advances in api development - informa markets

PLUS:

PEER-REVIEWED

Statistical Tools to Aid in the Assessment of Critical Process Parameters

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MARCH 2016 Volume 40 Number 3Extractables and Leachables

Process Control Data

Single-Use Technologies

FACILITIES Determining the Right Facility Size

SUPPLY CHAIN Redefining Pharma Agility

DATA INTEGRITY How Important is Data Integrity?

Advances in API Development

Join us at INTERPHEX New York, Booth #2341

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4 Pharmaceutical Technology MARCH 2016 PharmTech .com

EDITORIAL

Editorial Director Rita Peters [email protected]

Senior Editor Agnes Shanley [email protected]

Managing Editor Susan Haigney [email protected]

Science Editor Adeline Siew, PhD [email protected]

Manufacturing Editor Jennifer Markarian [email protected]

Science Editor Randi Hernandez [email protected]

Community Manager Caroline Hroncich [email protected]

Art Director Dan Ward

Contributing Editors Jill Wechsler [email protected]; Jim Miller

[email protected]; Hallie Forcinio [email protected]; Susan J. Schniepp

[email protected]; Eric Langer [email protected];

and Cynthia A. Challener, PhD [email protected]

Correspondent Sean Milmo (Europe, [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.

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 BudihandojoLachman Consultants

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

Robert DreamManaging DirectorHDR Company

Tim FreemanManaging Director, FreemanTechnology

Sanjay Garg, PhDProfessor and Director, Centre for Pharmaceutical Innovation and Development, 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, PhDProfessor & Vice DeanIrma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center

Russell E. MadsenPresident, The Williamsburg Group, LLC

Heidi M. Mansour, PhDAssistant Professor College of Pharmacy & The BIO5 Research Institute, University of Arizona–Tucson

Jim MillerPresident, PharmSource Information Services Bio/Pharmaceutical Outsourcing Report

Colin Minchom, PhDSenior Director Pharmaceutical Sciences, Shire Pharmaceuticals

R. Christian Moreton, PhDPartner, 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, ResearchBaxter Healthcare

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

Susan J. SchnieppFellow Regulatory Compliance Associates

David R. SchonekerDirector of Global Regulatory Affairs, Colorcon

Aloka SrinivasanPrincipal Consultant, PAREXEL International

Read board members’ biographies online at PharmTech.com/ pharmtech-editorial- advisory-board.

Pharmaceutical Technology’s eNewsletter Team:

t�ePT, Editor Caroline Hroncich, [email protected]

t�Sourcing and Management, Editor Rita Peters, [email protected]

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

t�Send news and product releases to [email protected]

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SALESPublisher Mike Tracey [email protected]

Mid-West Sales Manager Irene Onesto [email protected] Coast Sales Manager Joel Kern [email protected]

European Sales Manager Chris Lawson [email protected] Senior Sales Executive Stephen Cleland [email protected]

Executive Assistant Barbara Sefchick [email protected]

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PFIZER CENTRESOURCE

Bringing the best of

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to quality, compliance and supply reliability.

What’s Next

New name, expanded capabilities, same focus: YOU

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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.

March 2016 Volume 40 Number 3

FEATURES

API SYNTHESIS & MANUFACTURING

32 Polymorph Screening for Identification of Relevant Crystalline Forms

Gauging the adequate level and

type of screening is the challenge.

EXTRACTABLES AND LEACHABLES

46 Building Consensus for E&L Testing Standards

Standardized testing protocols are crucial

for acceptance of single-use systems.

DATA INTEGRITY

50 How Important is Data Integrity to Regulatory Bodies?

Data integrity is a widespread,

global problem that must be addressed.

PROCESS CONTROL

54 Gaining Insight from Process Control Data

Integrated data and cloud-based solutions

can be used for process optimization.

CRITICALITY ASSESSMENT

36 Statistical Tools to Aid in the Assessment of Critical Process Parameters

This article introduces a statistical approach to help determine when a statistically

significant relationship between a process parameter and a CQA is large

enough to make a practical meaningful impact (i.e., practical significance).

PEER-REVIEWED RESEARCH

SUPPLY CHAIN

56 Redefining Pharma Agility

Supply-chain success is measured by how

effectively new medications reach patients,

and how swiftly manufacturers can react to

internal and external changes.

FACILITY DESIGN

60 Flexibility vs. Right-Sizing: Determining the Right Facility Size

Choosing the right facility size requires

tailoring the design for current needs.

COMING IN MARCHVisit PharmTech.com/ebooks to

check out the 2016 Solid Dosage Drug

Development and Manufacturing eBook,

featuring articles on excipients, non-

gelatin capsules, tableting, continuous

manufacturing, regulations, and more!

Continued on page 10

COVER STORY

26 Specialty Markets and Services Drive API GrowthAs specialty API outsourcing grows, manufacturers

and CDMOs are investing for the long haul.

Cover Design by Dan Ward; Images: Ravitaliy/LAGUNA DESIGN/Getty Images

PharmTech.com

PHARMACEUTICAL TECHNOLOGY (Print ISSN: 1543-2521,

Digital ISSN: 2150-7376) is published monthly, except two

issues in June, by UBM Life Sciences 131 W. First St., Duluth

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» Science Citation Index (Thomson)

Pharmaceutical Technology is proud to be a member of DCAT, IPEC, and PDA.

NEWS & ANALYSIS

FROM THE EDITOR

12 Keynote Series Addresses Crucial Industry Issues

Thought leaders tackle drug shortages

and manufacturing innovations.

TROUBLESHOOTING

62 Designing a Biomanufacturing Facility Incorporating Single-Use Technologies

Asking the right questions is crucial.

OUTSOURCING

68 Pharma Outsourcing Market Expands

The pharma outsourcing market

starts 2016 with expansions,

acquisitions, and new offerings.

REGULATION & COMPLIANCE

US REGULATORY WATCH

18 Generic-Drug Production and Oversight Challenge FDA

and Manufacturers

Policy makers debate strategies for

promoting access to less costly medicines.

EUROPEAN REGULATORY WATCH

22 Tackling Regulatory Challenges of EU’s Variations Framework

The EU is striving to reduce the costs and

administrative burden when complying

with variations regulations for keeping

authorization dossiers up to date.

ASK THE EXPERT

78 Phase-Appropriate GMP

Siegfried Schmitt, principal consultant,

PAREXEL, discusses the regulatory

requirements for cGMPs in the

different phases of drug development

and manufacture.

DEPARTMENTS/PRODUCTS

14 Product Spotlight

72 INTERPHEX Planning Guide

77 Showcase/Marketplace

78 Ad Index

Continued from page 8

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See us at Interphex Booth #2221


FROM THE EDITOR

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PharmTech.com/forum

At INTERPHEX 2016 at the Javits Center in New York, Pharma-ceutical Technology will host a

Keynote Series on leading bio/pharma industry issues. Sessions will be pre-sented on the Innovation Stage in the exhibit hall. Admission is free to any attendee with an exhibit hall pass. The following is a preview of the topics.

Overcoming Bottlenecks inBiopharmaceutical Development(Tuesday, April 26, 10:15–11:45 am)Industry experts discuss how technol-ogy advances are addressing challenges in biopharmaceutical development.

Innovations in Solid Dosage Development and Manufacturing(Tuesday, April 26, 1–3:30 pm)Drop-On-Demand Manufacturing System for

the Flexible Production of Solid Oral Dosage

Forms. Dropwise additive manufactur-ing of pharmaceutical products uses drop-on-demand printing for auto-mated and controlled deposition of solution-, melt-, or suspension-based formulations onto edible substrates.

Polymer Thin Films for Drug Delivery: Pro-

cess and PAT Development. Polymer thin film is a platform technology for con-tinuous manufacturing, in which in-

line monitoring of product quality can be accomplished using various sensing and process analytical technologies, making the technology amenable for real-time release.

Minitablets: Manufacturing, Character-

ization Methods, and Future Opportunities.

Manufacturing techniques used to pro-duce minitablet-based dosage forms are essentially the same as manufac-turing of larger tablet images; however, some special considerations to manu-facturing techniques and analytical tests may be required.

Contract Services Market: 2016 Update(Wednesday, April 27, 10:30–11:30 am)How will consolidation in the bio/pharmaceutical and contract services market, a changing financial market, and an active political and regulatory year shape the fortunes of the con-tract services market? In his annual presentation, Jim Miller, founder and president of PharmSource Information Services, will offer his perspectives on the contract services landscape for the next few years.

Strategies and Innovations to Reduce Drug Shortages and Improve Availability of Medicines(Wednesday, April 27, 1:30–3:15 pm)An Interdisciplinary Approach to Address

Drug Shortages. The effects of drug shortages on patients, caregivers, hos-pitals, and medical professionals are often not observed or understood by the bio/pharmaceutical manufacturing segment. This presentation will explore

alternative, innovative, and cost-effec-tive ways to provide needed therapies to patients.

BARDA Innovation Initiatives in Medi-

c a l Co u n te r m e a s u r e M a n u f a c t u r i n g.

This presentation will describe the Biomedical Advanced Research and Development Authority’s (BARDA) program initiatives in manufactur-ing technologies for medical coun-termeasure advanced development, including opportunities with the Centers for Innovation in Advanced Development & Manufacturing and in continuous manufacturing.

Continuous Manufacturing for Rapid Pro-

cess Development. The pharmaceutical industry has begun to adopt continu-ous manufacturing technology for the manufacture of traditional solid-dos-age forms. Benefits include lower cost and expedited development due to the ability to develop at scale. This presen-tation will outline some of the new ap-proaches and potential benefits.

Panel Discussion: Addressing Sterile Manufacturing Challenges (Wednesday, April 27, 3:30–4:30 pm)

Sterile injectables have been in ex-tremely short supply, and industry efforts have been focusing on root causes involv-ing infrastructure, quality, and efficiency. Experts involved in this work discuss recent initiatives, and offer insights into what must be done to prevent injectables shortages in the future.

For more information about the Keynote Series, visit: www.PharmTech.com/pt/Interphex2016. PT

Keynote Series Addresses Crucial Industry Issues

Thought leaders tackle drug

shortages and manufacturing innovations.

Rita Peters

Rita Peters is editorial

director of Pharmaceutical

Technology. Send your

thoughts and story ideas

to [email protected].

Pharmtech.com/pt/forum


PRODUCT SPOTLIGHT

High-Speed Dispersers Prevent Explosions

High Speed Dispersers from Ross feature

a National Electrical Manufacturers

Association (NEMA) 7&9 Operator Panel

and grounding systems. The dispersers

can be used in hazardous environments

where flammable vapors, liquids, solids,

and/or dusts are present. The saw-tooth

blade of the High Speed Disperser turns

at tip speeds up to approximately 5000 ft/

min and creates flow in low to medium

viscosity formulations under 50,000

centipoise. The dispersers’ grounding

systems are designed to ensure that the

vessel is properly grounded before the

agitator is allowed to operate.

The dispersers’ control panel features start, stop, and emergency

stop pushbuttons; a speed potentiometer; digital readout for agitator

speed; and a 16-ft. grounding clamp device. Also supplied on the

mixer are explosion-proof limit switches for locking out the motor if

the blade is in a raised position or a mix vessel is not in place. The

dispersers are available in sizes from 1 to 500 HP for batches from a

gallon to more than 5000 gallons.

Ross, Charles & Son

www.mixers.com

Multimode Microplate Reader Improves Sensitivity

The Spark 20M multimode

microplate reader has the

ability to read 6- to 1536-

well microplates and

includes a high-frequency

xenon flash lamp that can

be combined with detec-

tion modules. The unit also

includes a fluorescence

module designed to

improve sensitivity and increase the speed of high-throughput

screening. The reader includes the Te-Cool cooling module that allows

the measurement chamber temperature to be set below the ambient

room temperature.

The Spark 20M features automated cell imaging and confluence

measurement, which allows incubation and monitoring of cell culture

microplates within the measurement chamber. The user can define

the confluence at which the assay starts or ends or the substrate is

injected.

Tecan

www.tecan.com/spark20m

Confocal Microscope for Surface AnalysisThe Zeiss Smartproof 5

wide-field confocal micro-

scope is designed for

applications in quality

assurance and quality

control, production, and

R&D laboratories. The

microscope system pro-

vides 3D reconstructions

and roughness measure-

ments for work piece surfaces.

The microscope has an embedded optics, electronics, and camera

minimizing the number of cables used. Smartproof 5 can be installed

and run in different working environments without anti-vibration

equipment. The machine can also complete roughness analyses in

2D (profile) and 3D (area)—both based on ISO standards. The

Smartproof 5’s software provides easy-to-operate workflow routines,

and a graphical user interface guides users through recurring tasks,

ensuring user-independent data acquisition.

Zeiss

www.zeiss.com

Cleanroom Oven The Class 100 cleanroom oven

from Grieve is used for a variety of

heat processes such as sterilizing,

depyrogenation, curing, and drying

workloads. The cleanroom oven

includes four-inch thick insulated

walls, aluminized steel exterior, and

a type 304 2B-finish stainless steel

interior with continuously back-

welded seams. The unit includes

a four-inch insulated floor with

removable truck wheel guide tracks.

In addition, the unit has two thick

stainless steel high-temperature HEPA recirculating air filters, digital

indicating temperature controller, manual reset excess temperature

controller with separate contactors, recirculating blower airflow

safety switch, and a circular chart recording temperature controller.

The Grieve Corporation

www.grievecorp.com

Emergent Contract Manufacturing:

Enhancing Life in Every Single Dose

BDSManufacture

Single-usePlatform

AsepticFill/Finish

Vials &Syringes

Clinical& Commercial

emergentcontractmanufacturing.com

800-441-4225

Emergent BioSolutions is a fully integrated Contract Development

& Manufacturing Organization, supporting both bulk drug substances

and sterile injectable drug products at clinical and commercial scale.


PRODUCT SPOTLIGHT

Mixing Systems for Rehydration and Mixing ApplicationsThe QuaDrum rigid outer con-

tainers (ROCs) from Meissner are

used for rehydration and mixing

applications. The retaining lid,

stainless steel dolly, and bottom

drain allow recirculation-based

mixing for process volumes

between 50 L and 200L. The

retaining lid for mixing applica-

tions provides access to fluid

paths located on the top of the

biocontainer and can positively

locate and support a 3-inch TC

port on top of the biocontainer.

