industry is to manufacture and distribute high quality, healthcare products and

therapies that benefit the public. One of the basic challenges to meeting this objective involves producing drug, bio-logic, and medical-device products that not only are safe, effective, and com-pliant with global regulatory require-ments but also readily available for use by the patient. Achieving this objective means that these products must remain available and affordable, as well as a reasonable business proposition for manufacturers. To that end, today’s drug manufacturing industry must address issues related to drug short-ages, quality metrics, drug-product costs, innovative therapies, counterfeit products, and supply chain integrity.

Industry associations, in particu-lar the Parenteral Drug Association (PDA), have a strong role in helping the industry meet challenges. For nearly 70 years, PDA has been the leader in pro-viding thoughts on the current needs, best practices, topics, and positions that are important to the manufacturing of quality drug products. PDA does this by providing venues for exchange of infor-mation and connecting people, science, and regulation through the publish-

ing of oft-cited technical reports and papers, international conferences and meetings, and hands-on Training and Research Institute education courses.

Learned principlesThrough these and other efforts, much knowledge has been gained throughout the years. This knowledge results in bet-ter process understanding, helping us de-sign processes, establish control systems, and make informed decisions. This un-derstanding is especially relevant in re-cent years, where the industry has seen changes, faced issues, and noted an evo-lution of product manufacturing tech-nologies and methods. As we consider the state of our industry, the following guiding and linked principles emerge:

• The use of science- and risk-based approaches to make decisions related to the evaluation, design, qualifica-tion, operation, and monitoring of sterile product manufacturing pro-cesses is beneficial, if not essential, for the development and implemen-tation of process control strategies.

• The use of technology should be considered and encouraged to re-duce risks to product quality iden-tified in manufacturing processes and operations. The best use of new technology will come from

a partnership of manufacturers, regulators, and suppliers.

• Traditional testing and monitor-ing methods may not always be the most effective way to mitigate risks from newer technologies and product manufacturing processes. Where this is true, critical think-ing and innovative methods must be considered.

• New products, therapies, and pack-aging configuration will continue to present challenges to existing and traditional methods for devel-opment, manufacture, validation, and testing of sterile products.

• Where scientific expectations are similar and agreed upon, require-ments and guidance should be consistent in technical language and definition, thus reducing the risk of misunderstanding of global regulatory expectations.

The industry is beginning to recog-nize that the most effective way to ad-dress drug product manufacturing is-sues is to focus directly on improving the manufacturing process. Efforts on quality systems, risk-based decision-making, process development, valida-tion, contamination control, and supply chain integrity are essential elements of information and knowledge exchange. Using all tools at our disposal to better understand and control the variables in-herent in our manufacturing process will provide opportunity to improve those processes. PDA will continue to support the industry as a leader in efforts to pro-vide that knowledge and understanding, as it has done for the past 68 years. PT

The Relevance of Industry Technical Associations

PDA will support

the industry as a

leader in efforts to

provide knowledge.

Industry associations play a strong role in helping

the pharmaceutical industry meet challenges.

Hal Baseman

Hal Baseman is

chief operating officer

for ValSource and

chairman, PDA Board of

Directors, hbaseman@

valsource.com.

PharmTech.com/forum


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It may seem to some members of the biopharmaceutical man-

ufacturing community that incomplete records and faulty doc-

umentation are much less serious than contaminated facilities

and unsafe products. But to FDA officials, data that are not valid

and trustworthy is a sign that an entire operation or facility is

out of control and cannot assure the quality of its medicines. As

FDA struggles to devise a more targeted, risk-based approach

to overseeing the vast, global network of pharmaceutical

ingredient suppliers and manufacturers, agency officials find

themselves hampered by unreliable industry information.

New mandates to attain parity in inspection of foreign

and domestic facilities further complicates the picture by

expanding FDA oversight to many firms less familiar with US

standards. As erroneous and fraudulent records continue

to surface during plant inspections and in submissions filed

with the agency—despite years of warning letters criticizing

such infractions—FDA leaders are ramping up the rhetoric to

compel manufacturers to clean up data operations.

A lack of data integrity often is “just fraud,” says Howard

Sklamberg, FDA deputy commissioner for global regulatory

operations and policy. FDA relies on company information

documenting adherence to cGMPs, he explained at a July

conference on “Understanding cGMPs” sponsored by the Food

and Drug Law Institute (FDLI). Yet almost all recent warning

letters cite evidence of altered and falsified records. If data are

“knowingly incorrect, we take that very seriously,” Sklamberg

stated, expressing dismay that some manufacturers still fail to

remedy record-keeping problems despite repeated warnings

from the agency.

Sklamberg anticipates more prosecution of data integrity

issues to deter violative behavior. FDA aims to make

biopharmaceutical companies that hide manufacturing

data discrepancies and that display a lack of integrity in

regulatory programs and policies “increasingly uncomfortable,”

said Thomas Cosgrove, acting director of the Office of

Manufacturing and Project Quality (OMPQ) in the Office of

Compliance (OC), Center for Drug Evaluation and Research

(CDER). In addition to warning letters, inaccurate and unreliable

data can expose a firm to product seizures, import alerts, and

broader injunctions, he explained at the FDLI conference.

The most serious data breaches are handled by FDA’s Office

of Criminal Investigation (OCI) in the Office of Regulatory

Affairs (ORA), which manages the agency’s 1800 investigators

and some 200 OCI special agents. FDA will perform extensive

audits and impose penalties, which can be more expensive to

a firm than “getting it right the first time,” Cosgrove observed.

High quality data also are “a very big issue” related to

medical product imports, which are rising exponentially,

commented Douglas Stearn, director of enforcement and

import policy at ORA. He noted that dealing with poor data

slows down FDA operations and thus imposes a visible cost on

the agency. “We’re looking at that very closely,” he said.

Not just India

Data integrity issues have always existed, but now FDA is doing

more to uncover the evidence of such problems, acknowledged

Carmelo Rosa, director of OMPQ’s Division of International

Drug Quality. FDA is training investigators to better detect signs

of data problems and is looking more closely at international

facilities for signs of altered and doctored records.

But it’s “not only India” that is experiencing these problems,

said Rosa; data integrity issues have surfaced in all regions. A

July 2014 warning letter, for example, cited Italian API producer

Trifarma S.p.A. for deleting key test data and failing to establish

systems to identify how and when changes are made in

manufacturing records. Tianjin Zhogan Pharmaceutical Co.

in China received a warning letter in June citing inadequate

records of manufacturing and cleaning operations (1).

Certainly, many of the most egregious data integrity

transgressions have sur faced at Indian API facil it ies.

From mid-2013 to mid-2014, seven Indian manufacturers

received warning letters referencing the integrity of their

records, procedures, and interactions with FDA investigators,

according to a report by International Pharmaceutical Quality

(IPQ) (2). Wockhardt Ltd. was cited in July 2013 for multiple

GMP violations, including efforts to cover up faulty and

incomplete anti-microbial studies, stability protocols, and

batch testing. Ranbaxy Laboratories recently was hit by an

import ban on two facilities in India, culminating in a series of

enforcement actions following the discovery of widespread

falsification of data and test results more than five years ago.

Drug makers should not look to contract manufacturers to

reduce their responsibility for data accuracy and reliability,

Rosa noted at the July CMC Workshop on “Ef fective

Management of Contract Organizations” sponsored by

CASSS. Some biopharma companies regard contract testing

and production operations as one way to alleviate their

involvement in inspections and dealings with regulatory

authorit ies. But Rosa emphasized that the l icensed

manufacturer remains responsible for products meeting all

quality standards and noted that FDA and other authorities are

looking closely at all facilities, including CMOs.

To document that manufacturing processes comply with

GMPs, biopharmaceutical companies are required to retain

complete and accurate production information and to make

that available to FDA inspectors, explained OMPQ branch

Data Integrity Key to GMP ComplianceFDA demands accurate manufacturing and test information to ensure product quality.

Jill Wechsler is Pharmaceutical TechnologyÕs

Washington editor, tel. 301.656.4634,

[email protected]. Read Jill’s blogs at

PharmTech.com/wechsler



chief Alicia Mozzachio at the FDLI conference. She observed,

however, that agency investigators continue to uncover

multiple data integrity issues: failure to record activities

contemporaneously; document back-dating; copying existing

data as new information; re-running samples to obtain better

results; and fabricating or discarding data. Parexel Vice-

President David Elder cited recent FDA warnings letters that

refer to “unofficial testing” and “trial” analysis of samples until

the data come out right and evidence that records are signed

by company personnel absent from work that day.

Rosa added that field inspectors encounter employees who

admit to falsification of records and that certain operations

were not performed as recorded. When FDA uncovers such

discrepancies at one company site, Mozzachio said, that

becomes a “red flag” for FDA to look closely at records and

practices at a firm’s other manufacturing facilities.

Key indicators

Data integrity matters because prop-

erly recorded information is the basis

for manufacturers to assure product

identity, strength, purity, and safety,

Elder pointed out. Frances Zipp, presi-

dent of Lachman Consultants, observed

that data integrity has become a main

focus of FDA inspections, as agency

audits aim to determine how well com-

pany management monitors sites and

ensures the “rigor and effectiveness” of

global compliance. Evidence of misrep-

resented data or problems with batch

records found during a preapproval

inspection is a prime factor leading to

delays in market approval.

Inaccurate manufacturing data,

moreover, threatens to undermine

FDA efforts to streamline regulatory

processes, which is of particular concern

to agency leaders. Cosgrove explained

that FDA is working hard to establish

systems for targeting inspections to

more high-risk products and operations.

The aim is to focus agency resources on

the greatest sources of risk to patients,

while also reducing oversight of firms

with “robust quality systems,” which,

he said, then may benefit from “less

interference from FDA.”

But for such a strategy to work, the

data that FDA receives “must be real,”

he stated. Cosgrove voiced particular

dismay over company executives and

attorneys who “shade the facts” and

that resulting integrity issues can “have

consequences.”

References

1. FDA, Warning Letter to Tianjin Zho-

gan Pharmaceutical Co., WL: 320-14-09

(June 10, 2014), www.fda.gov/ICECI/En-

forcementActions/WarningLetters/2014/

ucm400853.htm, accessed July 31, 2014.

2. International Pharmaceutical Quality,

www.ipqpubs.com, Apr. 28, 2014. PT

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Pharmacovigilance controls are becoming firmly embedded

in the European Union’s post-authorisation regulatory

system with the European Medicines Agency (EMA) acting as

the pivot for an EU-wide network of agencies monitoring medi-

cines throughout their market lifespan. The new pharmacovigi-

lance activities stemming from the EU legislation (1–3), the first

stage of which was approved four years ago, relate mainly to

the reporting of adverse drug reactions (ADRs) for the detection

of safety and efficacy defects. They also cover quality problems

such as deficiencies in manufacturing, inadequacies in

formulations, including excipients, as well as faulty drug-

delivery technologies.

EMA claims that the new pharmacovigilance legislation,

implemented in mid-2012 in both the EU and the two non-EU

countries of Norway and Iceland, has “brought about the biggest

change to the legal framework for human medicines” in Europe

since the creation of the central agency itself in 1995 (4). EMA’s

Pharmacovigilance Risk Assessment Committee (PRAC) has

already “made great strides towards a new era in protecting

public health,” according to its chair June Raine (4). Nevertheless,

as the pharmacovigilance infrastructure gradually becomes more

entrenched in Europe, drug manufacturers and other marketing

authorization holders (MAHs) are complaining that they are

shouldering an unfair proportion of its high costs.

The cost of pharmacovigilance

Pharmacovigilance can be particularly expensive for developers

and producers of biologics and biosimilars that are making

up a growing proportion of new market entrants, while being

burdened with a more rigorous post-authorization regime

than that for small-molecule medicines. Producers of generic

medicines are also unhappy. With a growing share of the EU

market due to patent expiration of blockbuster drugs and a

decline in new chemical entities, generic-drug manufacturers are

having to carry a larger burden of the costs and fees for pharma-

covigilance initiatives.

“It is vital that costs associated with regulatory processes do not

become a barrier to developing and improving generics and

biosimilar products or even to maintaining the product in the

market,” said Beata Stepniewska, deputy director general of the

European Generic Medicines Association (EGA), with reference to

pharmacovigilance and other new legislation, at a recent

regulatory affairs conference (5).

W h i l e s t re s s ing t he i r sup p or t f o r an e f fec t i ve

pharmacovigilance system to ensure patient safety, leading

European pharmaceutical trade associations protested earlier

this year about the lack of “proportionality and transparency”

in the fees mechanism for paying EMA for pharmacovigilance

activities. In a joint press release (6), the associations, including

the European Federation of Pharmaceutical Industries and

Associations (EFPIA), EGA and the European Association of

Bio-Industries (EuropaBio), claimed that prior to the adoption of

the pharmacovigilance legislation, the European Commission

had been expecting annual savings of €145 million. Instead, the

financial burden of the legislation on the industry has been

increasing. Given that the mission of EMA and the regulatory

agencies or National Competent Authorities (NCAs) in

the EU’s 28 member states is to safeguard public health, the

pharmacovigilance costs to industry should be partly covered by

public-sector funds, the associations argued.

The industry has been pressing the commission for a dialogue

on the issue that would aim to establish a fees system based on

the principles of fairness and cost-effectiveness. Instead, the

commission has been stressing its belief that the fees are both

justifiable and transparent. A preamble to an EU regulation,

published in June 2014 on the latest set of fees for

pharmacovigilance work by EMA on behalf of NCAs, states that

fees should be at a level that “avoids deficit and a significant

accumulation of surplus and should be revised when this is not

the case” (7).

Some types of medicines and MAH groups are benefiting from

lower fees. Generic medicines are subject to reduced fees

because of their well-established safety profiles. Small- and

medium-sized enterprises (SMEs) are paying less as well.

For pharmacovigilance work by EMA on centrally approved

products and to ensure harmonization of safety standards on

medicines licensed by the member states, fees are fixed by EU

regulation. The member states themselves set the fees for

pharmacovigilance activities that are entirely the responsibility

of the NCAs. At the EMA level, fees are incurred for individual

pharmacovigilance procedures that can affect some MAHs

more than others and are imposed annually to pay for functions

that are considered to benefit all authorisation holders, such as

the running of the Eudravigilance database (8) for information on

all ADRs.

Pharmacovigilance procedures and fees

There are three main procedures. Periodic safety reports (PSURs)

are risk-benefit medicine evaluations submitted at stipulated

intervals by MAHs. Post-authorization safety studies (PASS)

characterize safety hazards or the effectiveness of risk manage-

ment activities. The third is referrals to resolve concerns about

Extending the Scope of

Pharmacovigilance Comes at a PriceAs the pharmacovigilance infrastructure becomes more entrenched

in Europe, drug manufacturers are beginning to feel the burden of its high cost.

Sean Milmo

is a freelance writer based in Essex, UK,

[email protected].


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the benefit-risk balance of individual medicines or combina-

tions of them and disagreements among member states.

Under the latest set of published fees for pharmacovigilance

work on products licensed under the decentralised procedure, a

basic €19,500 will be charged per PSUR. The basic fee for a PASS

will be €43,000 per medicine. The most expensive item is dealing

with referrals for which €179,000 will be levied for assessments of

one drug or combinations of two medicines, with additional

combination substances costing €38,800 each. The total fee for

the procedure is limited to €295,400. The annual fee to help pay

for databases and monitoring operations will be €67 per active

substance and for each of its various pharmaceutical forms. The

set of fees confirms claims that in unusual cases, the total costs

of fees could exceed €250,000 per product (8).

The EGA has estimated that an average-sized generic-medicines

company could pay up to €20 million in annual pharmacovigilance

fees because its large portfolio of active substances will provide

the basis for a variety of authorised medicinal products (9). On top

of the expenditure on fees, pharmaceutical companies will be

incurring the additional administrative and managerial costs of

extra market surveillance, gathering data, maintaining records and

other requirements of the pharmacovigilance legislation.

From June 2014, MAHs have been required to start a process,

to be completed by the end of the year of updating and improving

the quality of information on authorized medicines (10). The

updating will be a permanent obligation on authorization holders

so that consistent information on all medicines licensed centrally

and decentrally in the EU—estimated to total over 400,000

products—are available for pharmacovigilance analysis.

A major responsibility of MAHs is the continuous monitoring of

pharmacovigilance data for safety signals of a possible new risk

from an active substance or medicinal product. These signals

could come not only from ADRs but from multiple sources,

including observations of manufacturing processes. The more

effectively an MAH manages signals detection, the less expensive

it will be to correct deficiencies when there are signs of adverse

events like manufacturing faults.

Increasing pharmacovigilance responsibilities

Over the next few years, pharmaceutical companies will see their

pharmacovigilance responsibilities gradually being extended

because the full implementation of the new rules will take time. At

the beginning of 2014, measures introduced by the legislation

such as monitoring of scientific literature, public hearings, PSUR

assessment by EMA of nationally approved products were not

being carried out because of the lack of fees to fund them (4).

Certain grey areas have to be clarified, such as the extent to

which pharmacovigilance responsibility extends to the avoidance

of medicine shortages. The scope of pharmacovigilance is,

however, becoming clearer in some areas, such as formulations.

An increasing number of relatively long established medicines are

being reviewed by PRAC because of concerns about their

formulations resulting from post-authorisation surveillance.

In July, PRAC recommended the market suspension of oral

methadone products containing high molecular weight povidone,

a polyvinylpyrrolidone polymer excipient (11). This suspension was

due to the risk of opioid-dependent patients causing themselves

serious harm from the povidone by injecting the medicine. The

committee’s decision was reached after reviewing ADRs data

from published literature and consulting experts.

Over the next few years, pharmaceutical

companies will see their pharmacovigilance responsibilities gradually

being extended. Pharmacovigilance procedures are also likely to result in more

ADRs being linked to weaknesses in manufacturing processes.

With some biosimilars, the pharmacovigilance rules are

particularly strict because of the possibility that adverse effects

could be directly related to the manufacturing process.

Furthermore, they could be different to the potential side effects

of the reference product.

Europe’s pharmacovigilance system is already considered to be

among the most advanced in the world, but exactly how wide its

scope will be could depend on how successful the regulators and

the industry are in coming to a long-term agreement on the

funding of it.

References 1. EU Directive 2010/84 Amending Pharmacovigilance Directive

2001/83 (Brussels, December 2010). 2. EU Regulation 1235/2010 Amending, as regards pharmacovigilance

of medicinal products for human use, Regulation 726/2004 (Brussels, December 2010).

3. Commission Implementing Regulation 520/2012 On performance of pharmacovigilance activities (Brussels, June 2012).

4. EMA Annual Report 2013 (London, April 2014). 5. EGA, “Austerity must prompt strategic regulatory rethink for generic

medicines industry,” Press Release, Jan. 23, 2014. 6. EFPIA, EGA, EuropaBio, Association of the European Self-

Medication Industry (AESGP), European Confederation of Pharmaceutical Entrepreneurs (EUCOPE). “The European health-care industry calls for balanced and transparent funding of the EU pharmacovigilance system,” Press Release, Feb. 21, 2014.

7. EU Regulation 658/2014. On fees payable to the European Medicines Agency for pharmacovigilance activities. (Brussels, May 2014).

8. EU Regulation 658/2014. Annex, Part I, II, III & IV. 9. EGA, “Pharmacovigilance fees unjustifiably high,” Press

Release, Sept. 14, 2012. 10. EMA, “Companies now required to update, complete and improve

quality of information on authorized medicines submitted to the European Medicines Agency,” Press Release, June 16, 2014.

11. EMA, “PRAC recommends suspension and reformulation of oral methadone solutions containing high molecular weight povi-done,” Press Release, July 11, 2014. PT


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Healthcare Reform in

ChinaOn March 25, 2014, the Chinese government announced a

string of initiatives in a continued move to overhaul the

healthcare system in the country. These initiatives include

expansion of public healthcare services, lifting the restrictions

of foreign investments in mainland China, and extending health-

care to rural areas. This move is in line with China’s Opinions

on Deepening Pharmaceutical and Healthcare System Reform,

whereby the government committed $138 billion between 2009

and 2011. After the plan’s implementation in March 2009, the

number of urban and rural residents covered by the basic medical

insurance scheme reached 1.26 billion in 2010. The government

also kick-started public hospital reform to come up with a mecha-

nism to segregate hospital management and operations, as well

as the duties between drug prescriber and dispenser in 16 pilot

cities. In another significant reform, the government announced

the price reduction of 82 drugs by 14% on Sept. 1, 2011 (1).

An appealing market

The Chinese market is attractive to foreign investors for many

reasons. It is the world’s third largest market for pharmaceuticals

with annual sale of US$71 billion. In fact, it is poised to become

the second largest market in 2015 given that its annual growth rate

of sales is between 15 and 20%, according to Yanzhong Huang, a

senior fellow of global health at the Council on Foreign Relations.