This port can be used for powder addition or other operations that

require large bore access to the biocontainer. The stainless-steel

dolly, which is required to facilitate bottom drain applications, can

be specified with swivel wheels that lock for added security.

Meissner

www.meissner.com

High-Pressure Ion Chromatography System The Dionex Integrion High-Pressure Ion

Chromatography system from Thermo

Scientific includes high-pressure capability

and electrochemical detection. The system

includes viper fittings, which minimize

peak dispersion and band broadening, a

detachable tablet with local language sup-

port, and a consumables device monitor

that regulates installation errors by logging

and tracking both system and consum-

able performance. The system’s thermally regulated detector

compartment provides extended life to consumables.

Thermo Scientific

www.thermoscientific.com/chromatography

Tool Management SystemThe IH-TMS Tool

Management System

from I Holland moni-

tors tool rotations,

tooling inventory,

and maintenance.

The stand-alone

system allows tablet

manufacturers to

keep a record of

tablet quantities by number of tablets, work order, or batch infor-

mation. The system incorporates a guide to tooling specification

and troubleshooting. In addition, the system has the capability

to archive tablet and tool images and drawings and incorporates

an alarm to alert users of any problems including over compres-

sion, tooling replacements, and when maintenance is required.

I Holland

www.tablettingscience.com


GLO

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It’s well known that generic drugs account for 88% of prescrip-

tion drug sales in the United States and have saved billions for

patients and healthcare systems since Congress enacted the

Hatch-Waxman Act more than 30 years ago. That growth, though,

has created difficulties for FDA in processing the hundreds of

resulting abbreviated new drug applications (ANDAs) and in

inspecting an expanding number of generic-drug manufacturers

and ingredient producers all over the world.

Concerns about ensuring the quality and safety of medical

products, moreover, have led to the closure of outdated and

noncompliant facilities, contributing to shortages and price spikes

for certain widely used generics, particularly sterile injectables.

These developments have raised questions about whether

government regulatory policies limit competition in certain drug

classes and support monopoly pricing.

Fees add resources

FDA’s ability to expeditiously approve new generics was compro-

mised by a budget squeeze over many years. The Prescription

Drug User Fee program (PDUFA) of 1992 bolstered funding for

new drug review by the Center for Drug Evaluation and Research

(CDER), but also shifted resources away from generics. ANDA

approvals slowed to a crawl, resulting in an enormous backlog of

pending applications.

Generic-drug makers finally agreed to pay user fees in 2012 to

strengthen FDA regulation of generic-drug development, review,

and inspection. In its first three years, the Generic Drug User Fee

program (GDUFA I) has generated nearly $1 billion to support

CDER’s Office of Generic Drugs (OGD) and certain operations of

the new Office of Pharmaceutical Quality (OPQ). FDA’s field force

also has increased inspections of overseas producers to help

level the playing field between US and foreign manufacturers.

As FDA and industry negotiate GDUFA renewal in 2017,

Congressional committees and the broader healthcare

community are examining FDA policies and programs governing

generics and the prescription drug market, as seen at a January

2016 hearing before the Senate Health, Education, Labor and

Pensions (HELP) Committee. Chairman Lamar Alexander (R.Tenn.)

cited concerns about “unnecessary regulatory burdens” that can

slow drug development and the importance of a pharmaceutical

marketplace that “remains competitive” (1).

The panel also is developing a Senate version of the “21st

Century Cures” legislation, which the House approved

in July 2015. Instead of combining multiple proposals into

a comprehensive bill, Alexander and ranking Democrat Patty

Murray (D-Wash) are considering numerous individual measures

on FDA policies, disease research, and expanded use of

electronic data technology to support broader research goals.

With deliberations running through April 2016, though, there’s

not much chance that Congress will adopt any final “Cures”

legislation this year, but will wait until 2017 when action is

required to reauthorize FDA user fee programs.

No more backlog

A main issue explored at the HELP hearing is whether too-slow

FDA approval of new generics limits drug access and com-

petition. Some legislators suggested that a pharma company

would be less likely to buy up a small drug firm with the intent

of boosting product prices if it knew that FDA could quickly

approve a new competing drug.

Despite complaints from generics makers about still-delayed

ANDA approvals, CDER director Janet Woodcock made a strong

case for agency progress in addressing the backlog problem,

speeding important new generics through the approval process

and expanding timely inspections of manufacturing facilities.

She explained that generic-drug makers submitted nearly 2500

applications in 2013 and 2014, making it difficult for OGD to

process those documents and to tackle long-pending submissions,

while also restructuring and expanding its program (2).

Even so, in the past three years CDER was able to “take

action” on approximately 85% of 4600 overdue ANDAs and

post-approval supplements, Woodcock stated. She promised

that all the backlog would be gone by 2017 and that OGD would

meet its goal for taking a “first action” within 10 months on

ANDAs submitted this year. No applications in the backlog

are first generics, she emphasized, and OGD’s “express lane”

policy moves these products to the front of the queue. She also

highlighted CDER efforts to promote advanced manufacturing in

the generic-drug industry, as continuous, computer-controlled

production systems would enable fast ramp-up of new

production.

Key to achieving these goals is an FDA-industry effort to

achieve more first-cycle approvals. A “right-the-first-time” policy

permits rejection of notably incomplete applications when they

first come in. CDER also is issuing more guidance on what data

it wants from sponsors and encouraging manufacturers to

conduct all necessary tests and processes before sending in

applications. A new pre-ANDA process that addresses approval

challenges for particular drugs prior to application submission

may be included in GDUFA II.

Supporting competition

In highlighting FDA efforts to quickly approve first generics,

Woodcock acknowledged that multiple drugs per innovator

may drive down costs and facilitate patient access to more

affordable therapies. Yet FDA does not approve a new drug or

generic in response to rising prices, she noted, and does not

have the expertise to calculate what qualifies as a “price hike:”

would that involve doubling a price from 10 cents to 20 cents, or

possibly raising a list price by more than 1000%?, she queried,

Generic-Drug Production and Oversight Challenge FDA and ManufacturersPolicy makers debate strategies for promoting access to less costly medicines.

Jill Wechsler is Pharmaceutical Technology’s

Washington editor, tel. 301.656.4634,

[email protected].


adding that a new report from the US Department of Health and

Human Services (HHS) better addresses generic-drug pricing (3).

The agency does keep a close eye on sole-source products

and those with only one or two competitors, as part of efforts

to anticipate drug shortages and supply disruptions. Woodcock

presented data indicating that 99 innovator drugs have only one

generic competitor; 66 drugs have two generics; and 623 drugs

have 3 or more generics. Of particular interest is the segment of

125 innovator drugs with no approved generics (and no patent or

exclusivity protections) (4).

These drugs may have limited competition, Woodcock

explained, because they are orphans or specialized therapies

that serve small patient populations. Many topical products,

inhalants, and complex substances also lack well-understood

methods for testing and documenting bioequivalence. To support

the development of generic versions of such therapies, GDUFA

provided FDA with approximately $35 million for research on

new bioequivalence test methods and guidances to “open up

previously blocked pathways” for new generics.

Woodcock acknowledged that, in some cases, innovator firms

take steps to block and delay generic drug entry. Generic-drug

makers have complained loudly about problems in obtaining

supplies for bioequivalence testing of brand products that are

subject to Risk Evaluation and Mitigation Strategies (REMS).

Woodcock said that FDA has advised brand firms that REMS don’t

warrant withholding drugs for research purposes, and indicated

that Congressional action would help address this problem more

directly. The Generic Pharmaceutical Association also wants

the legislators to repeal a recent budget provision that boosts

Medicaid rebates on generic drugs (5).

One strategy Woodcock strongly opposed is to turn to drug

compounders to provide less costly alternative medicines

when generics fail to meet demand. She emphasized that there

are “very great risks” in such proposals, citing two examples

of compounded drugs that sickened dozens of people. Mass

production of these drugs without adherence to GMPs, she

warned, “could have put thousands of people in the hospital.”

References

1. US Senate Committee on Health, Education, Labor & Pensions, “Alexander: Despite Extra $1 Billion to Speed Generic Drug Ap-provals, FDA Process Still Too Slow,” Press Release, Jan. 28, 2016, www.help.senate.gov/chair/newsroom/press/alexander-despite-extra-1-billion-to-speed-generic-drug-approvals-fda-process-still-too-slow., accessed Feb. 2, 2016.

2. Implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA), Testimony of Janet Woodcock, MD, Before the Committee on Health, Education, Labor and Pensions, Jan. 28, 2016, www.help.senate.gov/imo/media/doc/Woodcock5.pdf, ac-cessed Feb. 2, 2016.

3. Office of the Assistant Secretary for Planning and Evaluation, Understanding Recent Trends in Generic Drugs, Jan. 27, 2016, https://aspe.hhs.gov/pdf-report/understanding-recent-trends-generic-drug-prices, accessed Feb. 2, 2016.

4. FDA, Slides from FDA GDUFA presentation before the Senate Health, Education, Labor and Pensions Committee, January 2016, www.pharmtech.com/generic-drug-production-and-oversight-challenge-fda-and-manufacturers.

5. GPhA, “GPhA to Congress: Embrace Five Opportunities for More Generic Drug Savings,” Statement by Chip Davis, Presi-dent and CEO, GPhA, Feb. 1, 2016, www.gphaonline.org/gpha-media/press/gpha-to-congress-embrace-five-opportunities-for-more-generic-drug-savings, accessed Feb. 2, 2016. PT

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The European Union’s medicines licensing agencies have

committed themselves in a strategy document in December

2015 (1) to ease the regulatory burden on the pharmaceutical

industry by being more efficient in their control of pharma-

ceuticals throughout product lifecycles. This pledge has been

raising the hope of the generic medicines industry. One of the

generic medicines industry’s priorities is the reduction of the

costs and administrative difficulties that occur when com-

plying with variations regulations for keeping authorization

dossiers up to date.

Problems with variations rules were a major topic at an

annual regulatory and scientific regulatory affairs conference

in London in January 2016, which was organized by the

European Generic and Biosimilar medicines Association (EGA).

Approximately a third of the 200 participants were regulators

with most of the remainder from the industry.

As the EU’s pharmaceuticals regulations have been

tightened up in recent years, the submissions on variations

to regulatory agencies—comprising the London-based

European Medicines Agency at the center and a network

of national agencies in the EU’s 28 member states—have

increased substantially. As a result, variations have been

taking up a rising proportion of the pharmaceutical industry’s

regulatory costs.

Variations requirements

Pharmaceutical producers and importers are required to pro-

vide regulators with even more information about changes to

their medicines, such as modifications to manufacturing proc-

esses, improvements or extensions to formulations, and even

minor additions such as alterations to names and addresses.

The industry is seeing many of the variations requirements as

being the imposition of an unfair weight of responsibility on

their shoulders.

The current regulatory requirements are laid down by an

EU legislation (2) approved in 2008, which came into force in

August 2013. The aim was to provide clearer rules by dividing

the variations into four main categories. Two of these are type

IA, which have “minimal or no impact at all” on the quality,

safety, or efficacy of medicines and type II, which can have a

“significant impact.” An “extension” category covers changes

to an active substance or the strength, pharmaceutical form,

and route of administration of a medicine. Type IB variations

are changes that are neither minor, major, nor an extension.

Although the legislation’s main objective was to simplify

rules on the notification and approval of variations, a series

of guidelines have had to be issued to clarify their application.

At the same time, new EU pharmacovigilance legislation (3)

was introduced, which brought in additional requirements for

information of variations in the quality, safety, and efficacy

of medicines after their launch on the market. This new

legislation also had to be clarified by guidelines, the latest

of which was issued in the form of a questions and answers

document (4) in January 2016.

“Guidance covering matters that should be clearly described

in legislation has increased the regulatory work load of the

industry,” Susana Pereira, a principal regulatory affairs officer

at Teva Pharmaceutical Industries, told the conference (5). An

increasing proportion of variations are now related to details

about the production, origin, and composition of APIs. This

follows the migration of API manufacture out of Europe and

North America to China and India, which has considerably

complicated the supply chains for active substances, mainly

used in generic medicines. At the same time, rules on good

manufacturing practice (GMP) have been made stricter and

broader while GMP inspections of API facilities have become

more rigorous. A lot of additional variations information is

being generated by the more stringent application of GMP.

API changes and GMP rules

The average number of variations per marketing authoriza-

tion per year had increased by 45% in the five years leading

up to 2014 (5), the equivalent to one additional variation per

authorization. Variations in APIs are a major factor behind

this increase. Up to 60% of quality variations submitted by

marketing authorization holders (MAHs) are now related to API

changes, said Pereira (5). New interpretation of regulatory data

requirements had led to rises of up to 300% in the variations

related to the API supply chain, with a high proportion relating

to GMP matters, she added (5).

With the addition of stricter GMP rules and the new

requirements under the pharmacovigilance legislation,

“variations have become a mechanism to implement new

legal obligations,” Pereira claimed. The result was rises in

regulatory costs covering the maintenance of a product’s

lifecycle to a level that is higher than the authorization costs

for the marketing of the medicine. “This imbalance can lead

to the withdrawal of a medicine from the market, particularly

Tackling Regulatory Challenges of EU’s Variations FrameworkThe EU is striving to reduce the costs and administrative burden facing pharmaceutical

manufacturers when complying with variations regulations for keeping authorization dossiers up to date.

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if the cost of maintenance is higher than the product’s profit,”

she warned (5). Instead of taking a drug off the market, a

company may delay process improvements or hold back other

changes that would reduce the medicine’s cost.

Companies are also choosing carefully the regulatory

authorities to which they are submitting variations, particularly

because of dif ferences in the fees they charge. These

costs can range from zero to up to $1544 (€1400) for type

IA variations; up to $1654 (€1500) for type IB; and up to

$19,852 (€18,000) for type II, Pereira said. “The current system

doesn’t create incentives for [national licensing authorities] to

implement cost-effective mechanisms,” she added.

Other speakers pointed out how certain aspects of API

manufacture were increasing the requirements for variations

information, often as a result of the interpretation of

regulations made in guidelines. Marieke van Dalen, global

regulatory specialist at Aspen Oss B.V., a Dutch API producer,

said that a recent trend was a requirement for information on

starting and even pre-starting materials, even including the

names and addresses of the suppliers. This information was

passed to the MAH before being added to the authorization

dossier. Some authorities also wanted information on the

analytical methods used in the validation of the starting

materials and their intermediates.

Joseph Bondin, executive director, quality operations, at

the generic-drug producer Actavis, gave examples of how

much information had to be provided when an outsourced

API manufacture introduced intermediates from new

producers with new testing sites. In one example, details

of as many as 12 additional players in the API supply chain

had to be submitted because of changes in the suppliers of

intermediates. As a result of new regulatory interpretations of

the information requirements on API intermediates, he warned

that there could be a two- to three-fold increase in the total

number of variations, which in 2015 averaged just under three

variations per marketing authorization per year (6).

“This increase seems contradic tor y to several EU

policies,” he said. “[These policies include] have effective

and fit regulatory systems that foster supply-chain resilience

to prevent temporary supply disruptions.” In addition, it

would seem to refute the value of the systems adopted by

pharmaceutical companies themselves to validate the quality

of intermediates, even though these could be based on quality

guidelines proposed by the International Conference on

Harmonization (ICH).

Recommendations for improvements

In a regulatory efficiency report (7) published in September

2015, the EGA recommended a series of specific improve-

ments to the EU regulatory system on variations. These rec-

ommendations include reliance on the new database system

of Identification of Medical Products (IDMP) to make the API

supply chain more transparent. It proposed that API informa-

tion should be limited to details about the final API manufac-

turer. Information on other involved sites, such as intermediate

producers, would be managed through the drug manufac-

turers quality systems and regulators’ GMP inspections.

Much greater use, as a source of required variations

data, could be made of the central European inventory of

information on medicines and active substances, which is

being set up under the EU’s pharmacovigilance legislation.

Under article 57 of the law, companies have to provide up-to-

date post-marketing information on their products relating to

quality, safety, and efficacy (3).

Regulators at the conference reiterated their commitment

to making regulatory compliance easier and less costly for

the pharmaceutical industry, particularly for the generic-drug

sector. Noel Wathion, the EMA’s deputy executive director,

stressed that the article 57 database and the implementation

of IDMP would be used to improve the cost-effectiveness of

regulations for generic and biosimilar medicines within the

EU’s regulatory network. The regulators, however, were unable

to make pledges about specific measures, particularly on the

vexed issue of variations. This issue seems likely to remain a

matter of grievance among generic-drug companies for some

time.

References

1. European Medicines Agency (EMA) and Heads of Medicines

Agencies (HMA), EU Medicines Agencies Network Strategy to

2020: Working Together to Improve Health (London, Dec. 17,

2015).

2. EC Regulation No. 1234/2008 The examination of variations to

the terms of marketing authorisations for medicinal products for

human use and veterinary medicinal products (Brussels, Nov. 24,

2008).

3. EC Regulation No. 1235/2010, Amending as regards pharmaco-

vigilance of medicinal products for human use, Regulation No.

726/2004 laying down community procedures for the authoriza-

tion and supervision of medicinal products for human and vet-

erinary use (Brussels, Dec. 15, 2010).

4. EMA, Practical questions and answers to support the implemen-

tation of the variations guidelines in the centralised procedure,

EMA/427505/2013 (London, Jan. 18, 2016).

5. S.Pereira, “Challenges of the Current Variations System,” presen-

tation at the EGA Regulatory and Scientific Affairs Conference

(London, Jan. 28–29, 2016).

6. J.Bondin, “Management of the Active Substance Regulatory Dos-

sier,” presentation at the EGA Regulatory and Scientific Affairs

Conference (London, Jan. 28–29, 2016).

7. European Generic and Biosimilar medicines Association (EGA),

An Efficient Regulatory System for Patient Access to New Generic

Medicines” (Brussels, September 2015). PT

Companies are choosing

carefully the regulatory

authorities to which they

are submitting variations.

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For decades, APIs, the foundation of the pharmaceutical industry, have been a staid, solid, if somewhat

invisible market. Some drug product manufacturers make APIs inhouse, while others outsource their manu-facturing to contract development and manufacturing partners.

Recently, however, as drug approvals have approached levels last seen in the early 2000s, APIs have become a dy-namic focal point for mergers and ac-quisitions, investments in innovation, lab and plant expansions, outsourcing growth, and the development of new chemistry platforms.

The past few months have seen sig-nificant merger and acquisition activ-ity. In July 2015, The Siegfried Group bought BASF’s API facilities in France,

Germany, and Switzerland for $300 million (1). In October 2015, Merck KGaA bought Sigma-Aldrich Corp., a supplier of APIs and fine and labo-ratory chemicals, for $17 billion (2). The acquisition solidifies its biophar-maceuticals business and emphasizes chemical manufacturing in its product portfolio.

At around the same time, Johnson Matthey bought Pharmorphix, a spe-cialist in solid dosage form chemistry, from Sigma-Aldrich (3). The company brings expertise in understanding polymorphism and cocrystallization, and helps to bridge the gap between toxicity testing through Phase I.

Drug product innovation challenges are driving new developments in APIs.

“Our customers must find new ways to

bring new therapies to market,” says Nick Johnson, strategic marketing di-rector at Johnson Matthey. The com-pany, once synonymous with chemical catalysis, has rebranded its fine chemi-cals business to focus on custom API development, manufacturing, and life cycle management; chiral chemistry and catalysts; and controlled substance manufacturing. “From a contract man-ufacturing perspective, [our customers’ innovation challenge] affects how we structure our business and services. Our goal must be speed to market, and we must structure on areas of R&D and around technologies,” Johnson says.

Currently, market estimates peg the global API market at $121 billion, and expect it to reach nearly $199 billion by 2022 (4). Generic pharma firms such as Teva and Mylan produce many of their own APIs inhouse, but also sell to other companies, a practice that is becoming more common.

More than 10% of the business is made up of specialty APIs outsourced by pharma innovator companies for clinical research (5). Contract com-panies that focus on API development and manufacturing include Cambrex, Hovione, Siegfried, Johnson-Matthey, and Lonza, are seeing business growth.

Roughly 99% of API volumes (when measured in kilograms) are based on small molecules and 1% from biologics, says Matthew Moorcroft, global mar-keting director for Cambrex, a con-tract development and manufacturing organization (CDMO) that specializes in small-molecule APIs.

However, prices for small-molecule, and even some generic drugs, have been increasing, he notes. Market value share, historically reported be-tween 80–85% small molecules and 25–20% biologics, might tip tempo-rarily even further in favor of small-molecule APIs, Moorcroft adds.

Quality has displaced cost as the top requirement, even in commodity businesses. As a result, the API busi-ness is “no longer a race to the bottom,” according to Peter Werth, CEO of the generic API supplier, Chemworth, in an interview with CPhI for CPhI’s

Specialty Markets and Services Drive API GrowthAgnes Shanley

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2016 US Pharmaceutical Industry Outlook, which was released at the Informex show in February, 2016 (6).

“Four years ago, the main consideration that finished formulation companies would take when sourcing an API was cost. These past four years have seen a rapid rise in quality concerns, which are now at the forefront of everyone’s minds,” he said.

API outsourcing on the rise“Worldwide, large innovator companies are increasing outsourcing require-ments,” says Moorcroft. “Coupled with the increasing use of generics, and ad-ditional opportunities for increased penetration in developing markets, the industry will continue to experi-ence strong growth,” he adds.

Currently, API manufacturing is the largest business for pharmaceutical CDMOs, the operation most frequently outsourced by small-molecule manu-facturers, and the fifth most frequently outsourced operation for biopharma-ceutical manufacturers, according to

Kate Hammeke, research director with Industry Standard Research (ISR), who shared recent market research findings with Pharmaceutical Technology.

On the commodity API side, an aging population and government spending caps are driving global demand for ge-neric drugs and the APIs used to make them. Recently, Japan has been an area of high generics demand, according to a report by Nikkei Asian Review, as the Japanese government moves to boost use of generics from 50% to 80% of all prescription drugs by 2020 (7).

In Japan, a number of commodity APIs are in short supply, Nikkei Asian Review reported in February, and the pharmaceutical manufacturer, Eisai, plans to start selling APIs for allergy, high-cholesterol and other therapies to generic drug manufacturers in Japan. The company plans to double API pro-duction capacity at its plant in Andhra Pradesh, southern India (7), which had been previously used as a captive source. Eisai will use revenues to ex-pand its R&D pipeline, the report says.

Specialty API manufacturing moving back to the US and EuropeIn specialty areas, API outsourcing demand that had moved offshore is now coming back to the United States and Europe. “Ten to 15 years ago, its perceived economic benefits made offshoring very attractive. Now, com-panies are focusing more on quality, and regulations are becoming more stringent,” says Johnson.

While tax incentives have played some role in stimulating API capacity expansion in the US, insiders say that the onshoring trend has been fueled by concerns about ongoing compliance and data integrity issues at some offshore API manufacturing facilities (Sidebar). The Generic Drug User Fee Act (GDUFA), which charges a fee for manufacturers who want to sell their APIs in the US, is also said to be having an impact.

“Quality and regulatory concerns pertaining to China and India make the US market look increasingly at-tractive … We are in a renaissance for European and US manufacturing,”

Data integrity (see the article on p. 50 of this issue of Pharmaceutical Tech-

nology) has become a more serious compliance problem at pharmaceutical

manufacturing plants throughout the world. Over the past three years, as the

FDA has increased inspections of offshore facilities, the agency has penalized

a number of API manufacturers in India and China for cGMP violations, many

of them involving data integrity. In some of the FDA inspection reports, quality

control staffers said that they were ordered by superiors to back date lab data,

or to delete information and perform tests until samples passed. Some of the

companies whose plants were penalized were also put on an import ban list,

preventing them from shipping products to the United States.

As more of these plant issues became public, rumors spread in India in Febru-

ary 2016 that the US was banning all imports of API from India and China (1). In

fact, the ban only affects supplies that are covered by US government contract.

The panic might be understandable, given the growing number of regulatory

citations directed at offshore API facilities. Because India and China supply

80% of the APIs used in US pharmaceutical production, mostly commodity-

type products, the US government has been questioning FDA’s ability to moni-

tor quality in Chinese and Indian plants, according to a February 2016 report in

the Regulatory Affairs Professionals Society (RAPS) journal, Regulatory Focus.

API manufacturing company executives believe that data integrity issues and

perceptions that offshore suppliers are not sufficiently trained in current good

manufacuring practices (cGMPs) are driving a move back to outsourcing more

APIs manufactured in the U.S. and Europe.

According to the RAPS report (2), 41 manufacturing sites in China are now on

import alert, five are on alert in Hong Kong, and 42 sites in India (some of which

have only been cited for problems with specific products, not all of their manufac-

turing output). In December 2015, RAPS reported, US representatives wrote to the

US Government Accountability Office asking that it look into whether FDA could

handle the load of inspections now required in India and China. RAPS also pointed

out logistical issues that FDA has faced in getting visas that would allow more of its

new inspectors to work in China. The agency closed two Chinese offices in 2014 to

consolidate activities in Beijing, according to RAPS. In India, FDA plans to increase

the number of inspectors from nine to 19, RAPS reports. Below are just a few of

the offshore API manufacturing facilities involved and the penalties they received:

t� Indian-based Biocon Ltd. was placed on an import ban list

t� A Dr. Reddy’s facility in India received a warning letter for

documentation problems

t� Zhejiang Hisung’s plant in China was cited for data manipulation

t� Ipca Labs’ three API plants in India were cited for data integrity problems.

References1. D. Shenoy, “Misleading Reporting: Indian Pharma Company APIs are NOT

Banned in the U.S., “ CapitalMind.in, http://capitalmind.in/2016/02/mislead-ing-reporting-indian-pharma-company-apis-are-not-banned-in-the-us/

2. Z. Brennan, “US FDA Inspections in China: An Analysis of Form 483s from 2015,” Regulatory Affairs Focus, Regulatory Affairs Professionals (RAPS) Society, www.raps.org, http://www.raps.org/Regulatory-Focus/News/2016/02/10/24296/US-FDA-Inspections-in-China-An-Analysis-of-Form-483s-from-2015/

– Agnes Shanley

Concerns Mount Over Data Integrity and Compliance Issues Abroad

Pharmaceutical Technology MARCH 2016 29

said David Hoffman, president of US operations for the API manufacturer, Hovione, in an interview in the CPhI report previously cited (6).

US and European expansionsHovione plans to expand its facility in East Windsor, NJ, by the end of 2017 (8).The company will more than double API manufacturing capacity at the site, and will also add a new com-mercial spray dryer, as well as highly potent API capacity.

Meanwhile, Cambrex is expanding its Charles City, IA, facility. “In 2013, we added an additional 40,000 gallons of reactor capacity,” says Moorcroft,

“and during the first quarter of 2016, we will see the completion of a new manufacturing facility, which will ini-tially add a total of 70 cubic meters of glass-lined and Hastelloy reactors, sig-nificantly increasing the site’s current good manufacturing practices (cGMP)

manufacturing capabilities,” he says. Cambrex also plans to invest in its API site in Sweden to support new late-stage clinical projects, and in its Italian plant, to improve generic API develop-ment capacities, Moorcroft says.

As pharma’s drug products evolve, so are the drug substances that make them possible. Specialty actives are becoming more complex and struc-turally larger, reflecting the increased sophistication of today’s therapies, says Johnson.

Oncology drug growth drives investment in containment systemsOn the small-molecule side, Johnson notes, demand for oncology drugs, the fastest growing segment of the API market, is driving increased invest-ment in high containment capacity. Because fewer of today’s complex new API therapeutics can be separated by crystallization, Johnson Matthey is

emphasizing work in advanced separa-tions based on chromatography, John-son says.

R&D hubsJohnson Matthey is focusing some of its API research work and invest-ments in Cambridge, UK, a research hub for many Big Pharma companies, including AstraZeneca, GlaxoSmith-Kline, and Takeda. The company has expanded its facilities there to bring additional process R&D services and kilo-scale manufacture to the grow-ing site, and to integrate assets that it gained when it bought Pharmorphix.