A McKinsey report states that healthcare spending is

expected to nearly triple from $357 million in 2011 to $1 trillion

by 2020 (2). The Economist Intelligence Unit (EIU) projects that

China’s population will be the largest in the world with 1.36

billion people by 2016. The senior population (65 years and

older) is expected to rise to 9.7% from 8.4% in 2011, which in

turn translates to higher demand for healthcare services.

Given these encouraging facts, big pharmaceutical

companies such as Bayer Healthcare and Nova Nordisk consider

the Chinese market as one of the top three markets in terms of

total revenue contribution. Baxter International has also made

the move to relocate its Asia Pacific headquarters to Shanghai.

Challenges abound

As China’s healthcare reform program enters its second phase,

foreign players are now given more room to take advantage

of this opportunity. The State Council has announced that it

will give allowance on foreign investments in medical joint

ventures and collaborations. The number of locations will be

increased so that Hong Kong, Taiwan, and Macau investors

can set up wholly-owned medical centers. Overseas investors

can form their establishments in areas such as the Shanghai

free trade zone. Healthcare providers such as Singapore-based

Raffles Medical Group and US-based Chindex International

have started operations in China.

Investors, however, have a string of issues to contend with.

The government’s announcement of extending healthcare

coverage to rural areas may represent new export markets for

foreign firms, but the former’s intention to keep drug prices

low is a risk for them as well.

Recently, the government initiated an anti-corruption

campaign against work practices by foreign companies.

GlaxoSmithKline has been accused of corruption, and many

other companies such as Sanofi and Baxter are under China’s

Food and Drug Administration’s watchful radar.

Dr Neil Wang, global partner and managing director (China)

of Frost & Sullivan says, “The anti-corruption investigations in

the healthcare sector serve the reform goal to rein in costs

Jane Wan

Chinese healthcare reforms may be a

double-edged sword for foreign companies.


Pharmaceutical Technology SEPTEMBER 2014 25

of drugs and healthcare products. The damage to reputation

and the business disruption caused by bribery investigations

would drag on growth of pharmaceutical companies’ sales.

Furthermore, a criminal bribery conviction could lead to

debarment from government contracting, which could put

some healthcare companies out of business.”

Results from a China investigation could expand the corruption

investigation across the border beyond China, he added.

Companies operating in China also fear being investigated under

the US Foreign Corrupt Practices Act (FCPA) or Britain’s Bribery

Act, because investigation on corruption

in China may feed back into the FCPA

and possibly the UK Bribery Act.

Opportunities in adversity

Given the operating environment, for-

eign companies can look into gaining

a foothold via acquisition in a bid to

improve operational capabilities and

cost effectiveness. Sanofi’s move to

acquire BMP Sunstone Corporation in

October 2010, for example, has made

the former a leading consumer health-

care company in China because of the

joint venture between BMP Sunstone

a n d M i n s h e n g P h a r m a c e u t i c a l .

Companies can also explore the option

of collaborating with partners in China

or teaming with local biotech compa-

nies and research institutes.

In addition, opportunities can be found

in the generic-drug and over-the-counter

(OTC) markets. The country’s OTC and

generic-drug markets are projected

to leap from US$23 billion in 2010 to

more than US$369 billion by 2020, says

Benjamin Shobert, managing director of

Rubicon Strategy and senior associate of

the National Bureau of Asian Research.

The Chinese market will continue to

favor generic drugs to keep healthcare

expenditures in check. Also limiting

the possibility of launching domestic

patented drugs in the near future and

the wave of patented drug expirations

serve to strengthen the generic-drug

market. The OTC market registers

an encouraging approximate 17%

per annum according to China OTC

Association. China is expected to be

the world’s largest OTC market by 2020,

observers at Episcom say.

The biotechnology sector is another

key development that companies

can look to explore. The Chinese

government has invested $1.6 billion

to support major new drug innovations

from 2011 to 2015, focusing mainly on

genetic drugs, protein drugs, monoclonal antibody clone drugs,

therapeutic vaccines, and small-molecule drugs.

References 1. Deloitte, The next phase: Opportunities in China’s pharmaceuticals

market, www.deloitte.com/view/en_CN/cn/ind/lshc/723313bbb0943310VgnVCM3000001c56f00aRCRD.htm, accessed Aug. 8, 2014.

2. McKinsey & Company, Healthcare in China: Entering ‘un-charted waters’, www.mckinsey.com/insights/health_systems_and_services/health_care_in_china_entering_uncharted_wa-ters, accessed Aug. 8, 2014. PT

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mine product and process characteristics that will meet specific criteria set after careful analysis of the intended drug ap-plication. These critical quality attributes (CQAs) of the final drug product (and often of the API) include the physico chemical properties and performance behavior of the formulated drug (drug substance). The manufacture of small-molecule APIs often requires the produc-tion of multiple intermediates using dif-ferent processes. To consistently achieve these CQAs, it is necessary to ensure that

each of these processes is robust. Critical process parameters (CPPs) are, therefore, important components of an effective control strategy for ensuring that the API process consistently delivers product with the appropriate CQAs.

Linking CQAs with CPPsWhile true CQAs are found in the final specification for a drug product, there are several different aspects of a formulated drug, and particularly the API, that are affected by process parameters. These aspects, therefore, must be linked to the CPPs for each manufacturing process required for the preparation of an API,

according to Chris Senanayake, vice-president of chemical development for Boehringer Ingelheim Pharmaceuticals. These characteristics include, but are not limited to, total purity, individual impu-rity levels, the polymorph(s), solvates, pH, water content, and particle size.

For the API, the most common CQAs are related to impurities from chemical processes and the solid-state properties (e.g., particle size, polymorphism) of the drug substance, according to Gert Thurau, group leader, Technical Regula-tory at Roche. It is essential to control im-purities for the safety of the drug product, while control of the solid-state proper-ties of the drug substance is necessary to achieve consistent product properties, including bioavailability. “Once these attributes have been defined, it is pos-sible to define what is important to the process and build a process that comes closer to quality by design and is, there-fore, highly robust,” he says. The assay and impurity profile of an API are es-sentially inter-related and are important because low impurity levels translates to safety for patients, while a high assay indicates appropriate efficacy, according to Vishwanath Nadig, associate direc-tor of quality assurance for Dr. Reddy’s Custom Pharmaceutical Services (CPS). Nadig adds that moisture content is also important because, in some cases, the presence of moisture may accelerate deg-radation of the drug substance.

These CQAs should be selected such that if the final product has these attri-butes, then it will work for its intended purpose. CPPs should then be selected because they have a relationship to the final CQAs and, when controlled, will as-sure the manufacture or a product with the right CQAs, according to Senanay-ake. “CPPs are the process parameters that affect the critical quality attributes of the API, and it is important to deter-mine the range for each critical process parameter expected to be used during routine manufacturing and process con-trol,” adds Mark TePaske, director of reg-ulatory affairs, quality, and compliance for Cambrex. Most importantly, it is es-sential to establish appropriate CPPs for each individual process step because they H

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QbD in API ManufacturingConnecting critical process parameters with critical quality attributes

Cynthia A. Challener

With a quality-by-design approach, robust processes consistently deliver quality product.


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Cover Story: Quality by Design

will ultimately affect the quality of the drug, which in turn can impact efficacy, according to Nadig. “Establishing and meeting CPPs and CQAs allows quality to be built into the process and affords robustness beyond release testing,” adds TePaske. He also notes that well-defined CPPs ensure that a process operates in a state of control and in a validated state, which is crucial, because process valida-tion is a cGMP requirement.

The definition of the CQAs for the final drug product and API is the first step in a comprehensive risk-based ap-proach to product and process develop-ment, according to Thurau. “The start-ing point of the analysis is typically the quality target product profile, which leads to defining the critical quality attributes for the final product, and in turn, the critical quality attributes for the drug substance. Since the most important CQAs of the final API are the process-related impurities, which mostly result from the starting and raw materials, it is essential to understand the chemistry of the individual process steps,” he explains. In addition to risk assessment, Senanayake adds that prior knowledge, designed experiments, and regulatory expectations all play a role in determining CQAs and CPPs.

Risk-assessment approachesOnce CQAs are defined, typically dur-ing the initial scale-up phase, it is nec-essary to identify the appropriate CPPs.

“At Boehringer Ingelheim, we believe that using a design of experiment (DOE) approach is the best method for demon-strating the interdependency of CPPs and the CQAs for individual process steps,” Senanayake says. Along with general risk assessments, the use of design failure mode and effects analyses (FMEA) is also effective for defining critical parameters of drug products, drug substances, and production processes, according to Nadig.

“When applied appropriately, these two approaches are sufficient for defining the important attributes,” he says.

While orthogonal experiments can also be used, Senanayake notes that with DOE, knowledge is gained about the de-sign space for each process that cannot

be obtained using screening experiments, although they are useful when determin-ing certain aspects of processes, such as the most effective solvents or catalysts. TePaske adds that once defined, critical attributes should be affirmed experi-mentally and control limits established, with processes, procedures, equipment and/or facilities revised as needed.

It should be noted that the risk-assessment methods used today are much more rigorous than the processes used in the past. “Historically, process and CQA definition was driven by the process development chemist, and the depth and breadth of the investigations were chemist-dependent,” observes Te-Paske. As a result, process development was primarily viewed as a laboratory exercise. He goes on to note that cur-rent approaches are more disciplined, and studies are defined by multidis-ciplinary project teams. “These teams review and reconcile findings and risk assessments, and the concerns of the production, materials, quality, engineering, and other departments involved in manufacturing are inte-grated into the development process. In effect, CQA definition and process development have evolved from a labo-ratory exercise to a global preparation for process validation and commercial GMP manufacturing.” He concludes that this team-oriented approach is the best practice because it integrates the needs of all of the disciplines in-volved in commercial manufacturing and virtually eliminates the possibil-ity that CQAs and CPPs that cannot be performed in the available facilities and equipment will be defined.

Connecting CPPs to CQAsBased on the results of the quality risk as-sessment, various reaction and work-up conditions can be investigated, and the products from each process step can be carefully analyzed with regard to their impurity profiles and other properties, according to Thurau. “For example, the structures of the impurities can be de-termined, and consequently the process conditions can be adjusted to minimize the impurities and/or their fate in down-

stream steps can be determined. The result is the elimination of the impuri-ties or the determination of safe limits for them,” he explains. He stresses that it is important in this part of the pro-cess to be systematic, and to consistently maintain a link between the CPPs being evaluated and the drug product and drug substance CQAs.

Barriers to developing CPPsWhile there are many benefits to a QbD approach and the establishment of CPPs that are linked to final prod-uct and drug substance CQAs, there are challenges to implementing such an approach. For Senanayake, the time and resources required remain the big-gest barrier to obtaining a useful under-standing of a process. “These barriers must be overcome, though, because having thorough knowledge of a pro-cess once it has reached commercial manufacturing is critical for success, and therefore, it is necessary to take the time to fully understand the design space,” he asserts. Thurau agrees that the major limitations are practical in nature and can typically be overcome. He does, however, note that there are some open questions on the definitions and differences in the applicability of the concept by various health authori-ties. “As registrations for products de-veloped and manufactured using the QbD approach become more detailed and explicit about criticality, the hope is that the increased knowledge will lead to more flexible approaches to change management (do and tell) as opposed to the current set approach (tell and do).

Both Nadig and TePaske point to the need for participation of knowledgeable team members from across different functions of the organization as a chal-lenging aspect of QbD and the establish-ment of effective CQAs and CPPs. “The multidisciplinary approach requires up-front involvement of disciplines whose primary job responsibility has histori-cally been manufacturing and requires a new way of thinking,” says TePaske. He also adds that the risk-assessment approach often focuses on what can be done, which can stifle innovation.


Pharmaceutical Technology September 2014 29

Practical use of CPPsDespites these barriers and limitations, many companies have recognized the value of a QbD approach and the impor-tance of linking critical process param-eters for individual process steps with the critical quality attributes of small-molecule APIs and the corresponding formulated drug products. Boehringer Ingelheim, for example, is monitoring process robustness at each development stage and focusing on understanding how this robustness translates to the commercial scale using batch histories, according to Senanayake. In addition, the company is trying to complete DOEs on the important steps in its manufac-turing processes. “Our success to date is demonstrated by our validation efforts and the control charts we have estab-lished for individual steps,” he says.

At Dr. Reddy’s CPS, when defining CPPs for each process step, a cross-functional team meets to discuss the key

sensitivities of the process parameters and material attributes, which are first weighted in importance, and then tol-erances on the variables are established, according to Nadig. DOE screening is then performed to identify the critical parameters, followed by optimization and definition of the design space to un-derstand what will happen to the CQAs under different parameter settings. “Im-portantly, we are trying to engage senior members from cross-functional teams during these pre-planning meetings so that an exhaustive risk assessment is conceptualized and a mitigation plan worked out,” he comments. The company also emphasizes the importance of clear communications, participation with the customer, and giving weight to all stake-holder concerns throughout the process.

Potential consequencesThe consequences of not establish-ing CPPs that are effectively linked

to CQAs can be severe. “If the proper controls for an intermediate step in the manufacturing process are not in place, then it is possible for a mate-rial to be produced that does not meet specifications for unknown reasons. Such a situation can in turn result in a recall if the intermediate is carried through the entire commercial process. In addition, without proper controls, processes often deliver poor quality product or product of inconsistent quality,” asserts Senanayake. In addi-tion, according to Thurau, if inappro-priate process parameters or in-process material attributes are established, the quality of the final product may appear high, but it is the result of testing qual-ity into it, and not of process design and process understanding. Finally, TePaske stresses that operation in a state of control is fundamental to pro-cess validation and continued process performance in a validated state. PT

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API Synthesis & Manufacturing

Although significant attention has recently been directed towards biocatalysis as the way forward

for commercial-scale asymmetric syn-thesis, chiral transformations mediated by traditional metal-based and organic catalysts remain important for the man-ufacture of pharmaceutical intermedi-ates and APIs. In addition, much effort continues to be invested in the develop-ment of novel enantioselective methods for the synthesis of building blocks nec-essary for the manufacture of biologically active molecules. A brief survey of recent literature underscores the breadth of chi-ral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds. Selected ex-amples are highlighted in the following.

Amino acid derivativesMany natural and non-natural amino acids and derivatives contain both ni-trogen and sulfur substituents, thus the synthetic methods for the enantiomeric synthesis of building blocks containing these two elements are of significant in-terest. Scott Denmark and Hyung Min

Chi reported an enantioselective route to chiral pyrrolidines, piperidines, and azepanes bearing thiol substituents (1). In their method, terminal and trans di-substituted alkenes with a pendant tosyl-protected amine group are converted to the desired products through the for-mation of a thiiranium intermediate via Lewis base-catalyzed intramolecular sulfenoamination using a chiral BINAM (1,1’-binaphthyl-2,2’-diamine)-based selenophosphoramide catalyst.

Tsuyoshi Mita and Yoshhihiro Sato at Hokkaido University in Japan reported the asymmetric synthesis of α-amino acids via the stereopsecific carboxyl-ation of optically active α-amino silanes, which were obtained through the en-antioselective silylation of N-tert-butyl-sulfonylimines using a Cu–secondary diamine complex (2). The carboxylation proceeded under 1 atmosphere of CO

2.

Spirocyclic oxindolo-β-lactams were pre-pared in high yields with excellent dia-stereo- and enantioselectivities by Song Ye at the Chinese Academy of Sciences (3). In this case, ketenes were subjected to an N-heterocyclic carbene (NHC)-cat-alyzed Staudinger reaction with isatin-derived ketimines using NHCs with free hydroxyl groups as the catalyst. S

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A survey of the recent literature reveals numerous advances in asymmetric chemocatalysis.

Asymmetric Synthesis Continues to AdvanceCynthia A. Challener

Fluorinated compoundsChiral fluorinated compounds are also of interest, because incorporation of the highly electronegative fluorine atom can have an impact on the physico-chemical properties of APIs. Gregory Fu and col-leagues at the California Institute of Tech-nology tackled the challenge of preparing chiral tertiary alkyl fluorides, and par-ticularly α-fluorocarbonyl compounds (4). They reported a method for the asymmet-ric synthesis of tertiary α-fluoroesters via the catalytic asymmetric coupling of aryl alkyl ketenes with commercially avail-able N-fluorodibenzenesulfonimide and C

6F

5ONa as a nucleophile using a chiral fer-

rocenyl PPY (4-pyrrolidinopyridine) cata-lyst. The alkoxide was crucial for freeing the catalyst from an acylated intermediate. Meanwhile, Qing-Yun Chen and Yong Guo at the Chinese Academy of Sciences reported the asymmetric synthesis of ter-tiary α-fluoro ketones via the Tsuji–Trost reaction of racemic acyclic α-fluorinated ketones using a palladium/phosphinoox-azoline catalyst (5). The desired products were obtained in up to 90% yield with up to 90% enantiomeric excess (ee).

The preparation of chiral compounds with trifluoralkyl groups is also important for drug development. Liang Hong and Rui Wang at Lanzhou University in China developed a practical method for the enan-tioselective introduction of a monofluoro-alkyl group into the oxindole framework (6). The reaction of a wide range of 3-bro-mooxindoles and α-fluorinated β-keto gem-diols afforded the desired products with diastereoselectivities of >20:1 and enantioselectivities of 93-99%. Xufeng Lin and colleagues at Zhejiang University re-ported the first highly enantioselective iso-Pictet–Spengler reaction of C-2-linked o-aminobenzylindoles with trifluoromethyl ketones (7). The reaction is mediated by chiral spirocyclic phosphoric acids as or-ganocatalysts, and the benzazepinoindoles bearing trifluoromethylated quaternary stereocenters were obtained in up to 98% yield and up to >99.5% ee.

Asymmetric hydrogenationAsymmetric hydrogenation is one of the most widely used enantioselective chemocatalytic reactions used at com-mercial scale. Even so, advances in this technology, including its application

Cynthia A. Challener is a contributing

editor at pharmaceutical technology.



API Synthesis & Manufacturing

to a widening range of substrates, con-tinue. A recent example was reported by Xumu Zhang at Wuhan University in China (8). His group developed a Rh-DuanPhos ((1R,1′R,2S,2′S)-2,2′-di-tert-butyl-2,3,2′,3′-tetrahydro-1H,1′H-(1,1′)biisophosphindolyl) complex for the syn-thesis of chiral cyclic allylic amines with up to 99% ee from cyclic dienamides. The products are ideal building blocks for the preparation of chiral, cyclohexane deriva-tives with multiple substituents. Mean-while, Virginie Ratovelomanana-Vidal at PSL Research University and Zhaoguo Zhang at Shanghai Jiao Tong University reported the enantioselective synthesis of γ-hydroxy amides with up to 99% ee via the asymmetric hydrogenation of γ-ketoamides in the presence of a Ru-Xyl-SunPhos-Daipen catalyst (9).

C-H insertion Functionalization of chiral intermediates can also be achieved via asymmetric C-H insertion reactions. In 2013, the H.M.L. Davies group at Emory University re-ported the enantioselective synthesis of highly functionalized 2,3-dihydroben-zofurans from derivatives of veratrol and anisole via two sequential enantioselec-tive C-H insertions involving an inter-molecular carbene insertion catalyzed by rhodium followed by an intramolecular C-H alkoxylation reaction catalyzed by palladium (10). The products could also be further functionalized via a palla-dium-catalyzed intermolecular Heck-type sp2 C–H functionalization reaction.

Carbon-carbon couplingCarbon-carbon (C-C) coupling reactions have become key tools in the synthesis of pharmaceutical and other fine chemi-cal intermediates, and chiral C-C cou-pling reactions are highly valued. Sev-eral new methods have been reported recently, including the diastereo- and enantioselective coupling of alcohols and vinyl epoxides to form asymmet-ric quaternary carbon centers, which was developed by Michael J. Krische at the University of Texas at Austin (11). In this iridium-catalyzed reaction, pri-mary alcohol oxidation leads to reduc-tive C-O bond cleavage in isoprene oxide

to generate aldehyde-allyliridium pairs that combine to form products of tert-(hydroxy)-prenylation, many of which are observed in terpenoid-type natural products. Notably, the reaction proceeds without the use of premetalated reagents or unwanted stoichiometric byproducts.

Meanwhile, Brian M. Stoltz at the Cal-ifornia Institute of Technology prepared (trimethylsilyl)ethyl ester protected enolates via fluoride-induced “thermo-dynamic” enolate formation and used them in palladium-catalyzed asymmet-ric allylic alkylation reactions to obtain α-quaternary six- and seven-membered ketones and lactams (12). The reaction expands the scope of allyl substrates be-yond traditional β-ketoesters and has a high tolerance for reactive functionality.

Two rhodium-catalyzed enantioselec-tive C-C coupling reactions were also recently reported. Vy M. Dong at the University of California, Irvine reported the enantioselective cross-coupling of aldehydes and α-ketoamides via inter-molecular hydroacylation to provide α-acyloxyamides using a new Josiphos ligand (13). Separately, Chen-Guo Feng and Guo-Qiang Lin developed the enanti-oselective rhodium-catalyzed 1,2-addition of arylboronates to cyclic N-sulfamidate alkylketimines, which provides chiral sul-famidates that can be readily reduced to chiral β-alkyl-β-aryl amino alcohols (14).

Finally, Amir Hovedya at Boston Col-lege reported the copper/NHC-catalyzed enantioselective allylic substitution of di- and trisubstituted alkenes with readily accessible (pinacolato)alkenylboron com-pounds to generate 1,4-dienes bearing an asymmetric tertiary carbon (15). The reaction tolerates a wide range of olefins and provides the desired products in up to >98% yield with >98:2 selectivity for the SN2′ vs. SN2 addition and a 99:1 enan-tiomeric ratio (er). The group also demon-strated the applicability of the reaction in the synthesis of several natural products.

Multicomponent couplingMulticomponent reactions are attractive because they often enable the synthesis of complex intermediates in an atom-eco-nomical manner from basic starting ma-terials. These reactions are even of more

interest when they proceed with high stereo- and regioselectivity. At the Uni-versidad de Oviedo in Spain, Francisco J. Fañanás and Félix Rodríguez developed a one-pot, gold phosphate-catalyzed, three-component coupling reaction of alkynols, anilines, and glyoxylic acid that generates sprioacetals with incorporated α-amino acid functionality (16).

Cascade reactionCascade reactions, like multicomponet reactions, are attractive because they pro-vide direct access to complex structures in one pot with few or no undesirable byproducts. Adrien Quintard and Jean Rodriquez of Aix Marseille Université developed a cascade reaction involving the enantioselective reaction of allylic alcohols with diketones catalyzed by an iron catalyst with iminium activation followed by chemoselective acyl trans-fer (17). The γ-chiral alcohol products (3-alkylpentanols) are obtained in up to 96% yield with a 96:4 er and are useful for natural products synthesis.

References 1. S.E. Denmark and H.M. Chi, J. Am. Chem.

Soc. 136 (25), 8915–8918 (2014). 2. T. Mita et al., Org. Lett. 16 (11) 3028–3031

(2014). 3. H.-M. Zhang et al., Org. Lett. 16 (11) 3079–

3081 (2014). 4. M. Zhaou et al., Org. Lett. 16 (13) 3484–

3487 (2014). 5. W. Wang et al., J. Org. Chem. 79 (13) 6347–

6353 (2014). 6. C. Wu et al., Org. Lett. 16 (7) 1960–1963

(2014). 7. X. Li et al., Chem. Commun. 50, 7538-7541

(2014). 8. M. Zhao et al., J. Org. Chem. 79 (13) 6164–

6171 (2014). 9. S.Y. Lee et al., J. Am. Chem. Soc. 136 (25)

8899–8902 (2014). 10. H. Wang, et al., J. Am. Chem. Soc. 135 (18)

6774–6777 (2013). 11. J. Feng et al, J. Am. Chem. Soc. 136 (25)

8911–8914 (2014). 12. C.M. Reeves et al., Org. Lett. 16 (9) 2314–

2317 (2014). 13. K.G.M. Kou et al., J. Am. Chem. Soc. 136

(26) 9471–9476 (2014). 14. Y.-J. Chen et al., Org. Lett. 16 (12) 3400–

3403 (2014). 15. F, Gao et al., J. Am. Chem. Soc. 136 (5)

2149–2161 (2014). 16. L. Cala et al., Chem. Commun. 49 (26)

2715-2717 (2013). 17. M. Roudier et al., Org. Lett. 16 (11) 2802–

2805 (2014). PT



Special Report: pMDI Testing

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Pressurized metered dose inhal-ers (pMDIs) are an inexpensive, frontline technology for the treat-

ment of asthma and other pulmonary diseases. Some patients, however, find it difficult to achieve the coordination needed to successfully use a pMDI. Along with novel breath-actuated pMDIs, add-on devices, such as spac-ers and/or valved holding chambers (VHCs), eliminate the requirement to coordinate device actuation with in-halation and make conventional pMDI technology more effective for a broader spectrum of patients. Globally, the incidence of asthma and chronic ob-structive pulmonary disease (COPD)

continues to rise, and the use of add-on devices is increasing proportionately. This increasing use is reflected in a new, draft United States Pharmacopeia (USP) chapter, issued January 2014, which specifies new test methods for pMDIs with add-on devices (1).

Mark Copley, sales director of Cop-ley Scientific, provides expert insight on why add-on devices are used, how these devices impact drug delivery with a pMDI, and the tests that can be applied to representatively characterize pMDI performance when an add-on device is required.

Add-on devices and the impact on drug delivery

What is an add-on device and why is it used?

Copley: The ‘go to’ technol-ogy for treating asthma and

COPD, pMDIs are small, inexpensive, convenient to use and suitable for the delivery of a wide range of drugs. When actuated, these products use a propel-

lant to aerosolize a fixed volume of liq-uid formulation to a respirable size. To ensure that the aerosolized particles are successfully drawn into the lung, the patient must inhale slowly and deeply upon actuation of the device. However, some patients lack the required coordi-nation to synchronize these two events. This limitation curtails the successful use of pMDIs by certain patient groups, such as pediatrics, geriatrics, and even some adults. Breath-actuated pMDIs are one solution but add-on devices are more routinely used to address this issue because they can be retrofitted to a range of pMDIs that are already on the market.

A spacer is an open-ended piece of tubing or plastic cylinder that is con-nected to the mouthpiece of the pMDI. A VHC is similar but incorporates a one-way valve close to the patient in-terface. With a VHC, the pMDI can, therefore, be actuated into an enclosed dead space. The valve only opens to re-lease the aerosol once the patient starts to inhale. An important advantage of a VHC is that uncoordinated use of the pMDI/add-on device does not result in the exhalation maneuver emptying the holding chamber of the therapeutic aerosol back through the pMDI actua-tor, which can be an issue with a simple spacer design.

Both types of add-on device inter-face with the pMDI at one end, typi-cally via a rubber connection, thereby creating a seal, and have either a mouthpiece or a face mask at the other end to enable easy use by the pa-tient. Either add-on device results in the patient inhaling the drug from a reservoir of aerosolized particles, not dissimilar to a nebulizer, rather than directly from the pMDI. In this way, the add-on devices eliminate the need to precisely coordinate inhalation and actuation, broadening the accessibility of pMDI technology to a wider range of patient groups.

How does the use of an add-on device affect the way in which drug is delivered to the patient?

Exploring Newly Introduced Methods for Testing MDIs with Add-On Devices Mark Copley

The role of add-on devices and how they affect drug delivery with a pressurized metered dose inhaler.

Mark Copley is

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Copley: When a patient uses a pMDI without an add-on device, the drug particles are inhaled almost instanta-neously as the formulation is aerosol-ized. Providing that the patient’s tech-nique is correct, the size of particles inhaled will, therefore, be relatively well defined. Delivered particle size is a function of the device design (actua-tor and canister) and the properties of the formulation, which includes the propellant.

In contrast, when an add-on device is used, the patient inhales drug from a reservoir of aerosolized particles. The additional dead volume provided by the add-on device not only provides an opportunity for aerosol expansion, but also particle impaction, settling, and/or electrostatic deposition, within the add-on device (2, 3). This means that the particle size distribution of the aerosol cloud made available to the pa-tient may change considerably ahead of inhalation. Certain sized particles may be preferentially retained in the spacer and the size distribution of par-ticles received by the patient may now differ from that delivered by the pMDI.

Variability in the drug-delivery process is also introduced by the fact that the device actuation may be completely co-ordinated with the inhalation maneuver, or completely uncoordinated, depend-ing on the technique adopted by the individual user.

Testing pMDI performanceWhat tests are recommended in the proposed USP chapter and how do they differ from the standard tests used for

pMDIs?Copley: The general pharmacopeia

tests for the assessment of pMDI per-formance and for quality control (QC) center on the measurement of two pa-rameters—delivered dose uniformity (DDU) and aerodynamic particle size distribution (APSD). In DDU testing, the pMDI is actuated into a dose uni-formity sampling apparatus (DUSA) that captures the emitted formula-tion on a filter. Subsequent analysis of the captured dose, usually by high-performance liquid chromatrography (HPLC), reveals how much active in-gredient is present.

APSD measurements are made using a multistage cascade impactor (4). This instrument size fractionates an emit-ted dose on the basis of particle inertia, which is a direct function of aerody-namic particle size. Chemical analysis of the collected, sized samples enables the determination of an APSD specifi-cally for the active ingredient.

Because the particle size delivered by a pMDI is generally unaffected by the patient’s inhalation profile, the test conditions applied for these analyses have been set on the basis of conve-nience. The first cascade impactors used in orally inhaled product analy-sis were developed for air sampling and originally designed and calibrated to operate at 1 SCFM (standard cubic foot per minute). This value directly translates to the 28.3 L/min used for APSD measurement today for pMDIs. The same figure has, therefore, been adopted for DDU testing.

The tests set out in the new, draft chapter for testing pMDIs with add-on devices (1) are based on experience gained in Canada over the past 10 years following the publication of a standard for testing by Health Canada (5). The methods ref lect that, as with a nebu-lizer, the amount of drug received by the patient with this type of set-up will be influenced by the inhalation profile of the user. The tests in the new chap-ter, therefore, call for the application of specific breathing profiles during DDU testing to reflect the physiology of the intended user (see Table I).

In DDU testing for pMDIs with add-on devices, the combined product is actuated into a filter housing, thereby collecting the dose in much the same way as a DUSA is used for standard

Table I: Breathing simulator specification for characterizing pressurized metered dose inhalers with spacers and valved holding chambers (1).

Pediatric Adult

Parameter Neonate Infant Child Normal 1 Normal 2

Tidal volume (mL) 25 50 155 770 500

Frequency (min-1) 40 30 25 12 13

Inspiratory/expiratory ratio 1:3 1:3 1:2 1:2 1:2

Minute volume (mL) 1000 1500 3875 9240 6500

The key to successful delivery of an API to the lung is the generation of a particle that is sufficiently

small to be delivered to the lung. In a traditional asthma dry powder inhaler, the micronized API with

a mass median diameter of between 1.1 μm to 5 μm would be blended with a milled carrier material,

such as lactose, and filled into a capsule or device. Upon inhalation, the API particle detaches from

the lactose carrier and travels through the respiratory system until it impacts on the surface of the

lung. Although used for decades, this approach is far from efficient because of the varied particle

size distribution produced as well as the disruption caused to the surface chemistry of the API and

carrier by the micronization and milling processes. In this article, the authors discuss methods of

creating engineered particles for inhaled drug delivery and the advantages of particle engineering.

To read this article in its entirety, visit PharmTech.com/Aesica_FitfortheLung

Fit for the Lung? By Jon Faulkes and Emma J Mickley, Aesica Pharmaceuticals



pMDI testing. However, a patient rel-evant breathing profile is applied dur-ing testing, rather than a constant 28.3 L/min air flow rate. Furthermore, tests are carried out to measure the effi-ciency of the valve, in the case of VHCs, by comparing the dose received when use is coordinated and uncoordinated with device actuation.

Performance is optimal and directly comparable with a pMDI without an add-on device, if the patient inhales as the device is actuated. This is termed ‘coordinated use.’ In contrast, the worst-case scenario, in terms of per-formance, is if actuation coincides with exhalation, (i.e., ‘uncoordinated use’). Using a suitable breathing simu-lator, testing can be carried out under both of these conditions to provide a ratio of drug delivered and hence the efficiency of the valve. For spacers (without valve), testing for co-ordi-nated use is all that is required. When testing spacers/VHCs with facemasks, these are generally removed, and test-ing is performed using the integral mouthpiece.

Cascade impactors operate at a con-stant flow rate so breathing simulators are not applied during APSD measure-ment. Rather, testing is carried out at a constant flow rate broadly representa-tive of the patient population within the constraints of calibrated commer-cial impactor performance. The next generation impactor (NGI), which has a calibrated f low rate range of 15 to 100 L/min, is a popular choice for this aspect of testing although other cascade impactors can be used. The particle size range of interest for in-halation to the lung is usually taken as sub-five micron, and this is reflected in the tests that recommend compari-son of the sub-five-micron dose (i.e., the emitted fine particle mass) with and without an add-on device.

As with DDU testing, the method specified for APSD measurement has been modified to assess the potential impact of coordinated and uncoordi-nated use. Testing is carried out with impactor sampling and actuation co-ordinated and, in the case of VHCs,

also with impactor sampling starting after a two-second time delay. This delay provides time for the particle size distribution to evolve inside the VHC and directly quantifies the im-pact of uncoordinated use in terms of the dose that is likely to deposit in the lung. Testing after five and 10 seconds provides further insight into the resi-dence behavior of the aerosol within the add-on device and is also recom-mended (5).

Is new equipment needed to test in accordance with the revised USP chapter?

Copley: For a laboratory working solely on pMDI technology, it may be that new equipment will be re-quired given that the new draft chap-ter calls for the application of breath-ing profiles during testing. However, breathing simulator technology has advanced considerably in the last de-cade, and cost-effective, compact mod-els are increasingly a standard piece of inhaled product testing equipment.

The Copley Scientific BRS breathing simulator range, for example, includes a number of models specifically tai-lored to the testing of different orally inhaled products. These systems en-able the user to:• Apply different wave patterns (e.g.,

square, sinusoidal, triangular, or user defined)• Alter tidal volume (i.e., the volume

of each inhalation and/or exhalation)• Separately vary the duration of in-halation and exhalation, if required (inspiratory/expiratory ratio)• Introduce a delay after inhalation

and/or exhalation• Control the number of breathing

cycles during each test• Commence the breathing cycle at the

beginning of the inhalation or exhala-tion maneuver.

The availability of such flexible sys-tems is supporting the application of breathing simulators beyond the scope of the pharmacopoeial test methods to more generally explore the per-formance of inhaled products in line with quality by design (QbD) (6). At

the same time, these units also make it straightforward to test under the conditions specified for pMDIs with add-on devices through the provision of specially developed adapters and filter holders.

To meet the requirement for a time delay between actuation of the device and the start of APSD measurement, a timer-controlled, fast-acting, two-way solenoid valve provides a simple, cost-effective solution. Products, such as the breath-actuated controller BAC 2000 (Copley Scientific), provide near instantaneous starting and stopping of the air flow during testing and have both delay and inhaled time functions (7). Such products streamline testing in line with the new draft chapter, eas-ing the task of gathering the informa-tion required to ensure the safety and efficacy of using pMDIs with add-on devices.

References 1. USP In-Process Revision <1602>, “Spacers

and Valved Holding Chambers used

with Inhalation Aerosols,” Pharmaco-

peial Forum 40 (1) (January 2014).

2. J.P. Mitchell et al., Respiratory Care 52

(3) 283–300 (2007).

3. J. Anhøj et al., Br J Clin Pharmacol.

47 (3) 333–336 (1999).

4. M. Copley, “Understanding cascade

impaction and its importance for inhaler

test ing,” whitepaper, w w w.copley

scientific.com/documents/ww/Under-

standing%20Cascade%20Impaction

%20W hite%20Paper.pdf, accessed

Jul 28, 2014.

5. CSA Group Sta nda rd , CA N/CSA-

Z264.1-02 (R2011) “Spacers and Holding

Chambers for Use with Metered-Dose

Inhalers,” (Canadian Standard Associa-

tion, 2011).

6. M. Copley, “Using breathing simu-

lators to enhance inhaled product

test ing ,”/documents/w w/COP%20

JOB%20251_Using%20breathing%20

si mu lators%20 to%20 en ha nce%20

inhaled%20product%20test ing.pdf,

accessed Jul 28, 2014.

7. F. Chambers et al., “Evaluation of the

Copley TPK-S as a Device for Control

of Delay Times and Inspiration Volumes

Applied to pMDI/Spacer Testing,” poster

presented at APS Inhalation (London,

UK, February 2003). PT

Special Report: pMDI Testing



PEER-REVIEWED

*Anand M. Lahoti, PhD, is research scientist-1, anandlahoti@

neulandlabs.com; Ponnaiah Ravi, PhD, is president–

technical; Neela Praveen Kumar, PhD, is general manager;

V. Innareddy is a research associate; P. S. Deepthi and

V. Shanmugam are both senior research associates; M.

Sudhakar Rao and Vivekananda Reddy, PhD, are both

research scientists, all at Neuland Laboratories Ltd, Research &

Development Center, Hyderabad, AP, India.

*To whom all correspondence should be addressed.

Submitted: Feb. 12, 2013. Accepted: Apr. 23, 2013.

Investigation of Various

Impurities in FebuxostatAnand M. Lahoti, Ponnaiah Ravi, Neela Praveen Kumar, V. Innareddy,

P. S. Deepthi, V. Shanmugam, M. Sudhakar Rao, and Vivekananda Reddy

Febuxostat is a novel, non-purine, selective inhibitor

of xanthine oxidase for hyperuricemia in patients

with gout. It is the first promising substitute for

allopurinol in 40 years. Various synthetic routes

to febuxostat, as well as polymorphic forms and

impurities of the drug, are reported in the literature.

The authors have also identified several impurities

that result from the synthesis of febuxostat. This

article describes the identification and control of

all isomeric, carryover, and byproduct impurities of

febuxostat and its intermediates.

Febuxostat is a novel, non-purine, selective inhibitor of

xanthine oxidase for hyperuricemia in patients with gout

(1). Febuxostat was discovered by Teijin and approved by

FDA in February 2009 (2, 3). The drug reduces uric acid

production by inhibiting the activity of xanthine oxidase, an

enzyme that, in the last step of purine metabolism, converts

xanthine to uric acid (4). Febuxostat has emerged as the

foremost treatment alternative for gout and is considered

the first promising substitute to allopurinol in more than

40 years. Research has shown febuxostat to be well toler-

ated in long-term treatment in patients with hyperuricemia,

including those experiencing intolerance to allopurinol (5, 6).

Febuxostat is a 2-arylthiazole derivative with a methyl

carboxyl group (-CH2COOH). More than 50 polymorphic

forms of febuxostat have been reported, including

Crystal A and several others disclosed by Teijin (7).

While various febuxostat synthesis routes starting from

4-hydroxybenzonitrile have been reported, far less

information on isomeric, carryover, and byproduct

impurities is available (8–11). The impurity profile of a drug

substance is of increasing importance for ensuring the

quality of drug products (11, 12). However, it is extremely

challenging for an organic chemist to identify impurities

that form in small quantities and particularly burdensome

if the product is non-pharmacopoeial (13). This article

describes the identification and synthesis of various

impurities that form during the production of febuxostat

and its intermediates as well as strategies for minimizing

the formation of all isomeric, carryover, and by-product

impurities of febuxostat and its intermediates.

Materials and methods

All chemicals and solvents were purchased from Avra

Synthesis (Hyderabad), Neogen Chemicals (New Bombay),

and Hangzhou Dayangchem (China). Hydrogen-1 nuclear

magnetic resonance (1H-NMR) was performed on a 300-MHz

Fourier transform (FT)-NMR (Brucker) using either deuter-

ated chloroform (CDCl3) or deuterated dimethyl sulfoxide

DMSO-d6 or both as solvent, and tetramethylsilane (TMS)

as the internal standard. Mass spectrometry (MS) was per-

formed on a Quattro micro API mass spectrometer 0–800 Da

in auto specifications. Infrared (IR) spectroscopy was carried

out using a PerkinElmer 100 FT-IR. High-performance liquid iMA

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Impurities

chromatography (HPLC) was per-

formed on a Shimadzu LC system with

Inertsil C18

columns (150 × 4.6 mm, 3.0

μm); acetonitrile mobile phase; 80:20

buffer solution (1.36 g KH2PO

4 in 1 L

water, pH adjusted to 2.0 ± 0.05 with

diluted H3PO

4); and a flow rate of 1.0

mL/min. For Impurity XIX, HPLC was

performed on a Waters LC system

with Chiralpak IC columns (250 × 4.6

mm, 5.0 μm); n-hexane mobile phase;

ethanol:trifluoroacetic acid (EtOH:TFA)

buffer solution (95:5:0.1); and a flow

rate of 1.5 mL/min.

2-Hydroxybenzenecarbothioa

mide (Impurity VIII). Magnesium

Chloride Hexahydrate (MgCl2.6H

2O,

34.1 g, 0.167 mol) was added to a

stirred solution of 2-cyanophenol (10.0

g, 0.084 mol) in dimethylformamide

(DMF, 100 mL) at 25 °C. To this

solution, 30% sodium hydrosulfide

(NaHS, 46.9 mL, 0.252 mol) was

added at 25 °C. The reaction mixture

was heated to 45–50 °C for 15–18 h.