The project has increased Johnson Matthey’s capacity to perform chem-istry and biocatalysis process R&D, route scouting, process development, optimization and scale-up of heteroge-neous, homogeneous and biocatalytic processes, as well as the non-GMP kilo-scale manufacture of APIs and

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intermediates. “We will now be able to scale up processes to the 100-L level,” says Johnson.

Developers have ambitious product-introduction goalsGiven robust drug product approval rates and pipelines, individual API suppliers are setting ambitious goals. Cambrex reportedly targets 10 new product introductions a year (9). For Neuland Labs, a specialized API sup-plier in India, the figure is 10 to 15, says Davaluri Suharsh Rao, director and president of contract research.

Neuland focuses on developing cus-tom manufacturing solutions for inno-vator companies in the US, Europe, and Japan. The company, which currently produces more than 75 APIs, has spent more than $2 million to expand its API R&D lab in Hyderabad, adding process engineering and parallel processing ca-pabilities, as well as such tools as reaction calorimeters, software and data mining capabilities. The expansion should be completed by the end of 2016, says Rao.

Neuland is investing in lab improve-ments and employee training to allow it to build skill sets around pharmaceuti-cal quality by design (QbD) and cGMPs.

“We’ve realized that QbD results in final product quality and reliability, so we are investing in the infrastructure required,” Rao says. “Companies getting ready to file investigational new drug (IND) and new drug (NDA) applications with FDA will need QbD data for these filings,” he adds.

QbD has also become important for Johnson-Matthey, says Johnson, particularly the use of design-of-ex-periments techniques. The company has also used modeling and rapid screening to evaluate the effectiveness of APIs for solid-dosage forms, he says.

Neuland’s strategy has been to avoid crowded areas where there is a lot of competition. “We prefer to focus on areas such as complex formulations where there is insufficient expertise, (e.g., metered dose inhalers for respira-tory therapies),” says Rao. “These ma-terials are hard to synthesize and have very complex particle size distribution requirements,” he says.

The company has also invested in micronization capacity, and in niches such as deuterated molecules for repur-posing approved APIs for new indica-tions. Deuteration is one of many drug repurposing strategies that are being explored today. The idea of repurpos-ing mature APIs in novel formulations may not be new, but Moorcroft says that it has been gaining more atten-tion, as companies develop drugs for rare diseases and unmet medical needs, or new dosage forms that would offer enhanced benefit in a new dosage form or application.

Repurposing challenges API de-velopers, both on the specialty and the commodity side. Deuteration, for instance, which replaces hydrogen atoms with deuterium, requires the use of special process and storage equip-ment, because deuterium is flammable. On the commodity side, repurposing challenges supplier agility, Moorcroft says. “It requires that generic API manufacturers respond more quickly to customer demands for material, and that they supply targeted volumes that address a smaller patient subset. Cam-brex has successfully supported many drug manufacturers working in the repurposing space,” he says.

Recently, Neuland has moved into peptides, an area where Rao sees great potential, because close to 1000 com-mercial drugs today are peptide-based.

“We started this business in 2010 in a very muted way, making building blocks,” he says, noting that the com-pany recently partnered with a US cli-ent, using solution-phase technology to synthesize a fairly long-chain peptide at 30 kilograms/year.

Another new area of interest is car-bohydrate chemistry, which Neuland is exploring through a partnership with a local university. Rao says the company started working on synthetic Vitamin D analogs about a year ago, challeng-ing compounds that are highly potent and require highly specialized synthe-sis and analysis.

Clearly, the market is becoming more competitive, and more consolida-tion can be expected as regulatory re-

quirements become more stringent and demands for complex APIs increase. For suppliers that have invested in the knowledge and infrastructure required, however, a stronger drug product pipe-line promises to yield more opportuni-ties in the future.

References 1. J. Miller, “CMO Consolidation Pace May

Slow Down, “PharmTech.com, January 6, 2016, accessed February 5, 2016, www.pharmtech.com/cmo-consolidation-pace-may-slow-down

2. C. Hroncich, “Merck KGA, Darm-stadt Germany, Announces Completion of Sigma-Aldrich Acquisition,” Pharm-Tech.com, November 18, 2015, accessed February 5, 2016, www.pharmtech.com/merck-kgaa-darmstadt-germany-announces-completion-sigma-aldrich-acquisition

3. Johnson Matthey Acquires Pharmorphix, Press Release, www.matthey.com/media_and_news/news/2015/pharmorphix

4. Active Pharmaceutical Ingredients Global Market Outlook –Trends, Forecast, and Opportunity, 2014-2022, Reportlinker Preview, Press Release, Accessed February 4, 2016, www.prnewswire.com/news-re-leases/active-pharmaceutical-ingredients-global-market-outlook---trends-forecast-and-opportunity-assessment-2014-2022--

-reportlinker-review-300159995.html 5. Cambrex Sell Off A Golden Oppor-

tunity, Seeking Alpha , p. 4, analyst report,accessed February 5, 2016, Site registration required for access. www.seekingalpha.com/article/3874116-cam-brex-sell-golden-opportunity?page=4

6. CPhI Worldwide Pharma Insights 2016, FiercePharma.com, www.fiercephar-mamanufacturing.com/press-releases/cphi-worldwide-launches-pharma-in-sights-2016-usa-report-informex-2016

7. “Eisai to Supply Generic Drug Makers With Bulk Ingredients,” Nikkei Asian Review, Feb. 9, 2016, accessed Feb. 19, 2016, www.asia.nikkei.com/Business/Companies/Eisai-to-supply-generic-drug-makers-with-bulk-ingredients

8. Hovione Announces the Expansion of its New Jersey Facility, Press Re-lease, accessed February 20, 2016, www.prnewswire.com/news-releases/hovione-announces-the-expansion-of-its-new-jersey-facility-529940241.html

9. Cambrex Sell Off A Golden Oppor-tunity, Seeking Alpha , p. 2, analyst report,accessed February 5, 2016, Site registration required for access, www.seekingalpha.com/article/3874116-cam-brex-sell-golden-opportunity?page=2 PT


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Solid-dosage drugs remain the pre-ferred dosage form due to ease of administration and typically

lower manufacturing costs compared to parenteral and other dosage forms. Many of the properties of a chemical relate directly to its physical form, and solid compounds can adopt numerous different crystalline forms (e.g., poly-morphs, solvates, and hydrates) and non-crystalline (e.g., mesophases or amorphous) forms. Extensive screening must be completed to identify the dif-ferent potential stable and meta-stable forms that an API may adopt during manufacturing of the drug substance and drug product, packaging, storage, and within the body. Potentially stable salts and cocrystals of the API may also be evaluated. In addition to the skills and knowledge required to conduct and evaluate the large quantities of struc-ture data generated during polymorph screening projects, the ability to design appropriate screening studies has a direct impact on their success.

Why polymorph screeningToxicology, efficacy, and stability are important criteria when selecting an appropriate candidate for the develop-ment of a solid-dosage drug. “These properties can vary depending on the physical structure of the API. It is necessary to understand the physical properties of each potential solid form and the relationship between these different forms in order to identify the candidates with the greatest like-lihood of success,” says Brett Cowans, director of materials science for SSCI (Solid State Chemical Information), a division of AMRI.

The chances of selecting the best candidate improve considerably the earlier these factors are known. “The challenge for companies is to balance the cost of development and risk of se-lecting the wrong solid form. Ideally, this balance will include understand-ing the true physical properties of the selected candidate compound, includ-ing polymorphism, and how these properties will affect the API manufac-turing and drug product efficacy and stability for each form, as well as the M

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Gauging the adequate level and type of screening is the challenge.

intellectual property position for the formulated drug,” Cowans observes.

Many forms to identifyFrom a technical point of view, the main challenge of polymorph screen-ing is to identify all crystalline forms relevant and potentially crucial to de-velopment. Solid forms may, for exam-ple, be observed in the presence or ab-sence of certain impurities in the final isolation step of the API, upon storage of its intended dosage form, or in vivo when administered orally, according to Patricia Andres, director of particle en-gineering for SSCI. “The screening of such forms typically requires a rational design of experiments often not ame-nable to high-throughput screening, and the unambiguous identification of new phases necessitates the prepara-tion of pure phases in sufficient quanti-ties for characterization,” she notes.

Andres cautions, however, that while thorough and targeted screening will considerably reduce the chances that a new critical form is discovered later in development, it is not possible to know without a doubt that all relevant forms have been found. She cites ritonavir as a classic example of a crystalline form not discovered during development. The product was developed using a form designated as Form I, which was later found to be metastable with re-spect to a new form exhibiting consid-erably lower solubility and rendering the initially developed drug product bio-unavailable.

Achieving the right balance“The ability to gauge the level and type of screening that is adequate based on considerations of development phase, dosage form, physicochemical and biological properties of the com-pound, and regulatory requirements is paramount,” Andres asserts. Risks associated with the discovery of a new crystalline form at a later phase of de-velopment must be weighed against the possibility of the compound failing in development. This risk assessment re-quires both experience of solid-state is-sues that can affect the performance of

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Polymorph Screening for Identification of Relevant Crystalline Forms Cynthia A. Challener

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the drug substance and drug product and intimate knowledge of the drug substance and drug-product processes.

Another practical challenge in poly-morph screening, according to Marco Gil, a general manager with Hovione, is to identify processes for isolation of different forms that can be scaled in a robust manner to yield the selected polymorphs (or cocrystals).

Fit-for-purpose approachPolymorph screening is a complicated process that involves many individ-ual experiments and significant data analysis. Significant resources have been invested in efforts to accelerate the process. The dream of displacing rational experimental design in phar-maceutical form screening (e.g., salts, cocrystals, and polymorphs) with

high-throughput screening was pur-sued for about a decade by mid-sized and large pharmaceutical companies, as well as material science contract re-search organizations (CRO), according to Jon Selbo, director of preformula-tion with SSCI. “Significant internal resources were dedicated to develop-ing home-built screening instruments and/or purchasing equipment and software to implement this new strat-egy,” he says.

The justification for high-through-put screening was that significant im-provement in identification of other-wise unknown forms could be more easily obtained by conducting large ar-rays of experiments in parallel. In most cases, however, this strategy failed for both identification of new forms and desired forms for development. “In

general, crystallization quality was poor, there was a lack of experimen-tal diversity (regardless of significant increases in solvents used in crystalli-zation attempts), the analytical results were inadequate, and analyzing the large quantities of poor quality data generated in the experiments often proved difficult,” Selbo observes. In addition, polymorphs identified using high-throughput screening must be considered as general lead compounds and must be thoroughly assessed, in-cluding evaluation of their pharmaco-kinetics, solubility, and other proper-ties, according to Gil.

The driver for large-scale screening in early development has, for the most part, also disappeared with the new molecular entities failing more often today due to efficacy and toxicity issues

FDA warns firms on data integrity and cannabidiol claims

Data Integrity Violations Earn Warning Letter for Ipca Laboratories

Ipca Laboratories, a Mumbai, India-based drug manufacturer, has received a

warning letter from FDA for good manufacturing practice violations identi-

fied during inspections in 2014 at three facilities including numrous data

integrity violations.

The Ratlam API facility was cited for failure to have sufficient computer sys-

tem controls to prevent unauthorized access or changes to data. FDA investiga-

tors noted a lack of basic laboratory controls to prevent changes to electronically

stored data; and use of incomplete records to evaluate the quality of drugs and

to determine whether the drugs conformed with established specifications and

standards. The Jan. 29, 2016 letter notes that Ipca “routinely re-tested samples

without justification and deleted analytical data. We observed systemic data

manipulation across your facility, including actions taken by multiple analysts,

on multiple pieces of testing equipment, and for multiple drugs.”

FDA noted that laboratory analysts had administrator access to chromatog-

raphy systems and used the access to manipulate raw data and test results. The

agency noted that the firm’s quality unit was aware of the lack of controls in the

computerized systems, but “senior management failed to take sufficient cor-

rective action and prevent the recurrence of these problems.” FDA noted that

the company failed to ensure that laboratory records at the Pithampur drug

product manufacturing facility included complete data derived from all tests

to assure compliance with established specifications and standards. Inspectors

documented multiple instances of analytical test results without original data,

injections overwritten and deleted without justification, and chromatograms

related to original test results overwritten by subsequent testing.

Additional violations related to laboratory records were found at the Piparia

Silvassa drug-product manufacturing facility where the firm failed to ensure

that laboratory records included complete data derived from all tests necessary

to assure compliance with established specifications and standards.

—Rita Peters

FDA Warns Cannabidiol Oil Sellers

FDA issued eight warning letters on Feb. 4, 2016 to various makers of a dietary

supplement called cannabidiol, which is derived from the cannabis plant. Can-

nabidiol, which is also known as CBD oil, is described as a nonpsychoactive (no

THC) dietary supplement that is purported to have numerous benefits, includ-

ing anti-inflammatory and antiemetic properties. The oils are also advertised

as being able to reduce depression, combat cancer, shrink tumors, facilitate

wound healing, and treat other serious, chronic conditions, such as rheumatoid

arthritis, schizophrenia, diabetes, lupus, and Crohn’s disease, among others.

The companies that received warning letters about the claims associated

with cannabidiol include Sana Te, PainBomb, Morguetorium, Michigan Herbal

Remedies, HealthyHempOil.com, Dose of Nature, Green Garden Gold, and ABC

Productions. FDA reviewed the websites, Etsy stores, and Facebook pages of

the companies, and concluded the companies were selling products marketed

as new drugs. FDA said the CBD oil products are being marketed as medications

and have not been adequately tested to prove they are safe and effective. The

agency wrote, “drugs may not be legally introduced or delivered for introduc-

tion into interstate commerce without prior approval from the FDA.”

To FDA, CBD products are excluded from the dietary supplement definition,

as CBD oil is already being investigated for its medicinal benefits in clinical trials.

The agency pointed out that CBD oil is currently undergoing clinical investiga-

tion, citing GW Pharmaceuticals’ studies in the United States of the products

Sativex and Epidiolex for the treatment of cancer pain and a form of epilepsy

called Dravet Syndrome, respectively. The agency says that unless a clinical in-

vestigation meets the limited criteria in that particular regulation, an investiga-

tional new drug (IND) application is required for all other clinical investigations

of products. Thus, any manufacturers of CBD oil making claims about clinical

efficacy for the treatment of disease must file an IND with the agency and have

scientific data to back up their claims.