Reaction progress was monitored by

thin layer chromatography (TLC). After

completion of the reaction, the solution was cooled to 25 °C,

and 100 mL of water was added. The solution was adjusted

to pH 1–2 using 5N hydrochloric acid (HCl). The product

was extracted using ethyl acetate (3 × 100 mL), with the

combined ethyl acetate layer washed with water (2 × 50

mL), and finally with brine (50 mL). The organic layer was

evaporated to dryness on a rotavapor. The crude compound

was dried in an air oven at 60 °C for 12 h to obtain Impurity

VIII (10.92 g, 85%).

Ethyl 2-(2-hydroxyphenyl)-4-methyl-1,3-thiazole-5-

carboxylate (Impurity IX). Impurity VIII (5 g, 0.033 mol) in

isopropyl alcohol (20 mL) was heated at 65 °C, and ethyl-2-

chloroacetoacetate (5 mL, 0.036 mol) was added dropwise

for 10 min. The reaction mixture was refluxed for 1 h and

cooled to 0–5 °C for 1 h. The isolated solid was filtered and

washed with cyclohexane (5 mL). The yellow solid was dried

in an air oven to obtain Impurity IX (8.1 g, 95%).

Ethyl 2-(3,5-diformyl-4-hydroxyphenyl)-4-methyl-1,3-

thiazole-5-carboxylate (Impurity X). Hexamine (26.6 g,

0.190 mol) was added to the stirred solution of Compound III

(10.0 g, 0.038 mol) in TFA (50 mL) at 25 °C. The reaction

mixture was heated at 100 °C for 12 h, and cooled to 25 °C.

Following that, 250 mL of water was added and stirred for

1 h and the yellow solid was filtered. The crude compound

was loaded on a silica gel column and eluted with ethyl

acetate: hexane (15:85) to obtain Impurity X (3.81 g, 31%).

Ethyl 4-methyl-2-[4-(2-methylpropoxy)phenyl]-1,3-

thiazole-5-carboxylate (Impurity XI). Potassium carbonate

(21.0 g, 0.152 mol), potassium iodide (0.315 g, 0.002 mol),

Figure 1: Reaction scheme for the synthesis of febuxostat.

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Impurities

and isobutyl bromide (10.37 mL, 0.095 mol) were added to

the solution of Compound III (10.0 g, 0.038 mol) in 50 mL

DMF. The heterogeneous mixture was heated at 70–75 °C

for 10–12 h. When the reaction was completed, the reaction

mass was cooled to 25 °C, and water (150 mL) was added.

The isolated solid was filtered, washed with water (50 mL),

and dried in an air oven to get Impurity XI (8.1 g, 67%).

Ethyl 2-[3,5-diformyl-4-(2-methylpropoxy)phenyl]-4-

methyl-1,3-thiazole-5-carboxylate (Impurity XII). The

experimental procedure is similar to Impurity XI but with

Impurity X used as the starting material.

Ethyl 2- (4-butoxy-3-formylphenyl) -4-methyl-1,3-

thiazole-5-carboxylate (Impurity XIII). The experimental

procedure is similar to Impurity XI but with Compound IV

and n-butyl bromide used as the starting materials.

Ethyl 2-[3-formyl-4- (1-methylpropoxy)phenyl]-4-

methyl-1,3-thiazole-5-carboxylate (Impurity XIV). The

experimental procedure is similar to Impurity XI but the

starting material was Compound IV and 2-methyl propyl

bromide.

Ethyl 2-(4-butoxy-3-cyanophenyl)-

4-methyl-1,3-thiazole-5-carboxylate

( Impur i t y X V ). Hydrox y lamine

hydrochloride (2.4 g, 0.035 mol) and

sodium formate (3.13 mol, 0.046 mol)

were added to a stirred solution of

Impurity XIII (10.0 g, 0.029 mol) in

formic acid (50 mL) and refluxed for

3–4 h (TLC). The reaction mass was

cooled to 25 °C and water (200 mL)

was added. The solid was filtered,

washed with water (100 mL), and

dried in an air oven to obtain Impurity

XV (8.4 g, 85%).

E t h y l 2 - [ 3 - c y a n o - 4 - ( 1 -

methylpropoxy)phenyl]-4-methyl-

1,3-thiazole-5-carboxylate (Impurity

XVI). The experimental procedure

is similar to Impurity XV but with

Impurity XIV used as the starting

material.

M e t h y l 2 - [ 3 - c y a n o - 4 - ( 2 -

methylpropoxy)phenyl]-4-methyl-

1,3-thiazole-5-carboxylate (Impurity

XVII). Compound I (5.0 g, 0.016 mol)

was suspended in methanol (25

mL). Thionyl chloride (3.5 mL, 0.047

mol) was slowly added. The reaction

mixture was heated to reflux for 12 h.

It was cooled to 25 °C and water (250

mL) was added. The solid was filtered,

washed with water (50 mL), and dried

in an air oven to obtain Impurity XVII

(5.0 g, 96%).

4-Methyl-2-[4-(2-methylpropoxy)

phenyl]-1,3-thiazole-5-carboxylic

acid (Impurity XVIII). MeOH:THF (1:1) (50 mL) was added

to Impurity XI (5.0 g, 0.016 mol). NaOH (0.80 g, 0.020 mol)

in water (25 mL) was added to this suspension at 25 °C.

The reaction mixture was heated at 45–50 °C for 1–2 h and

monitored by TLC. The reaction mixture was cooled to 25

°C and water (25 mL) was added. The reaction mixture was

adjusted to pH 1–2 by using 5N HCl (5–10 mL). The fall out

solid was filtered, washed with water (10 mL), and dried in

an air oven to obtain Impurity XVIII (3.5 g, 76%).

2-(4-Butoxy-3-cyanophenyl)-4-methyl-1,3-thiazole-

5-carboxylic acid (Impurity XIX). The experimental

procedure is similar to Impurity XVIII but with Impurity XV

used as the starting material.

2-[3-Cyano-4-(1-methylpropoxy)phenyl]-4-methyl-

1,3-thiazole-5-carboxylic acid (Impurity XX). The

experimental procedure is similar to Impurity XVIII but

Impurity XVI was used as the starting material.

2-[3-Carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl-

1,3-thiazole-5-carboxylic acid (Impurity XXI). The

experimental procedure is similar to Impurity XVIII but the

Figure 2: Impurities identified during the various stages of synthesis of

febuxostat.


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Impurities

starting material was Compound VII, NaOH (0.08 mol), and

recrystallization in MeOH.

2-[3-Carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-

1,3-thiazole-5-carboxylic acid (Impurity XXII). The

experimental procedure is similar to Impurity XVIII but the

starting material was Compound VII in NaOH (0.08 mol), with

recrystallization in MeOH.

Results and discussion

Figure 1 describes synthesis of febuxostat (I) from

4-hydroxybenzonitrile (II) in six stages. The synthesis shown

is a short, concise route and does not require use of poi-

sonous reagents such as KCN (14). Compound II was con-

verted to 4-hydroxybenzothioamide (III) with 85% yield using

NaHS in the presence of hydrated magnesium chloride as

Table I: Characterization data for the various impurities in febuxostat.

No. Impurity 1H-NMR (δ) ppm IR (υ) cm-1 MS (M++ H) m/z

1 VIII6.75–6.80 (t, 1H), 6.88–6.91 (d, 1H, J=8.1 Hz), 7.17–7.23 (m, 1H), 8.04–8.07

(d, 1H), 10.10 (s, 1H)

3364.1, 3191.1,

1621.3. 1604.1153.98

2 IX1.17–1.22 (t, 3H), 2.67 (s, 3H), 4.14–4.21 (dd, 2H, J=7.2 Hz each), 6.75–6.80

(t, 1H), 6.88–6.91 (d, 1H, J=8.1 Hz), 7.17–7.23 (m, 1H), 8.04–8.07 (d, 1H)

3053.6, 2994.3,

2530.3, 1703.4,

1605.7, 1298.7

264.01

3 X1.38–1.43 (m, 3H), 2.80 (s, 1H), 4.34–4.41 (dd, 2H, J= 7.2 Hz each), 8.58 (s,

2H), 10.32 (s, 2H), 11.89 (s, 1H)

2988.3, 1705.0,

1665.2, 1652.4,

1268.3

320.10

4 XI

1.04–1.06 (d, 6H), 1.39-1.42 (d, 3H, J= 7.2 Hz), 2.07–2.16 (m, 1H), 2.78 (s,

3H), 3.77–3.79 (d, 1H, J=6.6 Hz), 4.32-4.39 (dd, 2H, J=7.2 Hz each), 6.93–

6.96 (d, 2H), 7.91–7.94 (d, 2H)

2970.0, 1711.1,

1606.7, 1261.5320.24

5 XII

1.08–1.14 (m, 6H), 1.22–1.28 (m, 3H), 2.20–2.34 (m, 1H), 2.89 (s, 1H),

3.95–3.97 (d, 2H, J=6.3 Hz), 4.33–4.40 (dd, 2H, J=7.2 Hz each), 8.66 (s, 2H),

10.44 (s, 2H)

2958.1, 1710.1,

1684.0, 1607.4,

1258.3

376.16

6 XIII

0.99–1.04 (t, 3H), 1.37–1.42 (m, 3H), 1.51–1.62 (m, 2H), 1.83–1.92 (m, 2H),

2.77 (s, 1H), 4.15–4.19 (t, 2H, J= 7.2 Hz each), 4.32–4.39 (dd, 2H, J= 6.9 Hz

each ), 7.05–7.08 (d, 1H, J= 8.7 Hz), 8.19–8.23 (dd, 1H, J= 2.4 Hz each),

8.35–8.36 (d, 1H, J= 2.4 Hz), 10.52 (s, 1H)

2931.2, 1709.4,

1608.2, 1287.4348.36

7 XIV

1.00–1.05 (t, 3H), 1.37–1.42 (m, 6H), 1.70-1.88 (m, 2H), 2.79 (s, 1H), 4.31–

4.39 (dd, 2H, J=7.2 Hz each ), 4.53–4.59 (dd, 1H, J=6 Hz each ), 7.05–7.08

(d, 1H, J=8.7 Hz), 8.17–8.21 (dd, 1H, J=2.4 Hz each), 8.35–8.36 (d, 1H,

J=2.4 Hz), 10.51 (s, 1H)

2872.2, 1711.9,

1608.2, 1605.4,

1102.3

348.34

8 XV

0.99–1.04 (t, 3H), 1.37–1.42 (m, 3H), 1.53–1.63 (m, 2H), 1.83–1.92 (m, 2H),

2.77 (s, 3H), 4.13–4.18 (t, 2H, J=7.2 Hz each), 4.33–4.40 (dd, 1H, J=6 Hz

each), 7.02–7.04 (d, 1H, J=8.7 Hz), 8.08–8.12 (dd, 1H, J=2.4 Hz each), 8.18–

8.19 (d, 1H, J=2.4 Hz)

2971.2, 2226.7,

1711.0, 1262.2345.18

9 XVI

1.00–1.06 (t, 3H), 1.37–1.42 (m, 6H), 1.69–1.91 (m, 2H), 2.77 (s, 3H), 4.33–

4.40 (dd, 2H, J=7.2 Hz each), 4.48–4.54 (dd, 1H, J=6 Hz each), 7.00–7.03 (d,

1H, J=8.7 Hz), 8.06–8.10 (dd, 1H, J=2.4 Hz each), 8.17–8.18 (d, 1H, J=2.1 Hz)

2970.0, 2226.8,

1711.1, 1261.5345.16

10 XVII

1.08–1.11 (d, 6H), 2.17–2.26 (m, 1H), 2.78–2.80 (d, 3H), 3.90–3.92 (m, 5H),

3.80–3.93 (m, 2H), 7.00–7.05 (dd, 1H, J=3.3 Hz each), 8.08–8.12 (dd, 1H,

J=2.4 Hz each), 8.18–8.22 (dd, 1H, J=2.1 Hz each)

2874.8, 2226.7,

1710.5, 1299.6331.08

11 XVIII1.04–1.07 (d, 6H), 2.06–2.19 (m, 1H), 2.80 (s, 3H), 3.78–3.80 (d, 1H, J=6.3

Hz), 6.95–6.98 (d, 2H, J=8.7 Hz), 7.91–7.94 (d, 2H, J=8.7 Hz)

2965.7, 2530.1,

1680.7, 1604.4292.14

12 XIX0.86–0.91 (d, 3H), 1.38–1.50 (m, 2H), 1.70–1.80 (m, 2H), 2.64 (s, 3H), 4.02–

4.06 (t, 2H), 6.92–6.95 (d, 1H), 7.95–7.99 (dd, 1H), 8.05–8.06 (d, 1H)

2959.2, 2226.4,

1731.7317.09

13 XX

0.92–0.97 (m, 3H), 1.25–1.31 (m, 3H), 1.63–1.74 (m, 2H), 2.65 (s, 3H), 4.64–

4.74 (m, 1H), 7.37–7.40 (d, 1H, J=9 Hz), 8.17–8.20 (dd, 1H, J=2.4 Hz each),

8.25–8.26 (d, 1H, J=2.4 Hz), 13.42 (bs, 1H)

2973.2, 2229.3,

1676.7317.10

14 XXI

0.99–1.00 (d, 6H), 2.08–2.16 (m, 1H), 2.66 (s, 3H), 3.96–3.98 (d, 2H), 7.24–

7.27 (d, 1H, J=9 Hz), 7.59 and 7.77 (2 bs, 2H), 8.01–8.05 (dd, 1H, J=2.4 Hz

each), 8.33–8.34 (d, 1H, J=2.4 Hz), 13.5 (bs, 1H)

3850.2, 2874.3,

1928.4, 1644.9335.21

15 XXII

0.89–1.00 (2d, 6H, J=6.3 Hz each), 1.99–2.08 (m, 1H), 2.65 (s, 3H), 3.87–

3.89 (d, 2H, J=6.3 Hz), 7.20–7.23 (d, 1H, J=8.7 Hz), 8.03–8.06 (t, 1H), 8.21–

8.22 (d, 1H, J= 2.1 Hz), 13.08 (bs, 1H)

3850.2, 2957.3,

1914.9, 1695.1336.11


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Downstream HCPsDetection of those individual HCP that persist

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well as a “% coverage” of individual HCPs.

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The conventional method of 2D Western Blot

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specifcity limitations.

Cygnus ofers a method called Antibody

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Impurities

Lewis acid. Intermediate III, on cyclization with ethyl-2-chlo-

roacetoacetate, gave thiazole ester (IV) with quantitative

yield. In these two stages, the source of potential impurities

was identified as an ortho isomer (i.e., 2-hydroxybenzoni-

trile), which can lead to Impurity VIII and subsequently to

Impurity IX (see Figure 2). Impurities VIII and IX can be con-

trolled in starting material II with appropriate specification.

The ortho formylation of hydroxyl compound IV by using

Duff condition (hexamine/TFA) gave aldehyde V (15). The

major impurity identified in this reaction was dialdehyde X.

Although we have used only 1.0 equivalence of hexamine

with respect to Compound IV, the dialdehyde X impurity

was formed to a 5–10% ratio in only 2.5 h. It is, therefore,

impossible to get rid of this impurity during the reaction, and

only effective recrystallization will eliminate it. Impurity X

was minimized (≤ 2%) by recrystallization using IPA/H2O (3:5)

to get aldehyde V with 50% yield and ≥ 97% HPLC purity.

Aldehyde V, on alkylation with isobutyl bromide in the

presence of potassium carbonate base, gave compound

VI with 90% yield. In this stage, Impurities XI and XII were

alkylations of carryover Compound

IV and dialdehyde, respectively. Two

more isomeric impurities n-butyl-

aldehyde XIII and 1-methyl propyl-

aldehyde XIV were also identified in

this stage. Both isomeric impurities

can be controlled with appropriate

specification for isobutyl bromide.

The reaction of Compound VI with

hydroxylamine hydrochloride and

sodium formate in formic acid at

reflux temperature gave Compound VII

with 85% yield. Impurities XIII and XIV

will also carry forward to impurities

n-butyl-nitrile XV and 1-methyl propyl-

nitrile XVI, respectively.

In the final step, Compound VII was

hydrolyzed using sodium hydroxide

in a MeOH:THF:H2O (1:1:1) solvent

combination to y ield febuxostat

(85%). During saponification, methyl

ester Impurity XVII was identified via

trans-esterification. Its hydrolysis

was comparatively slower than its

ethyl isomer VII. One way to avoid

Impurity XVII is to replace methanol

with ethanol. Carryover impurities

XI, XV, and XVI were also hydrolyzed

to their respective acid derivatives

impurities XVIII, XIX, and XX. However,

the acid derivatives of impurities X

and XII were unexpectedly absent

as impurities. It is believed that,

because they were present in low

concentrations during workup, they

were eliminated in the mother liquor.

Two additional impurities, amide XXI and diacid XXII, formed

by the side reaction of the febuxostat nitrile group with

sodium hydroxide, were identified during saponification.

The amide XXI and diacid XXII impurities can be controlled

by using appropriate equivalence of sodium hydroxide

and controlled reaction time. Febuxostat, on acetone

recrystallization and seed Crystal A at 45 °C, gave pure

febuxostat with 75% yield.

A total of 15 impurities of febuxostat and its intermediates

were synthesized and characterized by 1H-NMR, MS, and

FT-IR (see Table I). Figure 3 shows a HPLC chromatogram

for various impurities (VII, XVII, XVIII, XX, XXI, and XXII)

of febuxostat. Impurity XIX could not be separated with

the same HPLC protocol, so a separate method was

developed to detect its presence. Figure 4 shows a HPLC

chromatogram for impurity XIX. The single known and single

unknown impurity in pure febuxostat specification is ≤

0.10%, and total impurities should be ≤ 0.50%.

400

300

200

100

0

mV

0 10 20 30 40 50min

Det.A Ch1

Imp

uri

ty X

XI

Imp

uri

ty X

XII

Imp

uri

ty X

VIII

Feb

uxo

stat

(I)

Imp

uri

ty X

VII

Imp

uri

ty V

II

Imp

uri

ty X

X

0.005

0.004

0.003

0.002

0.001

0.000

AU

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00

Minutes

Fe

bu

xo

sta

t (I

) -

16

.01

5

Imp

uri

ty (

XIX

) -

17

.67

2

Figure 3: HPLC chromatogram (10% solution of each) for various impurities

(VII, XVII, XVIII, XX, XXI, XXII) of febuxostat.

Figure 4: HPLC chromatogram for Impurity XIX of febuxostat.

contin. on page 67


For the fastest path

to approval...shift to CMIC!

CMIC CMO USA Corporation

Cedar Brook Corporate Center

3 Cedar Brook Drive

Cranbury NJ 08512

609-395-9700

CMIC specializes in development

and cGMP commercial services

for oral solid dose products.

www.cmiccmousa.com

FORMULATIO

N

COMMERCIAL

ANALYTICAL C

LINICAL

[email protected]



PEER-REVIEWED

Melissa Hanna-Brown* ([email protected], tel.:

44.1304.642125) and Roman Szucs are in Analytical R&D at Pfizer,

Sandwich, Kent, UK, and Kimber Barnett, Brent Harrington,

Tim Graul, Jim Morgado, Steve Colgan, Loren Wrisley,

Gregory Sluggett, Gregory Steeno, and Jackson Pellett are

in Analytical R&D, Pfizer, Groton, Connecticut, US.

*To whom all correspondence should be addressed.

Submitted: Sept. 24, 2013. Accepted: Dec. 2, 2013.

Using Quality by Design to Develop

Robust Chromatographic MethodsMelissa Hanna-Brown, Kimber Barnett, Brent Harrington, Tim Graul, Jim Morgado,

Steve Colgan, Loren Wrisley, Roman Szucs, Gregory Sluggett, Gregory Steeno, and Jackson Pellett

The quality-by-design principles that enable a

manufacturer to limit and control the sources

of process variability are equally important to

measurement systems, because the variability in any

process is partly made up of the contributions of the

measurement system variability used to understand

the process. The authors use real-life examples

from drug development projects to outline how an

understanding of chromatographic measurement

system variability might be achieved.

The concept of quality by design (QbD) was introduced

to the pharmaceutical industry in the International

Conference on Harmonization (ICH) guidance documents,

ICH Q8–Q11 (1–4), as a way to develop robust manufacturing

processes for pharmaceutical products and substances.

The aim of these documents is to describe a framework

for developing a deeper understanding of how variability in

the parameters of a manufacturing process can affect the

quality of the final product.

In 2010, the European Federation of Pharmaceutical

Industries and Associations (EFPIA) Subteam on Analytical

Methods introduced the concept of applying QbD principles

to analytical methods (5) where they described two main

objectives: improved method performance and increased

regulatory flexibility. As yet, no pharmaceutical regulatory

standards (analaogous to ICH Q8–Q11) exist that describe how

to apply QbD principles to analytical procedures. This article,

therefore, focuses on how QbD tools may be used to obtain

improved chromatographic method performance in such a way

that is aligned with holistic drug product and substance control

strategies (regulatory flexibility will not be addressed here).

A QbD approach to understanding a measurement system

such as a chromatographic method involves more than

the demonstration of a depth of understanding regarding

the choice of chromatographic separation parameters (e.g.,

through multifactor experimental design/robustness studies).

Instead, to comprehensively follow QbD principles, the

process should start with a statement of method design intent

incorporating method performance characteristics focused

on the minimum quality standard of the data the method

must achieve so as to be fit for purpose. The foundation of

a QbD method is, therefore, a fundamental understanding

of the requirements of what the method needs to measure

and the reliability requirements to which the method will be

judged so as to produce data in compliance with a minimum

quality standard. In other industries, the understanding of data

“quality” is commonly communicated through an expression

of the “uncertainty” associated with a measurement “result”.

This uncertainty is treated with equivalent importance to

the result itself (as it gives confidence in the quality of the

measurement result and facilitates understanding in situations

in which, for example, pass/fail criteria with respect to

specification limits are being assessed). The concepts

0.9

1.1

25

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Rate

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Quality by Design

regarding how to express the uncertainty associated with a

measurement data result can be found in many publications

focused on measurement uncertainty (6-13).

In the pharmaceutical industry, the approach to understanding

the uncertainty associated with measurement results is being

addressed under analytical QbD principles. Here, the design

of method performance characteristics is the foundation for

ensuring measurement data quality can be rigorously controlled.

In line with this, the EFPIA subteam introduced the concept

of the analytical target profile (ATP) (5), which describes the

performance characteristics of the method such that data

the method produces will be “fit for purpose” (e.g., for making

decisions about whether a batch of drug substance or drug

product meets the specification criteria for assay or purity).

Once an ATP has been defined, a systematic process

follows that includes a focus on design of the method

(i.e., choice of technique and drafting of suitable starting

conditions) followed by a full evaluation of the method

using risk assessment tools and multifactorial experimental

approaches. The final step focuses on an expression of the

method conditions or ranges across which the ATP may be

met, together with specific instructions to ensure adequate

control of the method each time it is used. This process is

holistically defined in the schematic in Figure 1. It is important

to note that it is not a one-time process but instead is an

iterative one that should be revisited throughout the lifecycle

of a method. Risk assessments or experiments performed

against the ATP should be made each time any change to the

product or process is made or new knowledge is gained.

Method design

As outlined previously, the

f irst step in QbD method

development is to define the

ATP. There are at least three

important components to be

included in this statement:

• The range for which the ana-

lytical method is expected

to quantify the measurand

(i.e., analyte)

• T h e t o t a l u n c e r t a i n t y,

expressed in terms of system-

atic (accuracy) and random

(precision) uncertainty (i.e.,

variability) components

• A description of the analyte

to be tested, including the

sample or matrix in which it

will be tested.

Accompanying the second

consideration, the level of

risk should be understood for

making incorrect decisions.

The following discussion

outlines ATPs for a combined

assay and purity method for a

real-life drug substance, referred to henceforth as examplain

hydrochloride (HCl):

• Assay: The procedure must be able to accurately quantify

examplain HCl drug substance over a range of 90% to

110% of the nominal concentration with accuracy and pre-

cision such that measurements fall within ± 2.0% of the

true value with at least a 95% probability.

• Purity: The procedure must be able to accurately quantify

all related impurities relative to examplain HCl in the pres-

ence of drug substance and other impurities over a range

from the reporting threshold through twice the specifica-

tion limit. The accuracy and precision of the procedure

must be such that the measurements fall within ± 15% of

the true value for impurity levels ≤ 0.15% with at least 90%

probability and within ±10% of the true value for impurity

levels > 0.15% with at least 90% probability.

Justification of ATP statements. Assay ATP. The

ATP describes method performance requirements that

define the risk of making an incorrect decision concerning

the measurand (14). Analytical methods that adhere

to the criterion stated in the ATP allow decisions (e.g., to

accept or reject a batch based on the reported value) to

be made based on a predefined, maximum level of risk,

which is particularly important when the reported value

is near the specification limit. For instance, a method

that conforms to the assay ATP discussed previously will

produce measurements for which there exists at least 95%

confidence that these measurements reside within ± 2%

of the true (unknown) measurand. That is, there is no more

Selection of draft methodconditions

Continuous verifcaiton

Continuousimprovement

Knowledgemanagement

Technique Selection

Defne ATP

Risk Assessments

Multifactor experimentaldesign

MODR

Defnition of methodcontrol strategy

METHOD DESIGN

METHOD EVALUATION

METHOD CONTROL

LIFECYCLEMANAGEMENT

Figure 1: Enhanced science and risk-based tools and approaches used to develop

a quality-by-design analytical method. ATP is analytical target profile. MODR is

method operable design region.

Al

l f

igu

re

s A

re

co

ur

te

sy

of

th

e A

ut

ho

r



Quality by Design

than a 5% chance of making an incorrect decision against

the stated bounds of ± 2%.

Suppose a potency result of 100% label claim for a release

test of a particular lot is measured. Further, suppose the

analytical method used to obtain this result has been shown

to conform to the ATP discussed previously. The risk that the

true, unknown potency of the lot is below the specification limit

of 98% is less than 5%, because the method conforms to the

statement that at least 95% of measurements will reside within

± 2% of the true value. Consequently, there exists less than a

5% chance that the true unknown value differs by more than 2%

from the observed measured value (95% confidence true value

within 100% ± 2% or 98–102%).

The specification criteria for the assay is 98–102% label claim.

It should be noted that the initial assay specification was 97.0–

103.0%, and the ATP was established based on this orginal

specification. The specification was subsequently tightened

to 98.0–102.0% based on global regulatory feedback, and the

original ATP was found to be fit for purpose with respect to

the revised specification. The ATP criteria, as with ICH method

validation criteria, are established based on considerations for

patient safety and product quality and are consistent with the

capability of analytical methodology used to characterize APIs.

Figure 2a illustrates pictorially the ATP as a probability contour

plot (i.e., parabolic region in dark grey) for the examplain HCl

drug substance assay as described. Here, the total uncertainty

is comprised of precision (σ, random variability) and bias (μ,

systematic variability). Figure 2a also illustrates a rectangular

region corresponding to the more generally applied acceptance

criteria established for analytical measurements, in which

bias and precision are defined independently. In this case,

the rectangle represents the following method criteria: the

measurement has no more than ± 2.0% bias and no more than

1.25% variability.

Several items are notable in Figure 2a. First, the probability

curve (parabolic region in dark grey) is contained within the

more generally applied acceptance criteria (rectangular region

in green). As such, the ATP criteria are slightly more restrictive.

Second, when using the probability curve approach, method

precision criteria (y-axis) is dependent on bias criteria (x-axis)

and vice versa. This is because the total uncertainty, which is

specified in the ATP, is a combination of these two components.

Intuitively, a method with no bias can accommodate more

variability (or lower precision) compared to a method with some

non-negligible bias while providing the same total uncertainty. As

method bias increases towards the ATP limit (±2 in Figure 2a),

the required method variability decreases to zero to maintain the

same analytical performance in terms of total uncertainty. When

using the traditional approach of independent bias and precision

assessments, there is no natural trade-off between those

criteria, thus implying that a method may have both high bias

and high variability (indicated by the yellow diamond in the upper

right-hand corner of the green rectangle in Figure 2a), which

could be problematic if not properly linked to the specification

range. That is, a method operating at the yellow diamond (bias

approximately + 2% and precision approximately 1.25%) does

not maintain a 95% assurance that measurements will be within

± 2% of the true value. If the bias can not be corrected for, then

measurements have only approximately a 50% chance of being

within ± 2% of the true value. Even if this method is corrected

for a known 2% bias (i.e., bias can be measured as different

from random uncertainty), there exist < 90% probability that

measurements will reside within a ± 2% range.

The expression for defining the acceptance region is shown in

Equation 1:

ATP = μ,{ } | y : μ,( )T e

T +e

y p

(Eq. 1)

where µ is true mean/accuracy (a parameter); σ is true

sigma/precision (a parameter); e is allowable analytical

window (a fixed constant); y is individual assay value (a

1.25

1.00

0.75

0.50

0.25

0.00

–3 –2 –1 0 +1

a

+2 +3

True deviation from target (%)

σ(%

)

10

8

6

4

2

0

b

σ(%

)

–20 –15 –10 –5 0 +5 +10 +15 +20


Figure 2: Representation of the analytical target

profile (ATP) for (a) assay and (b) purity determination

of an example substance using the probability

curve approach (grey parabolic curve) where bias

and precision are interdependent compared to the

traditional acceptance criteria (green rectangle) where

accuracy and precision are treated separately.

contin. on page 56


www.cphi.com@cphiww #cphiww

Earlier this year CPhI Pharma Insights reports revealed

that 70 per cent of the pharmaceutical industry is actively

investing in manufacturing techniques and technologies,

and 41 per cent is outsourcing more of their manufacturing

to other organizations. The market continues to become

increasingly complex and segmented as these changes

take place. At the same time it has become vitally important

to reduce costs while improving product quality and safety

standards in order to remain competitive. Considering this,

efficiency in moving forward and the development of trusted

partnerships have become increasingly essential in achieving

success.

CPhI Worldwide, together with co-located events ICSE,

InnoPack, and P-MEC, offers products and services catered

to specific sectors of the pharmaceutical manufacturing

market, covering the entire supply chain. The expanded

exhibition makes the event the most effective and efficient

place to make valuable business connections.

This year, more than 34,000 attendees and 2,500 exhibitors

from more than 140 countries will converge at CPhI

Worldwide and co-located events for three days. The event

will take place at the Paris Nord Villepinte in France from

7th-9th October 2014. There, senior pharma professionals with global pharmaceutical suppliers

and buyers will gather under one roof to collectively drive business and innovation in the global

pharmaceutical industry.

Celebrating 25 Years of CPhICPhI has been instrumental in bringing together businesses in order to advance the pharmaceutical

industry and initiate business growth. This year marks 25 years of CPhI Worldwide’s success in

fostering innovation and partnerships. To mark this special anniversary, CPhI requested that past

participants submit their success story, highlighting how CPhI was a catalyst for initiating growth and

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Highlighting exhibitors and attendees who made valuable connections through CPhI Worldwide,

25 success stories will be featured in a special anniversary publication available after the event.

During the exhibition the winning success stories will be on display through CPhI TV, while additional

success stories will be filmed at the exhibition on October 7th. These short videos will be on display

at www.cphi.com after the event.

To continue the celebration, CPhI will host a 25th Anniversary Networking Event on October 8th

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Register today for FREE Use media code: NDWW1809

CPhI Worldwide 2014 - Celebrating 25 years of fostering successful pharma partnerships

Mix with the world of pharma products, people & solutions


Complete Supply Chain Sourcing in at One Event

CPhI Worldwide, along with three co-located events, provide attendees with access to suppliers

across every aspect of the supply chain including pharma ingredients, outsourced services,

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Whilst CPhI focuses primarily on pharma ingredients with exhibitors covering ingredients, APIs,

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A zone-based layout at CPhI and co-located events will make your search for the right business

partners much easier. Reflecting the current trends within the pharma industry, the zones in

each exhibit are adjusted annually to meet the needs of all attendees, providing the opportunity

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Given the increase in outsourcing and necessity of strategic investment, CPhI undoubtedly

provides the best opportunity to generate partnerships and business leads that will drive

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pharmaceutical supply industry.

Conferences and seminars

In addition to attending the exhibition, CPhI worldwide

offers conferences and seminars, introducing attendees

to industry trends and offering in-depth sessions. The Pre-

Connect Congress and new InnoPack Conference both

take place on October 6th, leading up to the exhibit. These

pre-exhibition events offer the exclusive opportunity to

join senior executives and influential speakers from across

the pharma industry in networking and strengthening

your knowledge base on a variety of key topics such as

packaging innovation, strategic partnerships, and drug

delivery systems.










The Pre-Connect Congress offers eight modules across

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Conference focuses on design trends, innovation,

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Taking place throughout the 3-day exhibition, the

new CPhI Pharma Insight Briefings offer in-depth

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and regional updates on specific markets including

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the challenges and opportunities in these niche areas,

these briefings provide valuable insights for improving

business methods or developing market entry

strategies.

Furthermore, the show features a constant stream of informative content on the latest key

developments via the free sessions in the Speaker’s Corners. Here attendees have the opportunity

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industry whilst also finding out about their latest products, innovations, services and more!

CPhI Global Meetings Programme- facilitating high-

quality business meetings

Every year, over 94% of visitors make new business contacts at CPhI Exhibitions. Taking place

across the three-day show, the Global Meetings Programme facilitates high-quality meetings,

boosting ROI for all participants. The Global Meetings Programme provides exhibitors and

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Once registered, the official show meetings service is accessible prior to your arrival at CPhI,

allowing for advanced research into potential meeting targets based on market, sub-sector and

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ensuring a full diary that suits your schedule.

Women’s Networking Breakfast

In 2013, 24% of women globally held senior leadership roles, up 5% from 2004. This welcome growth

in diversity is expected to continue. To celebrate, CPhI Worldwide hosts its first annual Women’s

Networking Breakfast, providing an inspirational morning of networking education and empowerment

for women in the pharmaceutical industry on October 8th at Villepinte Paris.

Women from across the pharmaceutical industry will have the opportunity to hear empowering

messages from some of the pharmaceutical industry’s female thought leaders, as well as an

inspirational program by our partner charitable organization, Global Angels. Ample time will also be

allocated for networking and creating connections within the pharmaceutical industry’s community of

women.

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innovations today

In their 11th year, the CPhI pharma awards continue to honour

distinguished thought leaders within the industry. In addition

to annual awards in ‘Formulation’, ‘Process Development’ and

‘Packaging’, a new category recognizing ‘Innovation in Partnering’

debuts this year. Supported by Pharmaceutical Outsourcing

magazine, this award honours partnering methods, use of

technology, unexpected outcomes and unique partnering practices.

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for the ‘Innovation in Partnering’ Award will be published on the CPhI website and in Pharmaceutical

Outsourcing magazine, inviting attendees and readers to vote online. Finalists for the three remaining

categories will present their innovations during the morning of the first show day (7th October) to the

jury, press and visitors. Winners will be announced at a ceremony on the afternoon of 7th October.

To learn more about the awards or to submit an award entry, please visit http://www.cphi.com/awards.

Bienvenue à Paris

When not at CPhI attendees can explore the beautiful city of Paris and the surrounding region.

Internationally renowned sites, including the Eiffel Tower, Notre Dame, Louvre, Musée d’Orsay and

Sacré-Cœur, are just a short trip from the exhibition centre. Home to more than 130 museums, 200

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Quality by Design

random variable with mean

µ and standard deviation σ);

T is true analytical content

(fixed target); p is minimum

probability for individual assay

to reside within error bound

e (fixed constant); ϕ is normal

density function centered at µ,

with standard deviation σ.

U s in g Eq u a t i o n 1, t h e

i n t e r p l a y b e t w e e n t h e

appropriate analytical window

(e), maximum sigma (σ), and

minimum probability (p) can

be probed for each unique

analytical method.

Purity ATP. In this example,

the speci f icat ion cr i ter ia

detail the limits for all related

(sp ec i f i ed ) impur i t ie s to

examplain HCl with specified

impurities A and B both with

limits of not more than 0.15%.

Figure 2b illustrates the

ATP as a probability contour

plot for the examplain HCl

drug substance impurities

a s d e sc r ib e d p rev io u s l y

(i.e., parabolic region in dark

grey). The total uncertainty

is comprised of precision (σ,

random variability) and bias (μ,

systematic variability).

Figure 2b also illustrates

a r e c t a n g u l a r r e g i o n

corresponding to the more generally applied acceptance

criteria established for analytical measurements, where

bias and precision are defined independently. In this case,

the rectangle represents the following method criteria: the

measurement has no more than ± 15.0% bias and no more

than 10% variability. Here, the maximum allowable bias and

precision is consistent with what can be expected for analytical

procedure performance at these levels. For example, for levels

≤ 0.15% relative to examplain, the maximum allowable precision

is 9.1% RSD and the maximum allowable bias is ± 15%.

There is a trade-off between precision and accuracy, such

that it is not acceptable for the method to exhibit maximum

bias and maximum variability concurrently, and, as with the

assay ATP, the purity ATP criteria is slightly more restrictive

when compared to the ICH validation criteria that would

have typically been applied. From a practical perspective,

the ATP criteria can be interpreted as follows: 9 out of 10

measurements will fall within 100% ± 15% of the true value,

which corresponds to a range in which at least 9 out of 10

measured values will reside within 0.13% to 0.17%. This

level of measurement uncertainty ensures patient safety. It

is consistent with the philosophy of ICH Q3A (Impurities in

New Drug Substances) as well as the current capability of

contemporary analytical methodology used to quantitate

low-level impurities in pharmaceutical drug substances.

In fact, contemporary method capability was taken into

consideration when the limits in ICH Q3A were established.

Analogous statements can be made for ATP criteria for

impurities > 0.15% where the maximum allowable precision is

6.1% RSD and maximum allowable bias is ± 10%. This means

that an impurity present at 0.3% (true value) corresponds to a

range in which at least 9 out of 10 measured values will reside

within 0.27%– 0.33% (i.e., true value ± 0.1 x true value). This

tiered approach ensures that performance of the procedure is

maintained for higher level impurities while ensuring patient

safety and aligning with contemporary procedure capability.

Technique selection. Once appropriate ATP criteria have

been established, a technique should be selected. This selection

Key predictive

sample set

If i.d. of

components

known

Plot of Log(P)

vs. pH

Column,

pH, buffer

organic solvent

screening/optimization

Temperature

gradient profle


pH


Seek alternative

mechanism

Separation

verifcationDraft

method conditions

Meeting analytical target

profle and business

requirements

Targeted

experimentation

Software assisted

optimization

N

Y

N Y

Figure 3: Representation of a systematic approach to reversed-phase liquid

chromatographic method development.

Peer-Reviewed – contin. from page 51



Quality by Design

depends not only on the match between measurement

technique capability and ATP, but also on other scientific,

practical, and business requirements. Typical considerations

to bring to the discussion table between scientists who may

be involved in using the method across the development

lifecycle could include the physicochemical characteristics of

the molecules in question, whether the method will be run in

an R&D environment or a manufacturing environment, if on-line

capability might be required, what sample turn-around times

(from sampling to data reporting) are going to be necessary, and

a plethora of other scientific and business-focused factors.

In the case examples discussed in this article, following

such a discussion between R&D and receiving laboratory

analytical scientists, reversed-phase high-performance liquid

chromatography (RP-HPLC) was the method of choice.

Systematic method development. Once a technique

has been chosen, a systematic process to arrive at “starting”

or “draft” method conditions should be followed. In the

case of RP-HPLC, the approach is shown in Figure 3. Here,

experimental studies are combined with in-silico modeling

software to maximize the value of the results by being able

to predict between experimental parameters (15, 16).

At the start of the process, it is essential to define

the correct key predictive sample set (KPSS). For a

pharmaceutical example, the KPSS available will be highly

dependent on the drug-development lifecycle stage, and the

ideal KPSS for an API purity method should include all known

process related impurities and known relevant potential

degradants. If structures are known, then the experimental

screening strategy may be supplemented by the information

to be gleaned from a Log(P) vs. pH plot (P is the octanol water

distribution coefficient of all analytes of interest). The column

screening strategy employed in our laboratories and for

the examples discussed here encompasses four stationary

phases; two organic solvents; and acidic, neutral, and basic

aqueous mobile phases (15). The primary objective of the

screening is to obtain the most promising starting conditions

with respect to overall selectivity, peak shape, and chemical

stability, as well as minimal reliance on accurate pH control.

The next step is to investigate the combined effects of

temperature and gradient profile using the starting conditions

from the first phase of screening experiments (i.e., stationary

phase, pH, and organic modifier). This experiment aims to

explore the impact of various gradient profiles together

with a range of temperatures across six experiments. The

data obtained are modeled using software (e.g., ACD Labs

LC Simulator), which allows the scientist to interpolate or

extrapolate beyond the tested range to gain maximum value

from a relatively low number of experiments. In the example,

the data from the six experiments are used as the input for

in silico optimization experiments. The result is a resolution

map and optimized chromatogram within which the optimum

conditions with respect to overall peak shape, resolution, and

analysis time may be predicted (Figure 4).