—Randi Hernandez



rather than biopharmaceutics proper-ties. “Only a few larger pharmaceutical companies and small CROs continue to employ high-throughput screening as a first pass strategy,” says Selbo.

What is important, according to Cowans, is how the results of high-throughput screening can contribute to better understanding of the proper-ties of potential solid-form candidates.

“As a screening tool, high-throughput technology provides a platform to evaluate the potential for crystallizing new solid forms under certain con-ditions, albeit with some limitations. The information obtained solely from high-throughput technology is not suf-ficient to select a solid-form candidate for development, however,” he says. Consequently, rational experimental design with fit-for-purpose screening strategies based on rational screening or mixed screening approaches have become the norm for the industry, ac-cording to Selbo.

Large-scale screening is still em-ployed as a part of intellectual prop-erty (IP) strategies for later-stage pro-grams where there is more certainty of compound survival. “High-through-put screening is today an essential technology for mapping polymorphic forms, generating IP, and broadening the protected space in terms of poly-morphs, and helping to avoid surprises as much as possible in advanced de-velopment phases,” Gil comments. For these programs, mixed screening services with rational, mid-, and high-throughput screens may be employed in an attempt to cover all bases, ac-cording to Cowans.

Sharp patternsWith respect to advances in technol-ogy for polymorph screening, Cow-ans points to improvements in x-ray powder diffraction (XRPD), which he refers to as the “quintessential tool for distinguishing different crystalline forms.” Most importantly, current-generation instruments are capable of providing the sharp, high-quality pat-terns that are necessary for identifying whether a material exists as a single

crystalline phase and are amenable to indexing algorithms.

The combination of indexing soft-ware and advanced XRPD technology improves the ability to identify crys-talline phases or mixtures, increases screening efficiency, and provides critical information about the various crystalline forms obtained, according to Cowans. SSCI has developed and patented its own indexing software

specifically targeting organic mol-ecules and integrated this tool into its routine screening activities.

Another important advance for polymorph screening is the reduc-tion in the quantity of API required for analytical techniques (e.g., XRPD), according to Gil. Automation has also increased the efficiency of these analyses and accelerated sample pre-characterization. PT

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PEER-REVIEWED

Statistical Tools to Aid

in the Assessment of

Critical Process ParametersKe Wang, Nathan D. Ide, Olivier Dirat, Ann K. Subashi, Nicholas M. Thomson, Kim E. Vukovinsky, and Timothy J. Watson

There are many different approaches for assessing

process parameter criticality, and assessing which

process parameters have a significant impact on

critical quality attributes (CQAs) is a particular

challenge. Including an unimportant process parameter

as a critical process parameter (CPP) in a control

strategy can be detrimental. The authors present a

statistical approach to determine when a statistically

significant relationship between a process parameter

and a CQA is large enough to make a practically

meaningful impact (i.e., practical significance).

The assessment of critical quality attributes (CQAs) and

the control of critical process parameters (CPPs) that

affect these attributes are important components of the

overall control strategy for drug substance and drug product

manufacturing. There are many different approaches for

assessing process parameter criticality, and statistics can

play an important role in these evaluations. One particular

challenge involves assessing when a relationship between

a process parameter and a CQA represents a significant

impact on that CQA. Assessing impact based solely on sta-

tistical significance (p-value) is not appropriate, because sta-

tistical significance does not take into account the strength

of the relationship relative to the relevant quality require-

ments and can lead to the inclusion of relatively unimpor-

tant process parameters as critical elements of the control

strategy. Including these unimportant process parameters

as CPPs is undesirable as it effectively dilutes the focus on

process parameters that are truly important for ensuring

product quality. The excessive assignment of criticality to

unimportant process parameters can also place an unneces-

sary burden on manufacturing operations.

This article introduces a statistical approach to help

determine when a statistically significant relationship

between a process parameter and a CQA is large enough

to make a practical meaningful impact (i.e., practical

significance). The assessment of practical significance can

then be used to determine if a parameter has a significant

impact on a CQA, thus helping to assess the criticality of

process parameters. The described statistical methodology

is intended to provide a consistent framework for

discussions on process parameter criticality and should be

used to support but not replace scientific judgment.

The statistical approach that has been developed takes

into account the process risk (Z score) and the parameter

effect size (20% rule). This article discusses some background

on criticality assessments, the motivation behind the

development of a new strategy for these assessments, and

examples of the implementation of this approach.

Background on criticality assessments

The control of CQAs, critical material attributes (CMAs), and

CPPs is an integral component of the overall control strategy

Ke Wang, PhD*, is associate director, Pharm Sci & Manufacturing

Statistics, Pfizer, MS 8220-4438, Eastern Point Road, Groton, CT 06340,

Tel.: +1.860.686.2888, [email protected]; Nathan D. Ide, PhD, is

principal research scientist, Process Research and Development, AbbVie,

1401 Sheridan Road, North Chicago, IL 60064; Olivier Dirat, PhD, is

associate research fellow, Chemical Research and Development, Pfizer,

Discovery Park House Ramsgate Road, Sandwich, CT13 9NJ, United

Kingdom; Ann Kathryn Subashi is director, Global CMC; Nicolas

M. Thomson, PhD, is director, Chemical Research and Development;

Kim Erland Vukovinsky is senior director, Pharm Sci & Manufacturing

Statistics; and Timothy J.N. Watson, PhD, is research fellow, CMC

Advisory Office, all four at Pfizer, Eastern Point Road, Groton, CT 06340.

*To whom correspondence should be addressed.

Submitted: May 19, 2015. Accepted: Aug. 14, 2015.

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Criticality Assessment

for drug substance and drug

product manufacturing. The

International Conference on

Harmonization (ICH) Q8(R2)

(1) provides the following def-

initions:

t� CQA is defined as a phys-

ical, chemical, biological. or

microbiological property or

characteristic that should

be within an appropriate

limit, range, or distribution to

ensure the desired product

quality.

t� CPP is a process parameter

whose variability has an

impact on a critical quality

attribute and therefore

should be monitored or con-

trolled to ensure the process

produces the desired quality.

ICH Q11 (2) states that:

“A control strategy should

e n s u r e t h a t e a c h d r u g

substance CQA is within the

appropriate range, limit, or

distribution to assure drug

substance quality. The drug

substance specification is

one part of a total control

strategy and not all CQAs

need to be included in the

drug substance specification.

CQAs can be (i ) included

on the specif ication and

confirmed through testing

the final drug substance, or (ii)

included on the specification

and con f i rmed th rough

upstream controls (e.g., as

in real-time release testing

[RTRT]), or (iii) not included on

the specification but ensured

through upstream controls.”

In addition, ICH Q11 states

that : “ Impurit ies are an

important class of potential

drug substance CQAs because of their potential impact on drug

product safety. For chemical entities, impurities can include

organic impurities (including potentially mutagenic impurities),

inorganic impurities (e.g., metal residues), and residual solvents.”

The term CMA is not defined in the glossary of ICH

Q8, but ICH Q11 clarifies that material attributes can be

intermediate, reagent, solvent, or starting material

attributes. It is appropriate to use the term CMA for any of

the starting material or intermediate attributes that have

an impact on a drug substance CQA (particularly in the case

where a specific CQA/impurity in the drug substance is

derived from a different chemical species upstream).

Based on the above definitions and ICH Q8/Q11 guidance,

the criticality of process parameters should be assessed for

their impact on the CQAs and CMAs. Upstream/intermediate

specifications can include quality attributes that are not

part of the control strategy for CQAs but are included for

monitoring and trending purposes only.

Design and run experiments

based on output from initial risk

assesments

Would considering the CPP enhance the control strategy?

Could the PP beexpected to be

critical based on established

science?

Holistic reviewof criticality

assessment andcontrol strategy

Non-criticalprocess

parameter

Criticalprocess

parameter(CPP)

Assess criticality of an individual

processparameter (PP)

Statisticallysignificant

relationshipbetween PP and

a CQA

Is therelationshippractically

significant?

Yes

Yes

Yes

Yes

No

No

No

No

Figure 1: Decision tree for assessment of process parameter criticality. CQA is critical quality

attribute.

Response

Target or specification

Explored space

Figure 2: Illustration of statistical significance and practical significance. The green

and blue lines represent two statistically significant relationships between a

process parameter and a response. The red dashed line indicates the acceptable

limit for this response. The relationship represented by the blue line is practically

significant, but the relationship represented by the green line is not, because the

effect size is small and all of the results are far below the limit.

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Assessment of process parameter criticality

Process parameter criticality can be evaluated using risk

assessments, experimental investigation, or a combination

of these two approaches. The determination that parameters

are critical or non-critical by risk assessment is relatively

straightforward—if established science, knowledge, or data

clearly indicates that a parameter will or will not have a signif-

icant impact on a CQA, criticality can be assigned. For many

parameters, however, the risk assessment will indicate that

experimental investigation is required to assess criticality (3).

In cases where data are available from multivariate and/

or univariate design of experiments (DoEs), these data

can be used to help assess process parameter criticality

(see Figure 1). The first question to consider is whether a

parameter has a statistically significant relationship to a CQA.

If so, the practical significance of this relationship should be

assessed. If the parameter is considered to have a practically

significant relationship to a CQA, then the parameter should

be considered critical. If the parameter is determined to

not have a statistically significant relationship to a CQA, or

it is determined to have a statistically significant, but not a

practically significant relationship to a CQA, the team should

still review the control strategy holistically, prior to assessing

the parameter as non-critical. In this review of the control

strategy, the team should evaluate the established science

related to this process parameter and consider whether

promotion of the parameter to critical would be beneficial to

the overall control strategy. Promotion of a parameter from

non-critical to critical during this final review process would

not be expected to be a common occurrence.

Statistical approach for practical significance

Using statistical significance as the definition of practical

significance is not appropriate, because statistical signifi-

cance does not take into account the strength of the rela-

tionship relative to the relevant quality requirements. An

appropriate statistical evaluation of practical significance

can take into account the risk of failing a limit/specification

and the parameter effect size. For example, the green and

blue lines in Figure 2 represent two statistically significant

relationships between a process parameter and a response.

The acceptable limit for this response is indicated by the red

dashed line. The relationship represented by the blue line is

practically significant, but the relationship represented by

the green line is not, because the effect size is small and all

of the results are far below the limit. Therefore, the severity

resulting from a parameter effect needs to be considered

for CPP assessment just as it is contemplated in evaluating

quality attribute criticality (3).

A statistical approach has been developed to help

determine when a statistically significant relationship

between a process parameter and a CQA can be defined

as a practically significant relationship. This approach uses

two statistical tools (Z score and 20% rule). The concept

behind the first tool, the Z score, is shown in Figure 3. Each

plot represents the data points from a 20-run multivariate

DoE (f ive parameters included in the study) with an

impurity (Area %) on the y-axis and the experiment number

on the x-axis. Variability present in the data could come

from different sources, including intentional changes in

parameters, analytical variability, and the natural variability

(i.e., random noise) inherent in the process. If there is too

much variability in the data that is not explained by the

intentional variation of parameters, the variability should be

addressed before proceeding with this analysis.

In Figure 3, the limit for this impurity is indicated by the

red dashed line. The data points in (a) are tight and far away

from the target, suggesting a low-risk process. Moving

any parameter over its experimental range is not going to

significantly elevate the risk of failing versus this limit; it

is reasonable to conclude that no parameter is practically

significant. By contrast, data points in (c) are very close to the

limit, therefore, even though the relative variability in the data

is the same as in (a), the process is at higher risk. In this case,

any statistically significant parameter should be considered

practically significant. Data points in (b) are neither far from

nor close to the limit. In these cases, the second statistical

tool (20% rule) is needed to quantify the individual parameter

effect size. This effect size, calculated using the statistical

model, can be used to assess practical significance.

Are

a%

A large z score

no practical significance

A small z score

practical significance

z>6

IDID

ID

z<21.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10 12 14 16 18 20

1.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10 12 14 16 18 20

1.0

0.8

0.6

0.4

0.2

0.00 2 4 6 8 10 12 14 16 18 20

(a) (b) (c)

Figure 3: Illustration of the Z score concept.

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As introduced conceptually in Figure 3, the distance

between the data and the limit plays an important role

in process risk evaluation, and the Z score can be used

to measure this distance. If ϰ and s are the average and

standard deviation of the data respectively, and U is the

upper limit of the specif ication, the Z score can be

calculated using Equation 1:

Z = (U- ϰ)/s [Eq. 1]

The Z score evaluates how close the entire dataset is

to the limit, without focusing on any individual parameter

effects. The value for Z effectively indicates how far the

data is from the limit/specification; a large Z score indicates

that the data are far from the limit/specification, while a

small Z score indicates that the data are close to the limit/

specification. Conceptually, the Z score is similar to a process

capability index (Cpk)(4); a large Z score indicates a low-risk

process and a small Z Score indicates a high-risk process.

In this approach, Z score values of two and six are used as

the cut-off values for assessing practical significance. In cases

where a Z score is larger than six, as illustrated conceptually

in Figure 3(a), there are no practically significant parameters.

In cases where a Z score is less than two as illustrated

conceptually in Figure 3(c), it is generally appropriate to

conclude that every statistically significant parameter is

practically significant. If a Z score is between two and six,

as illustrated conceptually in Figure 3(b), the individual

effect size of statistically significant parameters needs to be

quantified and compared to the limit/specification. Here, 20%

of the limit/specification range (20% rule) is chosen as the

threshold for practical significance. If a parameter effect size is

greater than 20% of the limit/specification range, it should be

considered practically significant. If the parameter effect size

is less than 20% of the limit/specification range, then it is not

practically significant. The selection of 20% as the threshold

for practical significance is similar to the conventional criteria

(0.2–0.3) for a small effect size, using Cohan’s d (5). This

procedure for assessing practical significance is outlined in

Figure 4. The described approach allows for the rapid and

consistent assessment of process parameter criticality.