The final stage of this systematic approach to method

development is to check the effect of small changes in pH

96

88

80

72

64

56

48

40

32

24

16

8

0

0.0045

0.0040

0.0035

0.0030

0.0025

0.0020

0.0015

0.0010

0.0005

3.44

3.30

3.15

3.01

2.87

2.72

2.58

2.44

2.29

2.15

2.01

1.86

1.72

1.58

1.43

1.29

1.15

1.00

0.86

0.72

0.57

0.43

0.29

0.14

0.000

5 10 20 30 40min

15 25 35

8 16 24 32 40 48 56 64 72 80 88 96

Solvent B, %

Co

lum

n T

em

pe

ratu

re,

ºC

TFA

0.025 0.075

TFA

0.025 0.075

43

3721

Change15

30 Start

End

43

3721

1530

43

3721

Change15

30 Start

End

43

3721

1530

43

3721

1530

43

3721

1530

43

3721

1530

43

3721

1530

0.9

1.1

25

35

Temperature

Flow

Rate

0.9

1.1

Flow

Rate

Figure 4: Example output of the in silico optimization of

temperature and gradient profile.

Figure 5: Experimental design for assay and purity of

example substance.



Quality by Design

on the method performance. The pH is typically varied by up

to +/- 1.0 pH units across five experiments (e.g., +1.0, +0.5,

0, -0.5, -1.0 pH units). Again, the data resulting from these

experiments may be evaluated using software packages,

such as the LC Simulator software, which allows for a more

thorough understanding regarding the most suitable pH that

will yield a more robust separation.

Experience with this systematic approach to method

development indicates that approximately 75% of all

applications lead to a successful (i.e., fit for purpose) method.

In the remaining cases, various degrees of variations from

the workflows have to be explored. For example, use

of alternative buffer components, ion-pairing reagents,

alternative column chemistries, and even completely different

separation mechanisms can be applied.

Method evaluation

Risk assessment. The risk-assessment exercise involves a

systematic assessment of the draft method. The risk assess-

ment process is designed to map individual method steps (e.g.,

standard and sample preparation or chromatographic separa-

35.0

32.5

30.0

27.5

25.015.0 16.5

TFA = 0.04%

a

18.0 19.5

Critical Pair Res: 1

21.0

Gradient Change Time (min)


= 0.04% TFA / 25 ºC / 15 min gradient


= 0.04% TFA / 32 ºC / 1.0 mL / min Flow Rate / 0.5 in

Gradient Start / 18 min Gradient Change



Gradient Start = 0.5 minFlow Rate = 1.05 mL / min

Tem

pera

ture

(ºC

)

35.0

32.5

30.0

27.5

25.015.0 16.5

TFA = 0.04%

c

18.0 19.5


21.0

Tem

pera

ture

(ºC

)

35.0

32.5

30.0

27.5

25.015.0 16.5

TFA = 0.04%

b

18.0 19.5


21.0


Tem

pera

ture

(ºC

)

Injection volume* (µL)

Mobile phase TFA** content (%)

Column temperature (°C)

Flow rate (mL/min)

Gradient start time (min)

Gradient change time (min)

Gradient end time (min)

Chromatographic Parameter 1 2 3 4 5 Target

Condition

9, 10, 11

0.04

25

1.05

0.5

15.0

40.0

9, 10, 11

0.04

32

1.05

0.5

19.0

40.0

9, 10, 11

0.06

32

1.05

0.5

15.0

40.0

9, 10, 11

0.06

25

1.05

0.5

19.0

40.0

9, 10, 11

0.04

32

1.00

0.5

18.0

40.0

10

0.05

30

1.00

1.0

18.0

40.0

Figure 6: Assay method operable design region (MODR) verification conditions and results. In (a) and (b), initial results

where condition 2 is seen to “fail” and in (c), final results using verification condition 5; TFA is trifluoroacetic acid.

Table I: Example substance (examplain hydrochloride)

initial experimental design chromatographic

performance acceptance criteria for assay and purity.

Chromatographic method attributes Acceptance

criteria

Accuracy/recovery assay 98.5–101.5%

Accuracy/recovery purity 90.0–110.0%

Critical pair resolution (impurity A: impurity B) >1.5

Relative standard deviation (RSD) at limit of

quantitation (LOQ): (impurity A at 0.05% LOQ)≤ 10% RSD

Tailingnot more than

1.7

Efficiency (theoretical plates) ≥ 50,000

Examplain hydrochlodride retention time 11–17 minutes

Last peak retention time* ≤ 40 minutes

*Retention time was assessed based on operational needs


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Quality by Design

tion) and identify method variables with the potential to affect

method performance with respect to the ATP requirements.

In the case described here, this exercise involved experi-

enced analytical chemists from the method development and

receiving laboratories and included those with some experi-

ence running the method. These participants were included to

ensure that knowledge from previous studies were included

and to understand differences in lab practices between the

development and receiving laboratories. Three distinct focus

areas were examined: (1) sample and standard preparation;

(2) chromatographic separation; and (3) detection and data

processing. Method variables were scored based on their

potential to affect method performance together with the

likelihood of occurrence using a cause-and-effect Matrix. Each

variable was categorized as follows:

• Experimental (X). Those that may vary and require further

experimentation to understand (e.g., temperature, flow rate,

mobile phase composition)

• Controlled (C). Variables that can be controlled or specified

at unique levels (e.g., column stationary-phase type and

particle size, column diameter, length, and supplier)

• Noise (N). Those that cannot be controlled or are allowed to

vary randomly from a specific population (e.g., column age).

Method variables with the highest scores (i.e., combined

high probability and high impact on chromatographic

performance relative to the ATP) were further assessed

by way of multifactor experimentation. An example of the

multifactor experimentation from the chromatographic

separation focus area follows.

Multifactor experimental design. Two separate design-

of-experiments (DoE) studies were performed to identify

and verify the optimum method conditions. The first DoE

was conducted to explore and identify a preliminary set

of chromatographic conditions for further verification. The

second DoE was conducted to verify conformance of the

method to the ATP criteria.

Figure 5 represents the experimental region from the first

wave of experimental design studies (DoE-1). This design

included the following parameters which were identified

during the risk assessment as having the highest potential

to influence the chromatographic separation: flow rate,

trifluoroacetic acid (TFA) content in mobile phase, column

temperature, gradient change, and start and end times. A

preliminary set of suitable operating conditions was identified

by assessing the chromatographic performance measured

during DoE-1 against the predefined criteria shown in Table I.

1.25

1.00

0.75

0.50

0.25

0.00

σ(%

)

Ð3 Ð2 Ð1 0 +1

Lab 1

Lab 2

+2 +3


Simultaneous 95% confinterval for {accuracy, precision}

Simultaneous 95% confinterval for {accuracy,

precision}

Simultaneous 95% confinterval for {accuracy,

precision}

Lab 2 - estimate ofaccuracy & precision




Estimate ofaccuracy & precision

10

8

6

4

2

0

σ(%

)

Ð20

10

8

6

4

2

0

σ(%

)

Ð15 Ð10 Ð5 0 +5 +10 +15 +20

True deviation from target (%)Ð20 Ð15 Ð10 Ð5 0 +5 +10 +15 +20


a

b c

Figure 7: (a) Probability contour plot illustrating the analytical target profile (ATP) assay criteria in terms of accuracy

(x-axis) and precision (y-axis) (shown in grey). (b) Probability contour plot for Impurity A at levels > 0.15% illustrating

the ATP purity criteria in terms of accuracy (x-axis) and precision (y-axis) (shown in dark green). (c) Probability contour

plot for Impurity B at levels ≤ 0.15% illustrating the ATP purity criteria in terms of accuracy (x-axis) and precision

(y-axis) (shown in dark green). In a-c the two points represent combined results for two separate laboratories.


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Quality by Design

The results of DoE-1 were used to identify the variables

that may affect chromatographic performance. Statistically

significant effects at the commonly-accepted 0.05 level of

statistical significance were determined using Student’s

critical t-values. Statistical models of these results were

developed for each method attribute and used to define

the variable ranges over which the method is expected

to meet the predefined criteria in Table I. These ranges

of chromatographic variables defined a preliminary

experimental design space referred to as the method

operable design region (MODR).

A subsequent experimental design study (DoE-2) was

executed to verify that the method complied with the

criteria specified in the ATP. Verification testing was

per formed using experimental conditions spanning

the preliminary predicted MODR identified from DoE-1

results. Based on the data analyses from DoE-1, the three

parameters that had the largest collective impact on both

resolution and limit of quantitation (LOQ) were the gradient

change time, the column temperature, and the mobile

phase TFA concentration. To select the method conditions,

a standard 23-1 design was chosen that spanned a predicted

acceptable range of method performance. Specifically, the

gradient start time was varied between 15–19 minutes,

the column temperature between 25–32 °C, and TFA

content between 0.04–0.06%. The other parameters that

had an impact on method performance were flow rate

and gradient start time. For this experiment, however,

those levels were fixed at values that would stress the

system in terms of performance; that is, at levels nearing

the predefined criteria. Flow rate was set at 1.05 mL/

min and gradient start time at 0.5 minutes. Gradient end

time did not affect method performance. Testing was

conducted over four days, by two analysts, in two different

laboratories (development and testing labs) using HPLC

systems from two vendors (Agilent and Shimadzu).

The chromatographic variables used to verify the MODR are

shown in Figure 6. Verification testing was initially performed

using conditions 1–4. Figure 6a and 6b show how results

using conditions 1, 3, and 4 all met ATP criteria. Results

generated using condition 2, however, failed to adequately

meet ATP criteria due to insufficient resolution (Rs < 1.0) for

the critical pair. This is illustrated in Figure 6a where condition

2 is clearly within the red shaded region. As a result of this

failure, the MODR model was refined, and a new combination of

verification variables, condition 5, was added.

In lieu of preparing separate solutions, injection volumes

of 9, 10, and 11 µL were used to verify conformance to the

ATP over the range of 90–110% of the nominal injection

concentration. The flow rate was held at 1.05 mL/min for

the original verification study (conditions 1 –4), as a flow rate

slightly above the 1.0 mL/minute target was considered a

worst case scenario based on the results from DoE-1. The

flow rate was changed to 1.00 mL/min (the target condition)

for condition 5. The final verified MODR incorporating

verification condition 5 is illustrated in Figure 6c.

As a means of visualising how these results from both

labs during DoE-2 comply with the ATP, Figure 7a shows the

probability contour plot (using Equation 1) illustrating method

variability (σ≈relative standard deviation or RSD) vs. calculated

bias/process acceptance criteria (98–102% potency). The

grey-shaded region is the graphical representation of the

ATP criteria for the assay method. Each point represents 24

replicates at each of the five MODR verification parameters

run in the two different labs. This graph illustrates minimal

(statistically insignificant) bias relative to the proposed 98.0–

102.0% assay acceptance criteria. Although slightly greater

variability was observed for Lab 2 results, all results fall within

the ATP for the assay method (grey region). The triangular

regions surrounding each point represent the simultaneous

95% confidence interval for accuracy and precision for each

of the points as described in Lindgren’s Statistical Theory (14).

Similarily, the probability contour plots in Figure 7b and

Figure 7c illustrate method variability (σ≈ RSD) vs. calculated

bias/process acceptance criteria for results generated from

both laboratories for impurity A at > 0.15% and impurity B at

≤ 0.15%, respectively. Each point represents 24 replicates at

each of the five DoE conditions run in the two different labs.

The simultaneous 95% confidence interval for accuracy and

precision is also shown on the plots. These results illustrate

34

32

30

28

26

15 16 17 18 19 20 21

(minutes)

Gradient Change

Tem

pe

ratu

re

(ºC

)Figure 8: Final verified method operable design region

(white region) for the example drug substance assay/

purity method.

Table II: Operating ranges for the final verified method

operable design region (MODR) for the example drug

substance assay/purity method; TFA is trifluoroacetic

acid.

Chromatographic parameter MODR range Target

Injection volume (µL) 10 10

Mobile phase TFA content (%) 0.04 – 0.06 0.05

Column temperature (ºC) 23 – 32 30

Flow rate (µL/min) 0.9 – 1.0 1.0

Gradient start time (min) 0.5 – 3.0 1.0

Gradient change time (min) 15 – 18 18.0

Gradient end time (min) 37 – 43 40.0


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Quality by Design

how impurity A and B quantitation data meets the ATP

criteria for quantitation of impurities in that > 90% of data are

within ± 10% of expected normalized value for values > 0.15%,

and > 90% are within ±15% of the expected normalized value

for values ≤ 0.15%.

Based on the statistical modelling from DoE-1 and DoE-2,

the entire white region in Figure 8 is predicted to be

capable of meeting the ATP acceptance criteria. For operator

simplicity, however, the operating ranges were constrained to

the ranges listed in Table II.

Method control

The final stage of the development of the method involves

establishing a meaningful control strategy that, when executed,

ensures the method is capable of producing data compliant

with ATP criteria. The concept is analogous to system suita-

bility and involves consideration of method variables that could

affect the ability of final results to meet ATP criteria. In contrast

to traditional practices, however, the control strategy is clearly

linked to ATP criteria and is established based on a rich data

set, including data collected during more rigorous method

development and multifactor experiments. This strategy ena-

bles a more relevant correlation to be established between the

method variables and performance, such that adherence to

ATP criteria is maintained over the lifecycle of the method.

The following method attributes were observed to be

crucial to ensure the method is capable of meeting the ATP at

the time of use:

• Resolution of > 1.0 between the critical pair (impurity A and B)

• Injection precision (% RSD)

• Assay: ≤ 0.85% RSD (n=6) for examplain HCl at nominal

assay concentration

• Purity: ≤ 10% RSD (n=6) for impurity A at 0.05% of nominal

assay concentration

• LOQ: 0.05%, confirmed using injection precision criteria for

purity.

The overall measurement uncertainty, which is constrained

by the ATP criteria, is composed of both systematic (bias or

accuracy) and random (precision or variability) components.

Two precision components associated with the method

that contribute to the total variance at the time of use are

presented in Equation 2.

σ2(Total) = σ2(Instrument) + σ2(Sample Prep) + σ2(Standard Prep)

(Eq. 2)

For this example, total variance is the sum of the

instrument, sample preparation variability, and standard

preparation variability. Based on information collected during

the development and verification of the MODR, standard

and sample preparation variability individually contributed

≤ 0.5% to the total variability. Controlling injection precision

to ≤ 0.85%, along with a maximum contribution of 0.5% for

sample precision, ensures that the operational variability will

be minimized and aligned with ATP criteria.

Continuous verification. The purpose of continuous

verification is to ensure that through the lifecycle of

a method there is a strategy by which assurance can be

gained that the measurement data quality remains within

the requirements of the ATP and, as such, ensures that the

method is under control. Verification would typically include

routine monitoring (e.g., control charts of the measurement

procedure). Such close monitoring of the measurement

procedure every time it is run would allow for close control

of the method and may lead, over time, to refinement of

the method control strategy or indeed the MODR itself. This

approach allows for continual improvement of the method.

It is important to note that to be successfully adopted in an

industrial environment where multiple laboratories may be

using a method, a robust knowledge management system

must be in place which transparently provides up-to-date

information on the most current status of the method

control strategy and MODR.

Conclusion

This article outlines a possible strategy which might be used

to gain an enhanced depth of understanding about a chro-

matographic method as applied to an assay/purity method

in a pharmaceutical setting. Although such an approach is

more resource-intensive than a traditional method devel-

opment exercise, the advantages of data quality, superior

method control, and enhanced confidence in decisions

made using data derived from such a method across its life-

cycle are significant enough to warrant adoption.

References

1. ICH, Q8 (R2). Pharmaceutical Development (2009).

2. ICH, Q9. Quality Risk Management (2005).

3. ICH, Q10. Pharmaceutical Quality System (2008).

4. ICH, Q11. Development and Manufacture of Drug Substances (Chemical

Entities and Biotechnological/Biological Entities) (2012).

5. M. Schweitzer, et al., Pharm. Technol. Eur. 22 (2) 29-37 (2010).

6. V.R. Meyer. J Chromatogr. A. 1158, 15-24 (2007).

7. BIPM, JICM 100: Guide to the expression of uncertainty in measurement (GUM),

(2008).

8. S.L.R. Ellison, M.Rosslein, and A. Williams (Eds.), ‘’Quantifying Uncertainty

in Analytical Measurement,’’ in Eurachem/CITAC Guide (3rd ed.), available

from www.eurachem.org.

9. ISO, ISO 21748:2010, Guidance for the use of repeatability, reproducibility and

trueness estimates in measurement uncertainty estimation (Geneva, 2010).

10. ISO, ISO/IEC 17025:2005, General requirements for the competence of

testing and calibration laboratories (Geneva, 2010).

11. M. Feinberg, et al., Anal. Bioanal. Chem. 380 (3) 502-514 (2004).

12. W . Horwitz and R. Albert. Analyst. 122 (6) 615-617 (1997).

13. J. Wallace. Sci. & Justice. 50 (4) 182-186 (2010).

14. B.W. Lindgren, Statistical Theory (Chapman and Hall, 4th ed, 1993).

15. R. Szucs, et al., ‘’Pharmaceutical Analysis,’’ in Liquid Chromatography:

Fundamentals and Instrumentation, S. Fanali, P.R. Haddad, C.F. Poole, P.

Schoenmakers, and D. Lloyd, Eds. (Elsevier, Amsterdam, 2013), pp 431-453.

16. G. L. Reid, et al., J. Liq. Chromatogr. Relat. Tech. 36 (18) 2612-2638 (2013). PT


October 7, 2014, Paris Villepinte, France

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Technical Q&A: Flexible Manufacturing

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An important part of process design is optimizing manufacturing capacity, efficiency, cost, and, increasingly,

flexibility, which involves the ability to quickly change product capacity or even product type to meet market demand. In new construction or renovation, modular process skids and modular buildings create this flexibility. Pharmaceutical Technology spoke with Herman Bozen-hardt, principal at Bozenhardt Consult-ing Services; Dave Kenyon, PhD, vice-president of Process Sciences at Gallus BioPharmaceuticals; Maik W. Jornitz, president of G-Con Manufacturing; and George Wiker, vice-president, US Life Sciences and Chemicals Market Segment lead, at M+W Group, about modular bio/pharmaceutical manufacturing systems.

Trends in modular constructionPharmTech: What is driving the increasing need for flexibility in bio/pharmaceutical manufacturing?

Kenyon (Gallus): The need for ‘in coun-try/for country’ manufacturing, pressure

to reduce healthcare costs, uncertainty of molecule performance, and uncertain market demands are driving the need for flexibility.

Jornitz (G-Con): There are a multitude of drivers, including cost of goods sold (COGS) and capacity utilization. Every-body wants to use their production ca-pacity to the fullest, which brings down COGS. Optimizing capacity utilization requires either running multiple prod-ucts through a process or being able to easily scale the process without produc-tion interruptions (i.e., requalification).

Single-use technology supports flex-ibility in process technologies, but this flexibility can be hindered by facility in-flexibility. New, flexible facility designs that enable single-use systems and en-hance their flexibility are desired.

PharmTech: How would you describe the current use of modular construction and what trends do you see for the future in pharmaceutical manufacturing?

Bozenhardt (Bozenhardt Consulting): Ex-isting facilities have three main design

problems: old, large, inefficient heating/ventilation/air-conditioning (HVAC) systems that are not segregated for dif-ferent production areas; architectural layouts not designed for today’s regula-tory requirements for unidirectional workflow; and outdated architectural finishes that create the potential for high bioburden. Renovations, some-times completely demolishing and then rebuilding with modular systems, are being used to eliminate these problems and, at the same time, create more flex-ible capacity.

Wiker (M+W): The current commercial use of modular buildings is limited. There is a broad spectrum of modu-larity, and newer technologies provide customers a range of options and cre-ate market competition. The spectrum includes building modules with utility systems and complete cleanrooms (i.e., pods or building modules with process systems), which are available today and expected to be more widely used in the near future. Another modular option is self-contained unit operations that are interconnected with single-use transfer systems.

Product processing systems are also becoming modular, with ‘plug-and-play’ equipment that can be rolled into a cleanroom suite, bolted-on, ands started up quickly. While one module is oper-ating, we can install another module right next to it. Once the new module is qualified and fully functional, we can interconnect the two with just a short in-terruption (e.g., over a weekend) to the existing process.

Jornitz (G-Con): Today’s modular stick-built or container-built structures are becoming obsolete because most of these systems cannot be repurposed and do not have the flexibility required for the future. Modular designs will be replaced by podular designs in the near future. These structures can be used for laboratory purposes, unit op-erations, or whole facilities, which then could become clonable facility plat-forms. These structures can meet new production needs for the cell therapeu-tic and personalized medicine markets, for example.

Modularity Creates Flexible Manufacturing Systems Jennifer Markarian

A roundtable discussion on modular bio/pharmaceutical manufacturing systems to enhance flexibility in facility design.



Kenyon (Gallus): There are more choices on the market today, and module manu-facturers are becoming more familiar with the regulatory constraints modular struc-tures need to meet. Modular construction is an area that will continue to grow in the future as large capital investments are less available and companies work through op-tional strategies. Modular construction can also be a solution for CMOs and their cli-ents to develop and manufacture products.

Benefits and challengesPharmTech: What do you see as the key benefits of modular building in bio/pharmaceutical manufacturing?

Wiker (M+W): Key benefits of modular building include predictability (i.e., mod-ules are pre-engineered and pre-defined) and faster execution that speeds up ‘time to manufacturing’. The construction schedule is accelerated and equipment can be brought up and running quickly. Although the actual cost of the physi-cal materials might be 5–10% more in a modular construction, the net present value is better because construction is faster. With this modular approach, you can add capacity when the market needs it, creating a successful outcome. Ex-pandability (i.e., ‘bolt-on’ capacity) and repeatability (i.e., the ability to replicate plants) are also advantages.

Bozenhardt (Bozenhardt Consulting): Mod-ular building blocks can be constructed

off-site and moved to locations as needed. Off-site construction is generally more consistent with a higher level of quality.

PharmTech: What are the benefits of separating utilities from the overall pro-cess and creating self-contained clean-room modules?

Jornitz (G-Con): Utilities include water, compressed gasses, electricity, and fil-tered air. Connecting these to the entire cleanroom infrastructure would be det-rimental to flexibility, because it would be difficult to verify that the convolution of ductwork is truly clean and sanitized in a product changeover. Leaks, pres-sure losses, and temperature changes in such ductwork accumulates to high operating costs. Having unit operations as separated cleanroom structures with their own air handling systems enables the rooms to be more easily sanitized or turned down when idle, and enhances containment and process control.

G-Con created PODs, which have their own air handling system in a me-chanical space in the back of the POD. This space holds the controller, fire suppression system, and a compact air-handling system; the ductwork can be sanitized with vaporized hydrogen per-oxide. With its own air handling, a POD is a containment system, comparable to an isolator. With the ability to be cleaned and sanitized, the PODs are able to be used for multiple products. In addition,

the system can be scaled up and down, because these autonomous air handling system do not need to be rebalanced when an additional POD is connected.

PharmTech: What are the primary challenges in implementing modular construction?

Wiker (M+W): The market still does not fully understand the value of modular-ity and has not grasped that modularity is closely linked with standardization and the ability to quickly and easily replicate modules. Although clients often select modular systems for pro-cess and facility systems, they often customize those systems, thus dimin-ishing the value by increasing cost and lengthening the overall project sched-ule. As the bio/pharmaceutical market becomes more commoditized (similar to food and nutrition), these clients will likely have little choice but to uti-lize standardized modular systems to rapidly and predictably develop manu-facturing infrastructure.

Jornitz (G-Con): The main hurdle we have to overcome is the typical hesi-tancy to adopt new, revolutionary tech-nology. Also, some calculate only cost per square foot of cleanroom area in-stead of taking the total cost ownership into account. After much education and discussion, however, we are seeing rapid adoption of podular technology by some industry leaders. PT

Peer-Reviewed – contin. from page 46

Conclusion

In summary, 15 impurities of febuxostat and its intermediates

were identified, synthesized, and characterized. All impurities

in the final stage (> 95% HPLC purity) exhibited a well-defined

separation from the parent febuxostat in the HPLC chroma-

togram. Only a single impurity XIX needed a separate HPLC

method. A method to eliminate or minimize these impurities

at various stages during the synthesis of febuxostat was also

demonstrated. This work will help in determining more strin-

gent specifications for the non-pharmacopeial drug substance

febuxostat and enable long-term surveillance on its safety.

References

1. M. Hu and B. Tomlinson, Ther. Clin. Risk Manag. 4 (6) 1209–1220 (2008).

2. S. Kondo, H. Fukushima, M. Hasegawa, M. Tsuchimoto, I. Nagata, Y. Osada,

K. Komoriya, and H. Yamaguchi, “2-Arylthiazole derivatives and pharma-

ceutical composition thereof,” US Patent 5614520, March 1997.

3. C.A. Woods and O. Hilas, Drug Forecast 35 (2) 82-85 (2010).

4. K.K.C. Liu et al., Bioorg. Med. Chem. 19 1136-1154 (2011).

5. L.A. Sorbera et al., Drugs Future 26 32-98 (2001).

6. P.I. Hair, P.L. McCormack, and G.M. Keating, Drugs 68 1865-1874 (2008).

7. M. Iwai, K. Nakamura, M. Dohi, H. Mochizuki, and S. Mochizuki, “Solid

preparation containing single crystal form,” US Patent 7361676, April

2008.

8. M. Hasegawa, Heterocyles 47 (2) 857-864 (1998).

9. J. Canivet et al., Org. Lett. 11 (8) 1733-1736 (2009).

10. T. Yamamoto et al., Chem. Eur. J. 17 10113-10122 (2011).

11. M.H. Kadivara et al., J. Pharm. Biomed. Analysis 56 749-757 (2011).

12. K.R. Wadekar et al., Pharm. Tech. 36 (2) 46-51 (2012).

13. G.D. Patil et al., Org. Process Res. Dev. 16 (8) 1422–1429 (2012).

14. K. Watanabe, T. Yarino, and T. Hiramatsu, “Production of aldehyde deriv-

ative,” Japan Patent 3836177, August 2006.

15. J.C. Duff, and E.J. Bill, J. Chem. Soc. 1987-1988 (1932). PT



Concerns for safety in administra-tion of injectable drug products have escalated in recent years and,

as a result, increased scrutiny of admin-istration practices including consistent withdrawal volume has occurred. In ad-dition, many drugs administered on a regular basis for chronic conditions are now being offered for at-home prepa-ration and administration. This shift highlights the importance of providing therapies that are not only effective, but also easy and convenient to use by providers other than healthcare professionals.

Delivering a consistent dose of drug product to the patient is a crucial as-pect of patient safety and therapeu-tic efficacy. Excess volume is often added to a vial to compensate for the variability in technique of drug withdrawal or reconstitution using a needle and syringe.

For drugs in short supply, formulat-ing a minimum and adequate overfill is vital to maximize available drug prod-uct so that the patient’s therapy is not interrupted. The United States Phar-macopeia (USP) General Chapter <1> Injections provides that each container of an injectable product is filled with a volume that slightly exceeds the content indicated in the labeling (1).

However, even when appropriately labeled, single- and multi-dose vials that contain significantly more drug

than is required for the dose may re-sult in the misuse of the leftover drug product. Similarly, the need to combine several single-dose vials for a single-patient dose may lead to medication errors and microbial contamination.

Inappropriate excess volume and labeled vial f i l l sizes are two fac-tors that may contribute to unsafe handling and injection practices by consumers and healthcare provid-ers. In March 2014, FDA published Draft Guidance for Industry, Allow-able Excess Volume and Labeled Vial Fill Size in Injectable Drug and Bio-logical Products, which addresses fill and packaging issues for injectable drug products packaged in vials and ampules. The draft guidance sug-gests that single-dose vials should not contain a significant volume beyond what would be considered a usual or maximum dose for the expected use of the drug product (2).

Innovations in the drug delivery market have provided administration systems such as needle-free transfer devices, including vial adapters, which are designed to provide consistency when transferring liquid for reconsti-tution of lyophilized drug products from a vial. An internal study (West Pharmaceutical Services) demon-strated that this consistent withdrawal, by use of a vial adapter, can minimize the impact of user variability and has the potential to aid in a reduction of the overfill associated with withdraw variability across users.

Misuse can lead to patient riskAccording to FDA, unsafe handling and injection techniques have led to vial contamination and an increased risk of bloodborne illness transmis-sion between patients (2). Inappropri-ate excess volume may contribute to these practices. When there is more drug than is required for a single dose, pooling of leftover doses may result, a practice that can lead to multiple punctures that may compromise vial integrity and increase the potential for contamination. In addition, excesses or deficiencies in volume may lead to medication errors if the withdrawn dose is too high or too small.

Allowable excess volume, or over-fill, must follow the requirements of 21 CFR 201.51(g) and comply with USP General Chapter <1151>, which requires justification for deviations from the recommendations. FDA rec-ommends that:

• Single-dose vials should not con-tain a significant volume beyond what would be considered a usual or maximum dose for the expected use of the drug product

• Multiple-dose vials should contain no more than 30 mL of the drug product except under specific cir-cumstances.

Determination of the appropriate vial fill volume and excess volume should be included during formula-tion development and should happen no later than the end of Phase II testing.

Minimizing variation of withdrawn volume Maintaining a consistent dose of drug product to the patient is a crucial as-pect of patient safety and therapeutic efficacy. Reconstitution of lyophilized drug product has historically occurred through the transfer of liquid from the diluent vial to the lyophilized drug vial through the use of a disposable needle and syringe. This method can create safety concerns and potential needle-stick injuries.

A variety of technologies are avail-able to aid in the reconstitution and administration of drug products, in-

Minimizing Variationin Vial Withdrawal PracticesZach Marks

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Drug Delivery Safety

Vial adapters can reduce variation of volume withdrawn from injectable drug vials.

Zach Marks is director of marketing,

West pharmaceutical Services, Inc.


API Characterization for a Speedy and

Successful Formulation Strategy

ON-DEMAND WEBCAST

Register for free at http://www.pharmtech.com/strategy

EVENT OVERVIEW:

The physicochemical properties of the API in a solid state are

extremely important as they afect the choice and design of

formulation as well as the performance of the dosage form. A

robust solid-state characterization of the API at an early stage

helps drug developers better understand the properties of

the API and the efect these characteristics have on the drug

behavior, especially on uniform distribution, solubility, stabil-

ity, and its in-vitro dissolution and bioavailability. This informa-

tion impacts formulation and development decisions. In this

webinar, experts examine key API properties and their impact

on formulation design and development decisions.

Key Learning Objectives:

n Understand critical API solid-state characterization

parameters

n Review the impact on formulation design and addressing

drug product performance challenges

n Improve speed and fexibility in early phase development

Who Should Attend:

Presenters:

Anil Kane, Ph.D., MBA

Executive Director,

Global Formulation

Sciences, PDS

Friedrich Brandl

Quality Manager

DSM Pharma Chemicals

Regensburg (ResCom®)

Moderator:

Rita Peters

Editorial Director

Pharmaceutical

Technology

Sponsored by

Presented by

For questions, contact Kristen Moore at [email protected]

n Pharmaceutical

Development Scientists

n Pharmaceutical Analytical

Chemists

n Project Managers

n Process Development

Scientists

n Pharmaceutical Chemists

n Research and

Development Scientists

n Formulation Scientists



Drug Delivery Safety

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cluding vial adapters. A vial adapter functions by snapping securely over the top of a vial, while utilizing a plastic spike to puncture the rubber stopper. It is compatible with Luer lock and Luer slip syringes for liquid transfer. The process of reconstitution and transfer of drug product is accom-plished without the use of a needle.

Vial adapters allow rapid transfer and reconstitution of drugs between vials and syringes. Vial adapter spike technology provides a reproducible engineered depth for drug and diluent aspiration, which reduces the end-user variability associated with traditional needle aspirations, according to in-ternal company testing. Vial adapt-ers are designed to reduce exposure to needle-stick injuries; provide fewer steps, parts, and sharps versus needle and syringe systems; reduce overfill re-quirements associated with withdraw variability across users; simplify the transfer and reconstitution process for novice and experienced users; and reduce the incident of coring associ-ated with hollow needle penetration of the stopper, as demonstrated by West Pharmaceutical Services studies.

Options for vial adapters include air venting, which features a dual-channel spike that facilitates rapid large-volume withdrawal without having to manually over pressure the vial. The design allows for sterile in-bound air and proper aspiration of the drug product while reducing sprayback potential of toxic materials through pressure equalization. A swabable vial adapter features a sterile resealable silicone rubber valve with a Luer-com-patible connector that helps to main-tain sterility for repeat vial access. For multi-dose vials, this adapter can help to reduce the potential for coring and stopper integrity issues. In addition, the swabable valve opens only when connected to/compressed by standard Luer slip or Luer lock syringe to help prevent misuse.

To better understand industry con-cerns surrounding consistent dosing, a study sponsored by West was initiated to compare the volumes of liquid with-

Figure 1: Schematic of needle (left) and vial adapter (right) aspiration methods.

Figure 2: Consistent withdrawal, through the use of a vial adapter can minimize the

impact of user variability.



drawn from a vial using two methods: traditional needle penetration and vial adapter with spike penetration. Figure 1

provides a schematic of the two aspira-tion methods. On the left is a depic-tion of the needle penetration method using a standard needle and syringe system. On the right is a depiction of the vial adapter, which uses a spike in the center of the device to puncture the rubber stopper.

The study compared the with-drawal capabilities of users with vary-ing skill levels using a vial adapter (see Figure 2) and a traditional syringe and needle system.

MethodsThe study included an evaluation of three groups of users and two aspi-ration methods. Table I shows the test matrix, which includes one control group and two experimental groups. The experimental groups consisted of 10 certified nurses and 10 hemophilia patients who had not previously used the vial adapter devices. These groups were chosen as representatives of the clinical (nurses) and at-home (hemo-philia patients) administration settings. The control group consisted of four ex-perienced lab analysts with previous experience using the vial adapters.

The subjects were provided with instructions for use, a video presen-tation, and verbal instructions on how to aspirate the liquid using the two methods. They were supplied with vials containing distilled water, plastic disposable Luer-lock syringes, 19-gauge needles, and 13-mm vial adapters with siliconized spikes. Each subject group completed 100 aspira-tions using each method. The volume of aspirated liquid was determined by weighing the syringes before and after the aspiration procedure. Nurses were given a nine-minute time limit to complete all 10 aspirations for each method to more closely simulate their actual working conditions.

Results and conclusion The average volume withdrawn for each subject group and the standard

deviation for all the subjects within that group are provided in Table II. The lab analysts’ (control) results were similar for the needle and vial adapter withdrawal. A more signifi-cant difference with withdrawal vol-ume between needle and vial adapter withdrawal methods was noted for the nurse group (experimental). The average volume withdrawn was simi-lar between the two methods, but the standard deviation was greater using the needle. The patient group (experi-mental) demonstrated the greatest variability between the needle and vial adapter withdrawal methods.

Overall, the use of the vial adapter resulted in greater consistency for liq-uid withdrawal than the use of a tra-ditional needle withdrawal for both experimental groups. To control the volume of drug product delivered to a patient, it is necessary to first confirm that the appropriate volume of liquid is present in the delivery device and that consistency is maintained from dose-to-dose, as well as user-to-user. As demonstrated in this study, the use of the vial adapter is one method for maintaining consistent liquid with-drawal across doses and users.

Because the vial adapter can provide more consistent dosing withdrawal, its usage may also provide the opportunity to reduce overfill associated with vari-

ability of dosing across users. Reducing risk of inadequate or excessive overfill protects both the patient and the phar-maceutical manufacturer. For a patient or a nurse, the use of the vial adapter provides confidence that they are pro-viding a consistent drug withdrawal. A pharmaceutical manufacturer may realize benefits of cost controls associ-ated with overfill practices and a con-tribution to patient safety as a result of facilitating proper dosing.

It is recommended that pharmaceu-tical manufacturers determine the opti-mum amount of withdrawal volume of the proposed formulation for intended use early in the development process. Manufacturers should then test the re-sidual liquid left in the vial at several overfill volumes, such as 5, 10, 15, and 20% when using the appropriate vial adapter to determine minimum excess volume. By including technologies such as vial adapters during the clinical studies, pharmaceutical manufacturers will be able to evaluate and potentially reduce the excess volume associated with withdraw variability across users.

References1. USP 34-NF 29 General Chapter <1>, “In-

jections”. 2. FDA, Draft Guidance for industry Allow-

able Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products (Rockville, MD, 2014). PT

Table II: Time to visual cleanliness (min).

Needle Vial Adapter

Volume

withdrawn (mL)

Standard

deviation

(mL)

Volume

withdrawn

(mL)

Standard

deviation

(mL)

Lab analysts 2.04 0.102 2.04 0.025

Nurses 1.98 0.106 1.99 0.057

Patients 1.92 0.237 2.00 0.047

Table I: Demographic of test subjects.

Aspiration method Patients Nurses Lab analysts

(Control)

13-mm vial adapters 10 x 10 times 10 x 10 times 4 x 25 times

Needle (19-gauge) 10 x 10 times 10 x 10 times 4 x 25 times

ES493835_PT0914_071.pgs 08.28.2014 19:04 ADV blackyellowmagenta


TROUBLESHOOTING Equipment and Processing

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PharmTech.com/Troubleshooting

In pharmaceutical manufacturing, it is imperative to remove all dirt, debris, and abrasive contaminants, as well

as molds, bacteria, and toxic chemicals from equipment parts. Pharmaceutical manufacturers have successfully used ultrasonic cleaning to clean solid-dos-age tooling, such as pill punches and molds, as well as other equipment, suchas filling-machine valves and nozzles, for years. Cleaning these molds, filling valves, and hoses by hand with a variety of implements, such as toothbrushes or wire brushes, is labor intensive and not always effective because brushes cannot reach many internal surfaces. In addition, hand cleaning or simple agitation often requires fairly aggressive sterilizing clean-ers, which in some instances may requiretechnicians to wear extensive protective gear. Vertical agitation and high impact spray cleaning are other alternatives to hand cleaning, but because contami-nants often settle into minute cracks andcrevices that are hard to reach, ultrasoniccleaning is the most reliable method to remove them. Ultrasonic cleaning elimi-nates hand labor and allows the entire surface to be cleaned. In addition, ultra-sonic cleaning can sterilize equipment if the item is cleaned with 60 °C deionized water and the item’s full surface comes in contact with the ultrasonic wash.

In the ultrasonic cleaning process, a technician places the dirty parts into astainless-steel basket and submerges it into the ultrasonic cleaning tank, which contains an environmentally friendly, water-based cleaning soap. An energy-

converting transducer produces sonic fre-quencies approaching 40,000 cycles per second, creating millions of microscopicvacuum bubbles that implode when they come in contact with a surface. Cleaningoccurs because energy is released by the creation and collapse (called cavitation) of these bubbles. The resultant shock waves break up and lift off dirt, residue, and other contaminants. The implosions work similarly to small vacuum cleanersthat literally pull off caked-on pill residue from any area. Threads, blind holes, and internal cavities are efficiently cleaned when the water-based solution comes in contact with these otherwise inaccessible areas. The contamination is lifted from the machined face and carried away as a suspended particle.

Ultrasonic equipment used in phar-maceutical applications typically isequipped with multi-stage filtration

systems so that these floating particu-lates are filtered out with a micron filterand kept from reattaching to a different area of the part. The micron filters vary in pore size and can be as large as 20microns and charcoal-based to pull out oils, or as low as a one micron. Manu-facturers can use two different rinse baths with different sized filters so that there are no particulates bigger than the smallest filter passing back into the bath.

Parts that are cleaned more thoroughly,such as pill punches or machinery parts with internal mold passages, will not clogwith contamination as quickly, which al-lows pharmaceutical manufacturers to extend the time between scheduled rou-tine maintenance for machinery parts and thus improve productivity. Other benefits of ultrasonic cleaning are lower labor costs and less employee contactwith potentially harsh chemicals. PT

Frank Pedeflous is president of

Omegasonics, [email protected].

An ultrasonic method cleans hard-to-reach

surfaces of solid-dosage equipment tooling.

Frank Pedeflous

Using Ultrasonic Cleaning for Equipment and Tooling

Pharmaceutical Technology spoke with Andy Dumelow, PharmaCare product and market manager at I Holland, about using ultrasonic cleaning.

PharmTech: Why do you recommend ultrasonic cleaning for your tablet tooling?

Dumelow (I Holland): Cleaning is the first step in a planned maintenance and audit program. The main benefit of ultrasonic cleaning is that it is effective at cleaning the fine and delicate details of tablet compression tooling. The microscopic bubbles created by the ultrasound transducers give a very gentle yet thorough cleaning action around the whole punch including the embossing, without the need for abrasive cleaning.

PharmTech: What conditions do you recommend?

Dumelow (I Holland): With the units we supply, we recommend cleaning tablet tooling for 10 minutes at 50 0C. The units must contain a detergent designed for use in an ultrasonic cleaner and for cleaning steel components. Also because the majority of tablet tooling is not stainless steel, a corrosion inhibitor must be used.

PharmTech: How should tooling be inspected after the cleaning process?

Dumelow (I Holland): Without proper cleaning, tooling damage or wear can be missed during an assessment phase of any maintenance procedure. After cleaning and ensuring that the tooling is dried thoroughly, the next step in the process is to assess it carefully. Tooling should be inspected under magnification for defects that can lead to tabletting issues. PT

Ultrasonic cleaning for tablet-press tooling — by Jennifer Markarian


WORRY-FREE WEIGHINGDealing with Static and Drafts

LIVE WEBCAST: Thursday October 9th, 201411:00 am EDT/ 15:00 GMT/ 16:00 BST/ 17:00 CET

EVENT OVERVIEW:

Weighing is one of the most common activities carried out in

the laboratory. In most cases, weighing is the critical frst step in

the preparation of a substance or sample for further analysis or

processing. If the weighing result is unreliable, it can have a pro-

found efect on the quality of the fnal results. However, many

factors that can infuence the accuracy of a weighing are often

overlooked. Learn how to improve the reliability of weighing

and have more confdence in the weighing results generated.