For simplicity, the above discussion of Z scores is focused

on one-sided, upper-limit specifications (U). It is worth noting

that the approach can be easily extended to one-sided, lower-

limit specifications and also to two-sided specifications.

Examples

Two examples are included to illustrate the implementation

of the described approach. The first example shows the criti-

cality assessment for six crystallization process parameters

in a drug substance intermediate step. The studied parame-

ters were seed temperature, temperature ramp rate 1, tem-

perature ramp 1 end temperature, temperature ramp rate

2, temperature ramp 2 end temperature, and seed loading.

These parameters were incorporated into a 26-2 fractional

factorial with four replicates, at the target conditions, for

a total of 20 experiments. Shown in Figure 5 are the bar

charts for one process-related impurity (impurity 1) with a

limit of not more than 1.0% at the intermediate step. This

impurity is a CMA, as it tracks forward to an impurity (CQA)

in the drug substance. The limit was set based on down-

stream fate and purge data. Statistical analysis revealed that

ramp rate 1 and seed loading had statistically significant

relationships with impurity 1. Given the calculated average

Statisticallysignificant

relationshipbetween a PP

and CQA

Assess practicalsignificance

Target is > 6sfrom average

(Z>6)

Target isbetween 2s and6s from average

(6≥Z≥2)

Is the effect size> 20% of targetor specification

value?

Relationship isnot practically

significant

No YesRelationship is

practicallysignificant

Target is < 2s from average

(Z < 2)

Calculateaverage and

standarddeviation (s) forresponse data

Calculatedistance from

average totarget

in units of s

Figure 4: Decision tree for practical significance. PP is process parameter. CQA is critical quality attribute.

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(0.31%), the standard deviation (0.037%), and the limit of

1.0%, a Z score of 18 is obtained. The Z score of 18 is greater

than six, and therefore none of the studied parameters have

a practically significant relationship with impurity 1.

A second example is shown in Figure 6. This example

is based on a measurement of tablet assay, in a 17-run

experimental study for a drug product process, with a two-

sided specification of 95%–105%. The study was designed

to explore the impact of excipients (magnesium stearate

quantity, dicalcium phosphate [DCP] source) and process

parameters (Comil shear force, pre-blending) on tablet

assay. Statistical analysis revealed a significant interaction

between DCP source and Comil shear force. The fitted

regression model is shown in Equation 2 as follows:

��ComilShearForce – 0.70 �

�� ComilShearForce * DCP [Eq. 2]

For a two-sided specification, two Z scores are calculated,

and the lower of the two values is used to assess practical

significance. Given the calculated average (99.24%) and

standard deviation (1.64%) for tablet assay, the upper limit

and lower limit had Z scores of 3.5 and 2.6, respectively. Both

Z scores require additional assessment via the 20% rule to

quantify individual parameter effect sizes. For a model with

a significant interaction between two parameters, each

calculated parameter effect needs to take into account both

the main effect and the interaction effect. The statistical model

in Equation 2 predicts that the maximum change in assay

is 3.36% for Comil shear force and 3.20% for DCP. Given the

specification range of 10% (105%–95%) for tablet assay, the

20% threshold is 2.0%. As both effect sizes are greater than

2.0%, Comil shear force and DCP are practically significant.

Summary

In general, it is expected that the evaluation of practical sig-

nificance presented in the two examples discussed would

encompass all relevant experiments that assess a given

parameter (i.e., the entire explored range). Given the expec-

tation that criticality assessments should be performed by

evaluating effects across the entire explored range, bounda-

ries of the explored ranges should be set in a pragmatic

fashion. These explored ranges need to effectively support

the development of process understanding and the need for

usable ranges in manufacturing, while avoiding unnecessary

expansion of the investigation into ranges that would never

be considered for manufacturing.

Conclusion

Process parameter criticality can be determined using risk

assessments, experimental investigation, established sci-

ence, or a combination of these approaches. The proposed

statistical methodology is intended to provide guidance and

a common language to facilitate discussions on process

parameter criticality. Criticality is assessed by determining

when a statistically significant relationship should be consid-

ered a practically significant relationship, which is then used

to aid the overall criticality assessment.

Acknowledgements

The authors would like to thank Brad Evans, Greg Steeno, Leslie

Van Alstine, Brian P. Chekal, Mark T. Maloney, Shengquan Duan,

Steven Guinness, and Ken Ryan for their helpful discussion and

feedback during the development of this approach.

References

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

2. ICH, Q11 Development and Manufacture of Drug Substances (2012).

3. L.X. Yu et al., The AAPS Journal, 16 (4) 771-783 (2014).

4. D. Montgomery, “Process Capability Analysis”, in Introduction to

Statistical Quality Control (John Wiley & Sons, Inc., New York, 3rd ed.,

1997), pp. 430-470.

5. J. Cohen, “Analysis of Variance”, in Statistical Power Analysis for the

Behavioral Sciences (Lawrence Erlbaum Associates, 2nd ed., 1988), pp.

273-406. PT

Target

Are

a%

Average

>6s

1.0

0.8

0.6

0.4

0.20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

ID

Z=3.5

Z=2.6

Target

Target

105.0

102.5

100.0

97.5

95.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

ID

Figure 5: Bar chart for impurity 1 (y-axis) in Example 1

design of experiment (DoE) (x-axis). Black dashed line

is the average of impurity 1 and red dashed line is the

target. Z = 18.

Figure 6: Scatter plot of tablet assay (y-axis) in Example

2 design of experiment (DoE) (x-axis). Black dashed

line is the average of tablet assay and red dashed lines

represent the two-sided specification. Z1 = 3.5 and

Z2 = 2.6.

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Single-use systems (SUS) featuring plastic components and materials are widely used in bio/pharmaceu-

tical development and clinical-trial ma-terial manufacturing, and are expected to become more common in commer-cial manufacturing. Drug manufactur-ers and contract manufacturers favor SUS for the benefits of fast changeover, reduced cross contamination, and man-ufacturing system flexibility.

Concern about the potential for con-taminants from the plastic materials interacting with the drug, unacceptable extractables data, and a lack of standards for evaluating SUS materials could, how-ever, slow adoption.

Nearly three-quarters of biophar-maceutical manufacturers surveyed for the 2015 BioPlan Associates industry study (1) identified extractables and leachables as a concern that may limit further use of SUS. The only greater concern was breakage of bags and loss of production material. Concerns about extractables and leachables have been steady during recent years, par-tially due to the increased use of dis-posables and increased awareness of the uncertainties about related regula-tory issues, according to the report.

Current good manufacturing practices (CGMPs) require that manufacturing equipment must be constructed so the surfaces that contact components, in-pro-

cess materials, or drug products “must not be reactive, additive or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product” (2). For bio-logic products, “All surfaces that come in contact with products shall be clean and free of surface solids, leachable contami-nants, and other materials that will hasten the deterioration of the product or other-wise render it less suitable for the intended use” (3). Similar requirements are in place for the European Union (4).

Therefore, bio/pharma and contract manufacturers must—using scientific- and risk-based approaches—test the materials and surfaces that come in direct or indirect contact with the API, ingredients, and drug product to demon-strate equipment and process suitability for regulatory filings.

Extractables studies identify chemi-cals that migrate from a material when exposed to a solvent at an elevated tem-perature, generating a worst-case test for contaminants. The data are used to assess toxicities of the extracted chemicals and to assess the potential for leachables—com-pounds that migrate into a specific drug product or process under normal condi-tions during the drug product’s lifecycle.

Some suppliers of manufacturing components and packaging materials provide extractables data that can be used for preliminary screening and risk assess-ment; however, the information often is

not available or sufficient. A complex supply chain, where different parts of an SUS technology may be manufactured or processed by multiple subcontractors at multiple locations, adds uncertainty to the quality and completeness of the data.

In the BioPlan study, more than 80% of the respondents “agreed” or “strongly agreed” that vendors of SUS should gen-erate and validate extractables and leach-ables data. The study authors concluded that drug owners believe SUS vendors need to do more testing and analysis of materials used in SUS devices, or they are not comfortable dealing with extract-ables and leachables issues and defer to suppliers for the testing (1).

The cost of acquiring data was also considered. Nearly one-third of the re-spondents said they would not pay SUS suppliers more for extractables and leachables data; 22% said they would pay up to 25% more. The estimated average upcharge was 13.4%. The study authors attributed the drug manufacturers’ price sensitivity to SUS-supplier upcharges for data to general cost-consciousness, in-creased knowledge about regulatory is-sues, a better assessment of developing the data internally, and an increasing number of contract service providers offering test-ing services of extractables and leachables.

Willingness to pay a markup for data has largely stabilized, the study concludes, although a growing number of drug owners are willing to do their own testing for early-phase development, where data requirements are less stringent.

Industry effortsThe lack of sufficient extractables data from suppliers of SUS has spurred activ-ity for standardized testing protocols for these technologies. Representatives of drug manufacturers, testing laboratories, SUS manufacturers and suppliers, inde-pendent consultants, and regulatory au-thorities have participated in discussions, authored position papers, proposed best practices and standards, and developed databases. Often, the proposals conflict on key points; however, the groups are reporting efforts to build consensus.

The Product Quality Research In-stitute (PQRI), a collaborative effort of

Building Consensus forE&L Testing StandardsRita Peters

Extractables and Leachables

Standardized testing protocols are crucial for acceptance of single-use systems.

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T E C H N O L O G Y, I N C.

LYOPHILIZATION


Extractables and Leachables

FDA’s Center for Drug Evaluation and Research (CDER), industry, and aca-demia, has published several documents including safety thresholds and best practices for extractables and leachables in orally inhaled and nasal products (5), and a similar publication for parenterals and ophthalmic drug products (6).

Bio/pharma and medical-device com-panies formed the Extractables and Leach-ables Safety Information Exchange (ELSIE) Consortium to compile toxicological data on leachables and extractables to study their impact on drug product packaging, delivery, and manufacturing systems. As of October 2015, the consortium had devel-oped a database of nearly 400 compounds listing chemical, chronic toxicity, muta-genicity/carcinogenicity, reproductive/developmental toxicity, and absorption, distribution, metabolism, and excretion information (7).

An ELSIE materials working group also piloted an extraction study protocol on polyethylene and polyvinyl chloride that included extraction solvents, extrac-tion techniques, and a range of analytical techniques. The study investigated whether a reduced number of extraction techniques or a reduced number of solvents could be used to obtain information useful for mate-rial selection, regardless of product type (8).

Trade associations, including the Par-enteral Drug Association and the Inter-national Society of Pharmaceutical Engi-neers, also have been active in sponsoring presentations and publishing papers about extractables and leachables testing.

Proposals and consensusThe Bio-Process Systems Alliance (BPSA), a corporate member trade asso-ciation of component suppliers, systems integrators, users, and testing laborato-ries, was founded in 2005 to accelerate the adoption of single-use manufactur-ing technologies. Representing the in-dustry supplier market segment, BPSA has published recommended practices for extractables and leachables testing and has initiated efforts to standardize testing procedures for other aspects of SUS materials (9).

The BioPhorum Operations Group (BPOG), which represents the drug-owner segment of the industry, defined a standardized extractables testing proto-col for SUS manufacturing systems that covers methods for extractables testing studies, including sample preparation, extraction conditions, and reporting data. The authors, members of the BPOG extractables working group, wrote that a testing protocol, with agreed-upon test methods, would establish common ex-pectations among suppliers, users, and regulators on the type of testing data to be generated. The enhanced data would help users compare components from different suppliers, would assist suppliers in selecting materials that end users need, and would help in controlling product variability (10).

Following publication of the BPOG paper, BPSA published a perspective arti-cle noting a difference of opinions among end-user companies, suppliers, testing laboratories, and standards-writing bod-ies that must be resolved to achieve a full industry consensus standard (11).

Representatives of BPSA and BPOG are participating in an ASTM Interna-tional working group developing prac-tice documents for extractables studies. The extractables test solutions practice will define a standard method to create extraction samples from single-use bio-

process systems using model bioprocess extraction solutions. Data generated from these studies could be used to make risk-based decisions about the potential im-pact on the API or drug product and the selection of equipment or components. Analysis of extractables test solution will be covered in a separate practice (12).

ASTM is also developing a practice for testing of leachables for single-use mate-rials that contact APIs, intermediates, or the final drug product. The studies are designed to provide a leachables profile based on testing methodology compa-rable to extractables studies (13).

References 1. BioPlan Associates, 12th Annual Report

and Survey of Biopharmaceutical Manufac-turing Capacity and Production (Rockville, MD, April 2015), www.bioplanassociates.com/12th

2. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 211.65(a).

3. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 600.11 (b).

4. EudraLex, EU Guidelines for Good Manu-facturing Practice for Medicinal Products for Human and Veterinary Use (Brussels, Belgium, August 2014).

5. PQRI, Safety Thresholds and Best Practices for Extractables and Leachables In Orally Inhaled and Nasal Drug Products (September 2006).

6. D. Paskiet, PDA J. Pharm. Sci. Technol, 67 (5) 430-47 (2013).

7. Extractables and Leachables Safety Infor-mation Exchange, online www.elsiedata.org/elsie-database/, accessed Feb. 26, 2016.

8. A. Teasdale, et al., AAPS PharmSciTech, 16 (3) (June 2015).

9. BPSA, Technical Guides, Extractables and Leachables, online www.bpsalliance.org, accessed Feb. 26, 2016.

10. W. Ding, et al, Pharm. Eng, 34 (6) (2014). 11. BPSA, Toward Industry Standardization

of Extractables Testing for Single-Use Systems: A Collective BPSA Perspective, (March 10, 2015) online, www.biopro-cessintl.com, accessed Feb. 21, 2016.

12. ASTM WK43975, “New Practice for De-termining and Characterizing BioProcess Extractables from Components, Subas-semblies, and Assemblies Used in Single-Use Applications,” ASTM International, www.astm.org (West Conshohocken, PA), accessed Feb. 22, 2016.

13. ASTM WK48084, “New Practice for De-termining and Characterizing Leachables released from Materials used in Single-use Systems under bioprocess operating conditions,” ASTM International, www.astm.org (West Conshohocken, PA), accessed Feb 22, 2016. PT

The US Pharmacopeial Convention (USP) will pub-

lish a revision to the United States Pharmacopia

Chapter <661> on Plastic Containers in May 2016,

renaming the chapter Plastic Packaging Systems

and their Materials of Construction. New General

Chapter <1663> Assessment of Extractables As-

sociated with Pharmaceutical Packaging/Delivery

Systems describes scientific practices for accom-

plishing an extractables assessment. New General

Chapter <1664> Assessment of Drug Product

Leachables Associated with Pharmaceutical Pack-

aging/Delivery Systems outlines a framework for

the design, justification, and implementation of

assessments for drug-product leachables derived

from pharmaceutical packaging and delivery sys-

tems. General Chapter <1664.1> addresses spe-

cific considerations for leachables in metered-dose

inhalers, nasal sprays, dry-powder inhalers and

inhalation solutions, suspension, and sprays.

USP updates standards

for packaging plastics

May 16-18, 2016Sheraton Boston Hotelton Boston HotelBShera

SVISIT: www.aaps.org/nationalbiotechFOR MORE INFORMATION!


Data integrity is a major regulatory topic in GMP-regulated laborato-ries. The problem is widespread,

as cases of non-compliance have also been observed in laboratories regulated by good laboratory practice (GLP) and good clinical practice (GCP), not just GMP. Non-compliances from the European Medicines Agency (EMA) or warning letters from FDA show ex-amples from companies in the United States, Canada, the United Kingdom, and Italy, as well as China and India. So, it is not just a problem for Asia—it is a global issue.

The non-compliances are not con-fined to falsification and fraud. In

fact, in the majority of labs, the main data integrity issues concern poor data management, which account for 95% of non-compliance cases; only 5% are a re-sult of falsification or fraud. Problems arise from basic errors such as relying on paper as raw data and failing to protect electronic records, rather than deliberate manipulation of data. It is the latter, however, that gets the major headlines. In July 2014, FDA issued a stern warning that data integrity was a key focus of its enforcement efforts (1).

Regulatory guidance on data integrityIn January 2015, the UK Medicines and Healthcare products Regulatory Agency (MHRA) went further and is-sued Guidance for Industry on Data In-tegrity (revised in March 2015) (2). This guidance consists of descriptions, defi-nitions, and expectations based around

those definitions, which include raw data, original records, file structures, and audit trail. The regulatory expec-tations presented in this guidance are useful. However, the definitions are simply presented as a shopping list; a diagram explaining and linking key definitions would be more beneficial.

The guidance presents data integ-rity as the extent to which all data are

“complete, consistent, and accurate” throughout the data lifecycle, which covers the period from data acquisi-tion through to interpretation, report-ing, and archiving and then destruc-tion after the record retention period. There are similarities in the US regula-tions; a 20-year-old FDA definition of data integrity describes the degree to which a collection of data is complete, consistent, and accurate (3).

In European GMP regulations, doc-umentation constitutes a key part of quality assurance and, therefore, com-pliance with GMP (4). An organization must have good documentation, follow standard operating procedures (SOPs), and demonstrate compliance with the applicable regulations. Several require-ments focus on data integrity for com-puterized systems (5). If critical data are entered into a data system, a second check is required, which can either be a second person or can be automated using the computer system itself.

In the US, the regulations for labo-ratory records focus on the concept of complete data (6).

A review of data integrity warning letters reveals several citations for fail-ure to have complete data including a failure to have a complete procedure (7), a failure to fully document the work that is carried out (8), or being selective in re-porting data (e.g., using test samples to

“check” if an instrument is working cor-rectly) (9). Complete data includes the actual observation, which can be visual or by computerized system. Contextual metadata, which puts the data or result in context, is also required. Examples of metadata include operator ID, units of measurement, sample information, identity, batch number, instrument suit-ability, and readiness. Audit trail events

Data Integrity

Data integrity is a widespread, global problem that must be addressed.

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Dr. Bob McDowall is director of R D

McDowall Ltd., [email protected].

Dr. Joanne Ratcliff is communications

project manager at Mettler Toledo GmbH,

[email protected].

How Important is Data Integrity to Regulatory Bodies? Bob McDowall and Joanne Ratcliff


are also part of the metadata. If a hy-brid system or a fully electronic system is used, FDA and European regulatory agencies require companies to review and evaluate audit trail events to see if data have been manipulated without authorization.

FDA guidance comprises a list of com-monly asked questions and answers that are crucial for maintaining data integrity (10). Detailed explanations are given for:t� Why paper records from a hybrid

system should not be defined as raw data—instead it should be the

underlying electronic records; Al-though the reasoning focuses on chromatography, it is applicable to any computerized system.

t� Why sharing of user identities in a computerized system is not al-lowed—as it makes it impossible

Table I: Good Automated Manufacturing Practice (GAMP) criteria for data integrity—ALCOA+.

ALCOA Term Criteria Definition

A Attributable Who performed the action and when? If a record is changed, who did it and why? Link to the

source data.

L Legible Data must be recorded permanently in a durable medium and be readable.

C Contemporaneous The data should be recorded at the time the work is performed and date/time stamps should

follow in order.

O Original The information must be the original record or a certified true copy.

A Accurate No errors or editing performed without documented amendments.

+ Complete All data including any test, repeat, or reanalysis performed on the sample.

+ Consistent Consistent generation of records and application of date time stamps in the expected sequence.

+ Enduring Data should be recorded on controlled worksheets, in laboratory notebooks or in validated

electronic systems.

+ Available Data needs to be available and accessible for review, audit, or inspection over the lifetime of

the record.

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to attribute the work carried out to a single individual.

t� Why actual samples should not be used as system suitability tests to see whether a batch passes or not. FDA warning letters reveal many citations for this transgression.

Data integrity criteriaThe criteria for data integrity are de-fined by the acronyms ALCOA and ALCOA+. ALCOA, which stands for attributable, legible, contemporane-ous, original, and accurate, was de-veloped by an FDA GMP inspector in the late 1980s. ALCOA has been used in many areas that are regulated both by FDA and other regulatory agencies worldwide. In 2010, EMA published a paper on electronic source data for clinical records, in which another four requirements relating to electronic data were added: complete, consistent, enduring, and available (11). The Good Automated Manufacturing Practice (GAMP) Data Integrity Special Inter-est Group (SIG) now refers to ALCOA+,

which includes the nine attributes or criteria for data integrity (see Table I).

Inspection trends In the past, an inspector would review piles of paper; to view a computer sys-tem, he would be shown print-outs of the screen. Now, the focus is on the computerized systems and the elec-tronic records within; the paper output is secondary. Inspectors will focus on the electronic records, looking at how they were generated and manipulated within the application. In the light of these changes, consideration needs to be given to the person who will manage the system during an inspection. How is the system configured to protect the electronic records? Are electronic sig-natures being used in the application, ensuring that the configuration of the application is documented and reflects the settings within the software?

Annex 11 now requires audit trail en-tries to be reviewed, and FDA considers these entries as part of the complete data. Many findings of non-compliance dur-

ing inspection have been discovered by looking at audit trail entries, therefore, an approach to reviewing audit trail events is needed. Citations have noted when audit trails were been turned off, the audit trail had not been reviewed, or user identities were shared, which is not allowed under the regulations. Ad-ditional citations can be found in the September 2014 issue of LCGC (12).

The ten compliance commandmentsThe 10 compliance commandments for computerized laboratory systems described in Table II should be consid-ered (12).

Where should the electronic data transfer begin?Let’s consider preparation of standards by way of example. In an analytical lab, standards are usually prepared using an analytical balance. The actual weight is typically printed on a strip printer and pasted into a lab journal. Afterwards, the standards are widely

Data Integrity

Table II: The 10 compliance commandments.

Commandment Comment

1 Management is responsible. Management must take the lead in making certain that the integrity of

data in the lab is managed and maintained.

2 Use a networked system, ideally with

a database.

Stand-alone systems should not be used in a regulated environment.

3 Document the system configuration

and manage all changes to it.

You must document and ensure the configuration protects the records.

4 Work electronically and use electronic

signatures.

Try to work electronically wherever possible. The advantage is that the

data are maintained within the system. Don’t use a hybrid because you

have two incompatible formats (worst possible situation).

5 Allocate each user a unique identity

and use adequate password strength.

Ensure that you have unique user identities, so that you can attribute the

work to a single individual.

6 Separate roles to avoid conflict of

interest.

Separate the roles within any computerized system. Typically “Admin” should only

be accessible by IT or a small group of people, not standard laboratory workers.

Exception if there are only 1–2 users (in which case it is necessary to share the

roles).

7 Define methods that can and cannot

be adjusted.

Consider which methods within a system can actually be changed and

which cannot.

8 Have a standard operating procedure

for data manipulation.

For chromatography data systems, a standard operating procedure

(SOP) for both automatic and manual integration is necessary.

9 Ensure staff are trained and

competent.

The need for an SOP is clear, but do people understand it and are they

competent to use it? Ensure the people are trained, both in data integrity

and the instrumental techniques they are using.

10 Carry out effective self-inspections or

internal audits.

Make certain that internal audits don’t just focus on paper. Instead, they

should go deeper and look at things within the computerized system.


used for analytical methods, such as high-performance liquid chromatog-raphy (HPLC), gas chromatography (GC), titration, etc. Data management and documentation for analytical in-struments are usually managed by dedicated software or a laboratory in-formation management system (LIMS). This procedure is currently allowed by regulatory bodies, which state that print-outs representing original data for simple devices (such as balances) are acceptable (2) but is not the case for more complex devices. Nevertheless, it is important that reference standards are accurate and traceable because they represent the starting point of many analyses. Warning letters have cited

“no details available on the preparation of standards or solutions, especially of analytical reference standards” (13, 14). Independent of process, it is important to ensure that all the data are available.

This then begs the question: Where should the electronic transfer begin? In

the process described above, there is a gap in the data transfer between the “simple instrument” (the balance) and the “com-plex instrument” (e.g., the HPLC). Clearly, this is not recommended because it in-troduces an additional level of risk; it is obvious why no gaps should occur.

Capturing the data at the point of origin and transferring the data elec-tronically throughout the whole work-flow is a much lower risk approach and reduces the risk of errors during the early stages of a process, giving addi-tional confidence in the compliance of a workflow or laboratory.

What data should be transferred?The next question then becomes: What data need to be transferred? It is essen-tial to associate results with metadata to build context around the values collected. Although integrating even a simple in-strument can be tricky, the advantages of an integrated solution are obvious.

When electronic data transfer starts from the beginning of the process, each piece of information needs to be input only once for it to be available through-out the whole system. This allows seam-less movement of data and other infor-mation from the start of a process to the end, without the need for manual effort, such as manual transcription, creating an efficient work environment.

This transfer of data is achievable using a laboratory execution system (LES), such as LabX, which enables a variety of instruments to be directly connected (balances, titrators, density meters, refractometers, thermal analy-sis instruments, and pH meters). Use-ful features such as SOP-user guidance on the instrument terminal, automatic results capture in a database, and real-time data access support traceability of data and compliance with the GAMP data integrity criteria in ALCOA+.

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Contin. on page 76


Process Control

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In the past, process control data were used simply to control the process. With the explosion of data collection

and analysis capabilities, however, data can be harnessed to do much more. Pharmaceutical Technology spoke with Dr. Hartmut Klocker, vice-president of the Pharma Market Development Board at Siemens, about how data from process control systems can be used to optimize manufacturing processes.

Integrating dataPharmTech: What can be accomplished by more effectively using process con-trol data?

Klocker: In the past, process control data were collected in the distributed control system archives and dedicated plant information systems, and their only purposes were to control the process and visualize the status of the

process in real-time and historically. Today, however, pharma companies try to gain additional information by bringing together all different types of data from many sources including control systems, programmable logic controllers (PLCs), analyzers, building management systems, and laboratories.

The analysis of key performance indicators (KPIs) using all these data will open new insights into manufac-turing processes and provide the basis for process optimization while keep-ing the quality within tight specifica-tions. In addition, new technologies, such as continuous processes for tab-let manufacturing or the production of personalized medicine, would not work without integrating process and analyzer data and even parameters of the scheduling and planning tools. In the future, the industry will focus on

using process data to predict the end-product quality and thus the expected therapeutic effect using model predic-tive control.

Some data generated within PLCs, smart sensors, and complex analyz-ers are not collected and not used at all. Collecting these data, transferring them to a database, and applying tools to generate valuable information out of the pile of data are key challenges. A cloud solution may provide suffi-cient storage capacity and calculation power. The data analysis can then be performed by the customer or even outsourced to the suppliers of the automation systems or the machine manufacturers by giving them access to the relevant cloud data. An example, available today, is equipment monitor-ing, with the purpose of getting a bet-ter understanding of the condition of the machines and the overall produc-tion process. Data could be then used for energy management and condition-based maintenance.

PharmTech: How can data from dif-ferent sources be integrated and pre-sented to users?

Klocker: Data integration platforms are key to bringing together these data. The networking capabilities of devices are increasing steadily in line with the general industry trends of digitaliza-tion. Key technologies that allow this integration are the open standards Ole for Process Control, Unified Architec-ture (OPC UA) and OPC Analyzer-Device Integration (OPC UA ADI), which is for complex analyzers with large quantities of multivariate data.

Cloud technologies can provide a basis for such data platforms. Different experts can then be granted access to a subset of these data to provide data an-alytical services. For example, equip-ment experts can be shown data for predictive maintenance, and process engineers can be shown data to sup-port continuous process improvement. In addition, the common problem of overloading plant operators with con-trol data that are not directly relevant to monitor the process can be avoided. Data can be hidden on the operators’

Gaining Insight from Process Control Data Jennifer Markarian

Integrated data and cloud-based solutions can be used for process optimization.


screens but transferred into the cloud, where other experts can look at various issues, such as machine health and per-formance or the relationship between climate and process quality parameters. The traditional operator screens will change, and instead of colorful graph-ics of process f low diagrams, process parameters and alarm messages with more focused views will prevail. The intent is to give a fast and clear picture of what is really going on, while hid-ing irrelevant details. Another tool is smart-phone apps that can be used to present the information needed to deal with specific tasks.

PharmTech: What are the security con-cerns with storing data in the cloud?