This 60-min webinar will describe the impact of environmental

infuences on weighing accuracy and provide advice on how to

minimize the impact of air turbulence and drafts, temperature

diferences and electrostatic charges. Discover how the latest

developments in weighing technology, including methods and

accessories for analytical and precision balances can help to

reduce or even eliminate these infuencing factors, to make the

tasks of a balance user more straightforward and less prone to

error.

For questions, contact Kristen Moore at [email protected]

Presenters:

Prof. Peter RyserProfessor of Micro-engineeringSwiss Federal Institute of Technology (EPFL)

Julian StaffordSales Trainer, Laboratory Weighing Mettler-Toledo AG

Moderator:

Jennifer MarkarianManufacturing EditorPharmaceutical Technology

Sponsored by Presented by

Key Learning Objectives:

1 Improve weighing accuracy by recognizing common external

infuences

2 Understand how to control electrostatic infuences on

weighing results

3 Discover how to manage temperature diferences to maximize

the accuracy of weighing

4 Recognize the corrective measures that can be implemented to

eliminate the efect of drafts or air turbulence on the weighing

result

Who Should Attend: n Quality Managers, Directors, and

Department Heads

n Analytical Laboratory Managers,

Directors, and Department Heads

n Laboratory Managers, Laboratory

Supervisors, and Production

Managers

n GMP and CMC Consultants, GLP

Auditors, and Quality Consultants

n Anybody who is concerned with

accurate weighing in the laboratory

Register free at www.pharmtech.com/worry



OUTSOURCING OUTLOOK

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es

Biopharmaceutical manufacturing is following the general phar-maceutical market trend toward

global expansion. Fewer clients are considering CMOs’ geographic prox-imity as a critical factor in their partner selection process, according to results from BioPlan Associates’ 11th Annual Report and Survey of Biopharmaceuti-cal Manufacturing Capacity and Pro-duction (1). The study identifies the markets best poised to profit from the internationalization of the outsourc-ing, finding that emerging markets such as China and India are among top potential destinations for both US and Western European companies.

As part of the study, BioPlan asked respondents to consider their five-year time horizon (lead-up to 2019) and to evaluate their facility’s current plans for future international capac-ity expansion (not domestic). BioPlan identified more than 25 countries as potential outsourcing destinations. In cases where respondents did not have an immediate outsourcing need, Bio-Plan believes their answers reflect their hypothetical biases for destinations of choice (see Figure 1).

Among all respondents, the United States ranked highest again as a po-

tential outsourcing destination, with 26.8% (up from 26.3% last year and 16.9% in 2012) of global respondents indicating that there was a “Likeli-hood” or “Strong likelihood” that they would outsource production to facilities there. Following the US was China (24%, up from 10.6% last year) in a rather dramatic jump to the sec-ond position after posting the ninth spot in 2013.

Germany (15.5%) and India (12.7%) were next on the list after the US and China, while Singapore and Switzer-land jointly rounded out the top five, each cited by approximately 1 in 10 respondents.

Although China and India remain popular outsourcing destinations, cer-tain factors limit their attractiveness to biomanufacturers. BioPlan’s 2014 study found that regulatory compli-ance expertise is an increasingly cru-cial CMO attribute. This expertise is likely a reflection of a growing interest in outsourcing core activities for which regulatory manufacturing-related re-quirements are more stringent com-pared with smaller-scale R&D, research reagents, and clinical supplies manu-

facture that have typified international outsourcing and off-shoring in the past.

A keener focus on regulatory issues might hinder the attractiveness of emerging destinations such as China and India, which may not fully have demonstrated, or at least perceived, expertise in this area to rival more es-tablished markets. As one respondent commented: “Off-shoring is too com-plex from a regulatory perspective out-side EU/US.” This sentiment is prob-ably more pronounced for developing markets, which also have to contend with companies’ intellectual property (IP)- and quality-related concerns when outsourcing to CMOs in devel-oping countries, with these aspects also being important considerations when choosing a CMO.

China’s rebound driven by Western EuropeDespite regulatory concerns, the data indicate that China and India are seen as potential destinations in the next five years. Interestingly, China’s prominence this year is the result of an increase in attractiveness in the eyes of Western European respondents. In-deed, this year, China tied the US as a potential destination for outsourcing over the next five years, each cited by approximately 47% of Western Euro-pean respondents. That level was the highest of consideration on record for China, which in 2013 was cited in the single digits.

When asked about predictions of a “Strong likelihood” or “Likelihood” for international expansion of outsourcing

Targeting Different Off-Shore Destinations

Annual study shows geographic

proximity not a factor in CMO selection.

Data indicate that

China and India are

seen as potential

destinations in the

next five years.

Eric Langer

Eric Langer is

president of BioPlan

associates, tel.

301.921.5979, elanger@

bioplanassociates.com,

and a periodic

contributor to

Outsourcing Outlook.


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Outsourcing Outlook

during the next five years, Western European biomanufacturers actually indicated that China was top of their list, a likely destination for 33% of re-spondents, followed by the US at 27%.

The US and China are clearly the top potential destinations for West-ern European biomanufacturers, with Germany, UK, Switzerland, Brazil and Japan each cited by slightly more than 13% of respondents. Of those, the UK and Switzerland both grew as likely destinations from 2013; it should be noted that India did not make the list of top likely destinations for Western Europeans.

US biomanufacturers look first to Singapore While China certainly appears to have increased in its appeal to Western Eu-ropeans, the same can’t be said when it comes to US biomanufacturers. Accord-ing to the study results, US respondents continue to see Singapore as a strong outsourcing destination, with a leading 39% citing the country as a ‘possible’ destination this year (up from 32% in 2013, 31% in 2012, and 28% in 2011). Germany is also growing in consider-ation, coming in a close second again this year, cited by 36% of US respondents as a possible destination (up from 29% in 2013, 25% in 2012, and 22% in 2011).

Trailing a little further behind are India (27%, up from 23%) and Ireland

(also 27%, up from 19%) (multiple re-sponses allowed). Rounding out the top five potential destinations was China, cited by one-quarter of US re-spondents, but the only country of the top five not to see an increase in appeal from 2013.

BioPlan also evaluated US responses indicating more positive consideration for country destinations as either a “Strong likelihood” or “Likelihood.” The top “Likely” destinations for US-based respondents are Singapore and Germany, each with 16% of respon-dents (19% last year) considering it either a “Likelihood” or a “Strong likelihood”. Next were China (14%) and India (11%), although Switzerland and Ireland each had more respondents indicating a “Strong likelihood” of out-sourcing there. It is somewhat surpris-ing that Canada did not make this list, despite Canadian CMOs likely used by more US clients currently than CMOs in countries such as Brazil and Spain,

which did make the list of likely des-tinations.

Offshoring during next five yearsThere will be growing opportunities for CMOs around the world to forge new partnerships with clients, accord-ing to the study, as 47% of respondents indicated that they will offshore at least some of their biomanufactur-ing operations in the next five years, a significant increase from the 30% sharing that sentiment just three years ago. More respondents this year also expect to outsource some process de-velopment for biomanufacturing (43% vs. 35%) and clinical trials/operations (58% vs. 56%). Nevertheless, clients will tread lightly, estimating that they will only offshore somewhere around 10% of those activities in five-years’ time for biomanufacturing operations, clinical trials/operations, and process develop-ment for biomanufacturing.

While there will be growing pool of client prospects for CMOs to market their services, the market will be ex-tremely competitive. Comments from respondents suggest that certain activi-ties will be more likely to go off-shore, including: •Viral studies and cell-line develop-

ment •Fill-finish•Off-shoring administration and

data management •Outsourcing services that do not

need to be performed in real-time •Testing and other routine activities

such as stability studies, analytical testing, and cleaning studies.

For global CMOs opportunities will continue to grow. And as the BioPlan study shows, while certain regional considerations will come into play, cli-ents are as ready as ever to work with partners around the world, if they have the right experience.

Reference 1. BioPlan Associates, 11th Annual Re-

port and Survey of Biopharmaceutical

Manufacturing Capacity and Produc-

tion (Rockville, MD, April 2014), www.

bioplanassociates.com/11th. PT

Figure 1: Top country selections as destination for international outsourcing of

biopharmaceutical manufacturing (all respondents).

USA

China

Germany

India

Singapore

Switzerland

14.1%

15.5% 8.5%

8.5%

1.4% 11.3%

7.0%

7.0% 2.8%

7.0% 2.8%

% Strong likelihood

Source: 11th Annual Report and Survey of Biopharmaceutical Manufacturing, April 2014.

% likelihood

12.7%

Fig

ur

e 1

is

co

ur

te

sy

oF

th

e a

ut

ho

r.

US respondents

continue to see

Singapore as a

strong outsourcing

destination.


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Pharma CaPsules


GE Healthcare Life Sciences Announces New US Headquarters in MassachusettsGE Healthcare Life Sciences

has announced that it will

open a 160,000-sq.-ft. facility

in Marlborough, Mass., as the

new headquarters for its US

operations. The $21-million

facility will employ more

than 500 GE Healthcare Life

Sciences employees.

The company reports that

the investment will transform

a currently unoccupied space

into state-of-the-art labs, cus-

tomer application facilities,

and office space to comple-

ment GE Healthcare Life Sci-

ences’ existing manufacturing

capability in Westborough,

MA. The facility will consoli-

date GE Healthcare Life Sci-

ences’ US East Coast presence.

When fully operational, the

facility will bring more than

220 highly qualified new job

opportunities to the area,

including highly skilled posi-

tions such as lab technicians,

biologists, medical doctors,

process engineers, and cus-

tomer service representatives.

WuXi Facility Passes FDA Inspection for Manufacture of APIWuXiPharmaTech, a phar-

maceutical, biotechnology,

and medical device R&D

outsourcing company with

operations in China and the

United States, announced

that a manufacturing facility

of WuXi’s wholly owned sub-

sidiary, Shanghai SynTheAll

Pharmaceutical (STA), passed

an FDA inspection in July for

the manufacture of API for a

branded commercial drug.

This inspection is the

first FDA inspection of STA’s

facilities for the manufac-

ture of an API. In 2013, STA’s

manufacturing operations

passed an inspection by FDA

for the manufacture of an

advanced intermediate.

Fujifilm Diosynth Biotechnologies Expands Cell-Culture CapacityFujifilm Diosynth Biotech-

nologies will expand its

cell-culture manufacturing

capabilities by adding two,

2000-L single-use bioreactors.

One each of these is being in-

stalled at the company’s sites

in Research Triangle Park (RTP),

NC, USA and Billingham, UK.

The new reactors will

complement the range of

vessels at both sites, adding

further flexibility for cus-

tomer requirements. Each

site currently operates 1000-L

single-use bioreactors with

250-L to 1000-L operating

volumes, with an additional

200-L single-use bioreac-

tor in the UK, and a 2000-L

stainless steel train in RTP,

which has been in place for

a number of years manufac-

turing a range of products.

“The addition of these two

new bioreactors will meet the

demand we are seeing for a

2000-L platform, and offer a

cost-effective, low-risk route

to market through ‘scaling-

out’ from early phase to com-

mercial manufacture,” said

Steve Bagshaw, CEO Fujifilm

Diosynth Biotechnologies,

in a press release. The new

bioreactors are expected

to be operational by No-

vember 2014 in the US and

in the UK in January 2015.

3M Drug Delivery Systems Forms Collaboration with Presspart Group for Dose Counter Technologies3M Drug Delivery Systems

Division has announced a

collaborative agreement

with specialist medical de-

vice and pharmaceutical

component manufacturer,

Presspart Group (a division of

the German-based Heitkamp

& Thumann Group). Under

the terms of the agreement,

Presspart is licensed to sell

3M’s Dose by Dose Counter

and Dose Indicator, adding

to its portfolio of capabilities

with metered-dose inhaler

(MDI) actuators.

The agreement enables

both organizations the

opportunity to accelerate

growth of dose counter tech-

nology in existing and future

MDI development, with

expanded access to a range

of actuator configurations.

Almac to Create 348 New Jobs and Invest £54 Million in Pharma and Clinical ServicesEnterprise, Trade and Invest-

ment Minister Arlene Foster

has announced that the

Almac Group is investing

more than £54 million and

creating 348 high quality jobs

over the next five years.

The Almac Group operates

in the pharmaceutical and

biotechnology sectors provid-

ing services including drug

discovery, diagnostics, R&D,

manufacture of APIs, formula-

tion development, and clini-

cal trials.

The company employs

more than 2100 staff at its

headquarters in Craigavon,

with an additional 1380 staff

located in facilities across

the United Kingdom, United

States, and Asia. The invest-

ment, supported by Invest

Northern Ireland, relates to

two of Almac’s operating

business units, Pharma Ser-

vices and Clinical Services.

G-CON Manufacturing Launches Transmissible Disease Containment PODG-CON Manufacturing

launched a transmissible

disease containment (TDC)

POD, the latest of its modular,

autonomous cleanroom pro-

duction structures. The TDC

POD differs from the typical

G-CON Manufacturing POD in

width (8.5 feet), such that it is

easily transported by tractor-

trailer or its own axle system.

The TDC PODs also have

double bag-in/bag-out HEPA

filters and will be equipped

with generator units. All POD

structures are readily deploy-

able containment and clean-

room systems that include air

handling systems and clean-

able epoxy internal surfaces.

All PODs can be cleaned with

a number of methods, in-

cluding vaporized hydrogen

peroxide (VHP) or chlorine

dioxide. Prefabricated PODs

are typically built in 18 weeks.

Integrated air bearings make

additional support equip-

ment unnecessary upon

delivery.



Ad IndexCOMPANY PAGE COMPANY PAGE COMPANY PAGE

AAPS National Biotech ..................................61

Airbridge Cargo Airlines ................................. 4

Amerisourcebergen Corporation .................11

Ash Stevens ....................................................41

Avantor Performance Materials ...................15

Blanver............................................................ 43

Catalent Pharma Solutions .......................... 84

CMIC CMO USA Corporation ....................... 47

Concept Heidelberg ...................................... 27

CPhI Worldwide ........................... 52-55, 63, 65

Croda Inc ........................................................ 49

Cygnus Technologies .................................... 45

Dow Europe GmbH ........................................13

DPT Laboratories ........................................... 75

EMD Millipore ................................................. 21

Eurofins Lancaster Laboratories ................... 9

GlobePharma ................................................... 6

Hetero USA Inc .............................................. 31

Hospira One 2 One ...................................Insert

INTERPHEX ..................................................... 59

ITT Engineered Valves ................................... 23

Jost Chemical Co ........................................... 37

Meissner Filtration Products .......................... 2

Mettler Toledo ............................................... 73

Parenteral Drug Association .........................18

Patheon Pharmaceutical Svc Inc ............. 3, 69

Pfizer CentreSource ...................................... 39

Pharmsource Information Services Inc ........ 4

Pyramid Laboratories ....................................17

Rapid Micro Biosystems ............................... 29

Rommelag USA Inc ........................................19

S M I ................................................................ 33

Sartorius Stedim N America Inc .................... 7

Spectrum Chemical Mfg Corp ..................... 25

Suheung-America Corporation ................... 40

Veltek Associates ............................................ 5

Vetter Pharma-Fertigung GmbH ................. 77

JULY 2012 Volume 2

ExtendedR


We’re more than just a magazine...

* 52 8 3

PharmTech Digital provides readers around the world with authoritative peer-reviewed research and expert analyses in the areas of process development, manufacturing, formulation and drug delivery, API synthesis, analytical technology, packaging, IT, outsourcing, and regulatory compliance.

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PTE e-Alert

Equipment & Processing Report focuses on pharmaceutical manufacturing process and technology, providing manufacturing news, related regulatory issues, and current trends.

Equipment &

Processing

Report

The PT Sourcing and Management monthly e-newsletter is the authoritative source on sourcing and management within the pharmaceutical’s global supply chain.

PT Sourcing &

Management

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PHARMA CONVERSATION & COMMUNITY

HEADLINES ON PHARMTECH.COM/NEWS

• Sabahaddin Akman, owner of the Istanbul, Turkey, firm

Ozay Pharmaceuticals, has pleaded guilty to charges

of smuggling misbranded and adulterated cancer

treatment drugs into the United States, FDA reports.

Akman pleaded guilty in the US District Court for the

Eastern District of Missouri in St. Louis, MO, where

he initially shipped his illegal drugs. The drugs did not

meet FDA’s standards and had not been approved

for distribution in the US. The FDA’s Office of Criminal

Investigations coordinated a complex, multi-layered

international investigation that led to Akman’s arrest in

Puerto Rico in January 2014. The investigation identified

Akman and his company as a source of Altuzan, the

Turkish version of the cancer treatment drug Avastin.

• FDA investigators identified significant violations of

cGMP regulations for finished pharmaceuticals during

inspections from Oct. 29 to Nov. 1, 2013 at the Kheda,

India manufacturing facility of Marck Biosciences,

according to an FDA warning letter dated July 8, 2014.

Violations included issues with record keeping, employee

training, and product labeling, as well as failure to

maintain buildings in a clean and sanitary condition.

• A new report, CPhI Pharma Insights USA, concludes

that the US market remains the most dynamic

pharmaceutical economy in the world and that

structural changes are presenting new and contrasting

opportunities. Conducted among all major domestic

manufacturers and key international companies,

the report examines domestic perceptions of the

market and how these perspectives contrast with

international organizations investing in the US.

• Bristol-Myers Squibb and Celgene have established

a clinical-trial collaboration to evaluate the safety,

tolerability, and preliminary efficacy of a combination

regimen of Bristol-Myers Squibb’s investigational PD-1

immune checkpoint inhibitor, OPDIVO (nivolumab),

and Celgene’s nab technology-based chemotherapy

ABRAXANE (paclitaxel protein-bound particles for

injectable suspension) (albumin-bound), in a Phase

I study. Multiple tumor types will be explored in the

study including HER-2 negative metastatic breast cancer,

pancreatic cancer, and non-small cell lung cancer.

ON THE BLOG

“Although globalization offers the prospect

of vastly expanding the market for

pharmaceuticals, grasping that opportunity

is easier said than done. For a start, firms

must ensure they understand and comply

with a plethora of ever-changing regulation

that varies from country to country.”Richard Freeman,

sales manager at MeetingZone

“The development of new treatments and

preventives to combat the lethal Ebola

virus has been slow, marked by caution at

public health agencies to approve testing

of high-risk compounds, and reluctance

of biopharmaceutical companies to invest

in a field with limited market potential.”Jill Wechsler, Washington editor

EVENTS

Fundamentals of Cleaning and Disinfectant

Programs for Aseptic Manufacturing Facilities

Oct. 1–2, 2014

Bethesda, MD USA

Management of Aseptic Processing

Oct. 6–8, 2014

Bethesda, MD USA

CPhI Worldwide 2014

Oct. 7–9, 2014

Paris Nord Villepinte, France

Strategies for Reducing

Human Error Non-conformances

Oct. 9, 2014

Bethesda, MD USA

Join our online community

www.PharmTech.com/LinkedIn

http://twitter.com/pharmtechgroup


JULY 2012 Volume 24 Number 7 PharmTech.com

REGULATORY UPDATEEMA and MHRA on the latest inspection deficiencies TROUBLESHOOTINGLyophilisation challenges

INDUSTRY POSITION PAPEREarly development GMPs for small-molecule drugs

Extended- Release InjectablesMeeting manufacturing challenges


G RO U P

We’re more than just a magazine...

Get all this and more. Subscribe now at

www.pharmtech.com

+ access to podcasts web seminars surveys

The PT Sourcing and Management monthly e-newsletter is the authoritative source on sourcing and management within the pharmaceutical’s global supply chain.

Equipment & Processing Report focuses on pharmaceutical manufacturing process and technology, providing manufacturing news, related regulatory issues, and current trends.

Pharmaceutical Technology Europe’s weekly electronic e-newsletter PTE e-Alert provides news, market developments, industry surveys and information on up and coming trade events.

PharmTech Digital provides readers around the world with authoritative peer-reviewed research and expert analyses in the areas of process development, manufacturing, formulation and drug delivery, API synthesis, analytical technology, packaging, IT, outsourcing, and regulatory compliance.

Equipment & Processing

Report

PTE e-Alert

Digital Magazine

The ePT weekly e-newsletter delivers critical information on recent contract awards, company mergers & acquisitions, and fresh news of interest to a highly desired community of pharmaceutical manufacturing professionals.

ePT@PT Sourcing and

Management


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