Klocker: Cyber-attacks are a chal-lenge that is mentioned in every in-dustry, especially when storing pro-cess data and accessing it broadly. To create the highest level of security, it is important to modernize and integrate the automation environment, with security built natively into the system from the field-level up. Siemens uses a ‘defense-in-depth’ concept that covers plant and network security as well as system integrity.

Using dataPharmTech: How can the collected data be used for determining KPIs, such as over-all equipment effectiveness (OEE)?

Klocker: KPIs, such as OEE and oth-ers, must use the whole range of data sources from automation systems, planning tools, building management systems, and laboratory management. There are two principal methods for achieving this. The first strategy is to collect all data in one large database and apply the KPI calculations to this database. This strategy is straightfor-ward as long as the intelligent device can be easily integrated into the plant information database using an open communication standard. In the alter-native strategy, the data are not copied into a database, but accessed from all the distributed databases on request. The databases accessed might be plant information systems and historical data from control systems, recipe-

control systems, enterprise resource planning data, and others. Intelligent caching of data to allow quick access using internet browsers is important. The advantage of this concept is to avoid copying of the original data, which might make the proof of data consistency (according to GMP regu-lations) cumbersome.

PharmTech: What are some best prac-tices for using process data to control the manufacturing process?

Klocker: Critical quality attributes (CQAs) determine the final product quality and are the basis for predict-ing therapeutic effect. Today, many CQAs can be measured in-line/on-line by applying process analytical technol-ogy (PAT). Data collected from experi-ments using the in-line/on-line mea-surement of the CQAs in the different unit operations of a production chain are the basis for process data model-ing. Correlation of the data provides a basis for understanding the process

and determining the critical process parameter (CPP) settings to obtain the right quality. Furthermore, the ap-plication of PAT, combined with model predictive control in the process con-trol system, allows us to adapt CPP set-tings dynamically and produce within specification all the time.

A good example of the need to combine data from several sources is personalized medicine, which is of increasing importance to the pharma-ceutical industry. The same principles in terms of manufacturing, quality control, and release of the drug apply to personalized medicine as to con-ventional drugs, but instead of large batches of active ingredients, a batch size becomes the drug product for a single patient. Without tight data in-tegration and a fully paperless pro-duction process, manufacturing costs would exceed any acceptable limit. To

Contin. on page 76


In the past decade, there was a move-ment within the pharmaceutical in-dustry to benchmark drug manu-

facturers’ performance against that of manufacturers in other industries, to improve such areas as process robust-ness, speed and consistency, and to reduce waste (1). Proponents of lean manufacturing urged pharmaceutical companies to adopt best practices from other industries.

Thought leaders began to look more closely at manufacturing, as well as such standard industry benchmarks as changeover times and inventory turns, and asked whether pharmaceu-tical companies could improve per-formance and become more agile. To see how closely the industry has been examining its approach to inventory management and supply chain agil-ity, Pharmaceutical Technology asked Lora Cecere, founder of Supply Chain Insights, for her opinion on progress.

“Pharma is stuck in the mud,” notes Cecere, who writes the Supply Chain Shaman blog (2) and has more than 40 years of experience managing major corporate supply chains, consulting, and analyzing industrial performance.

As a 2012 Supply Chain Insights re-port (3) noted, pharma is immature, compared to other industries, in its supply-chain management practices. It still has higher operating margins, but faces more complexity, commoditiza-tion, and globalization than it did in the past. Mergers and acquisitions have also had an impact, Cecere says. Today, most pharmaceutical companies still generally take a conservative, func-tional approach to their supply chains, and focus more on the demand cycle than on channel data, says Cecere, who suggests that more industry executives follow the advice of supply-chain ex-pert Carol Ptak, a partner at the De-mand Driven Institute. In a blog post

on SupplyChainInsights.com (4), Ptak suggests that companies focus, first, on return on investment and cash flow, and secondarily on profit and loss, so that they can sense changes in demand and adapt planning and production dynamically.

Cecere and her collaborators have developed a supply chain index to measure how individual companies and industries are improving their supply chain agility. Considering such big issues as overall growth, profitabil-ity and complexity, the index tracks industries’ and companies’ improve-ment by averaging metrics over differ-ent time periods.

Each industry is analyzed individu-ally, based on its unique characteris-tics, but then companies are ranked, with those that have made the greatest gains recognized as “Supply Chains to Admire” (5) within those industries, based on improvements in inventory turns, return on capital investment, and operating margins.

Companies in industries with lower operating margins tend to manage their supply chains better than those with higher margins, so Cecere was surprised to find that generic pharma-ceutical manufacturers were not more agile than Big Pharma. In 2015, no ge-neric or over-the-counter drug compa-nies made the cut, while Biogen-Idec was the sole pharmaceutical company to make the list of 26 Supply Chains to Admire.

Biogen-Idec listed on the 2015 “Supply Chains to Admire” ListBiogen-Idec improved its overall sup-ply chain index ranking from 6 (when considering the period from 2006 to 2014), to 2 (when considering 2009 to 2014), the study found. The company increased return on capital from 13% to 21%, respectively, during these same time intervals, and inventory turns, re-spectively, from 9.99 to 14.55. Table I,

shows performance for the seven top-ranking pharmaceutical companies from 2011 through 2014, comparing them with metrics for a manufacturer from a different industry: Apple, Inc.

Supply Chain

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Redefining Pharma Agility Agnes Shanley

Supply-chain success is measured by how effectively new medications reach patients, and how swiftly manufacturers can react to internal and external changes.


If traditional supply chain manage-ment is not a top priority, how is the industry becoming more agile, and what metrics best reflect its progress? Pharmaceutical Technology asked Greg Anthos, senior managing consultant at Tunnell Consulting, for his thoughts. Anthos says that pharmaceutical manufacturers are focusing more of their attention upstream, to improve the research and development process, and, in particular, the way they handle clinical trials.

More pharmaceutical manufactur-ers are moving to adaptive trial de-signs, he says, and a growing number of them are working to be able to bring life-saving products to market under accelerated approval in Phase II. This is a major feat, considering the Phase III failure rate for new drugs (6).

At a time when some commodity ge-nerics continue to be in short supply, the emphasis is not on reducing inventories but on ensuring adequate supplies, An-thos says. Companies are also address-ing the challenges brought by mergers and acquisitions, which can temporarily distract staff, at all levels, from opera-tional and agility goals. McKinsey ana-lysts argue for the need for greater CEO involvement, standardized processes, and greater communication and feed-back, the hallmarks of any good lean or operational excellence program, when a merger or acquisition is underway (7).

The following are some opinions on agile manufacturing that Anthos shared in an interview with Pharma-ceutical Technology.

Fear of stockouts and tendency to play it safe with inventoryPharmTech: It was one of Tunnell’s ana-lysts who first drew industry’s atten-tion to pharma’s inventory turns, com-pared to those in other industries, as a measure of its agility. Why is it that the industry appears to have made so little progress in improving its perfor-mance in this area?

Anthos (Tunnell Consulting): Not a lot has changed if you analyze the indus-try based on the classic supply-chain measures. Some manufacturers are

probably carrying well over a year’s worth of inventory. Today, however, supply chain agility has to mean get-ting medicines to the patient more reli-ably and efficiently.

You’ll see some progress in inventory management, but it has not been the primary focus. Today, the industry’s first goal is ensuring supply to market so that there will not be any stock-

outs. A growing number of processes, especially in biotech, can be complex and fickle, so there is a tendency to play it safe with inventory. In the end, pharma companies will be measured based on ensuring supply, but also on revenue and profitability and cash flow, so inventory turns are largely issues for manufacturing departments, the CFO, and the guys in the warehouse.

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PharmTech: So how is agility being defined in pharma today?

Anthos (Tunnell Consulting): Agility is much more about, in the short term, getting new products to market quickly. It’s about launching adaptive trials for breakthrough medications and having a sufficiently strong foundation to be able to launch a new product based on Phase II data.

In addition, agility means adapting immediately to changes in the market. These can be changes in demand, for example, when a competitor fails to get approval for a new drug and drops out of the market. But agility also means reacting to changes in internal pro-cesses or challenges within the com-pany that must be overcome.

In the end, agility is getting to mar-ket faster and better managing the supply chain, and overcoming, more dynamically, any issues, whether exter-nal or internal, that have disrupted the supply chain. It’s all about being more responsive to change.

The downsized challenge: doing more with lessPharmTech: How can companies be agile when they are dealing with more, and more complex processes, as well as with reductions in staff and resources?

Anthos (Tunnell Consulting): As I see it, the most progressive companies are focusing on three areas:

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DIBOHFT�� Recently, I had a con-versation with someone at a phar-maceutical company who had been in discussions with FDA regarding process changes. He told me that a number of people within FDA have become frustrated by the fact that they are spending most of their time addressing process changes (e.g., changes that incor-porate the use of more up-to-date equipment, or even simple changes in the location of manufacture).

As a result, less of their time is being spent on their primary mission: ensur-ing that safe and efficacious medicines get to the public. For drug develop-ers and manufacturers today, the key question is: How do we develop new products so that, in the future, no or

only minimal regulatory changes will be required, except maybe filing for new drug approval in a new geographi-cal market. It’s a great stretch concept, but it takes a fair amount of work to get to a point where you can think about, and address, all the issues involved.

Certainly some of FDA’s and the industry’s early work with quality by design (QbD) had that goal in mind. The idea was to better understand your product performance ranges and the design space, file for approval in a wider range that would allow you to make adjustments in that range.

Today, complexity, both of the prod-ucts and of the regulatory landscape, has boxed us in. Significant numbers of supplements must now be filed for individual products. That’s a challenge that the industry still has to surmount if it is to develop more robust supply chains and more robust processes.

PharmTech: How are manufacturers doing this?

Anthos (Tunnell Consulting): It requires figuring out design choices. For exam-ple, a company might choose to launch a new process using a stable platform that is already fairly well understood and characterized, and that has al-ready been scaled up. It also means doing more of the classic QbD work, such as design of experiments (DoE) to really understand how the product behaves, where it works well, and what the process’ fault lines are. Simplifica-

Table I: Supply chain rankings (2011–2014), pharma and biopharma vs. Apple, Inc. (data from Supply Chain Insights).

Company and ranking for its industry (2006–2014 vs. 2009–2014) Growth (%)Operating

margin

Inventory

turns

Return on

capital (%)

Revenue per

employee ($/year)

Apple (16, 16) 0.32 0.31 136.6 25 2,077,891

Novartis (1, 1) 0.01 0.30 8.44 11 436,307

Biogen Idec (2, 6) 0.20 0.36 14.55 21 1,115,679

Merck (3,8) -0.02 0.16 7.22 11 556,423

Teva (4, 2) 0.06 0.14 4 7 444,822

Novo Nordisk (5,5) 0.10 0.37 8.16 60 412,580

Abbott Labs (6,3) 0.10 0.12 8.11 10 297,141

Eli Lilly (7,7) -0.04 0.21 8.40 18 585,537

Source: Supply Chains to Admire, 2015, excerpted with permission. Biogen-Idec was listed on the Supply Chains to Admire list for

2015, representing the pharmaceutical industry. Apple was not on the list and was ranked 16 on the consumer electronics list, but

is included for comparison. The full report may be accessed via Supply Chain Insight’s community site, www.beetfusion.com.

Supply Chain


tion is key, so you lean out the process to reduce unnecessary complexity.

PharmTech: But how can companies do that effectively with biologics, and how can they do it when they are also rushing to get product to market faster?

Anthos (Tunnell Consulting): With biolog-ics, there is inherent complexity, so the key is designing in better controls or at least monitoring each process so that you better understand its behavior. It’s not easy. The industry is trying to move for-ward with greater process understanding while trying to get new products to mar-ket faster. These are competing forces.

PharmTech: How can all of this be done when international mergers are going on and day-to-day conditions are in such constant shift?

Anthos (Tunnell Consulting): Mergers distract staff. It’s not only a question of pondering who will get to keep his or her job, but such questions as which processes to follow, whether in manu-facturing or development. You want to create the best lean practices that are most effective, but you’re often in a rush to meet some cost reduction syn-ergy or regulatory target that a large consulting firm has told you to meet.

As a result, many companies reduce staff before they’ve figured out how to simplify and improve their processes.

Knowledge management is another major issue, because mergers and ac-quisitions drive a significant amount of employee turnover, both planned and unplanned. Knowledge often re-sides in individuals, rather than within the organization, and that jeopardizes business continuity. The way to avoid that is by understanding that you want to harmonize processes first, and en-gaging the folks who are already in the process of doing that to come up with the best work practices.

References 1. J. Macher and J. Nickerson, Pharmaceu-

tical Research Manufacturing Project,

Final Benchmarking Report, 2006, site

accessed February 20, 2016. http://apps.

olin.wustl.edu/faculty/nickerson/results/

PMRPFinalReportSept2006.pdf

2. L. Cecere, The Supply Shaman blog,

www.supplychainshaman.com/

3. A. Mayer, Supply Chain Metrics That

Matter: A Focus on the Pharmaceutical

Industry,” Dec. 3, 2012, Supply Chain

Insights, www.beetfusion.com (site reg-

istration required)

4. C. Ptak, What is Supply Chain Excel-

lence? Feb. 23, 2016, Supply Chain In-

sights, www.beetfusion.com/blogs/carol-

ptak/what-supply-chain-excellence

5. L. Cecere and R. Denman, Supply Chains

to Admire, 2015, Supply Chain Insights,

excerpted with permission, Sept. 8, 2015,

Accessible via www.beetfusion.com (site

registration and free membership re-

quired).

6. A. Shanley, Pharm Technol, 40 (13)(Feb-

ruary, 2016), pp 24-27.

7. A. Agrawal et al, Pharma M&A: Agile

Shouldn’t Mean Ad Hoc, McKinsey

and Co., site accessed February 19, 2016.

www.mckinsey.com/business-functions/

strategy-and-corporate-finance/our-in-

sights/pharma-m-and-a-agile-shouldnt-

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Facility Design: Right-Sizing

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Right-sizing implies operational ef-fectiveness and efficiency. Since the 1980s, the phrase has been

used in management circles as a euphe-mism for layoffs, but in facility design, right-sizing can be a euphemism for minimal cost. Flexibility, on the other hand, is about having the capacity to adapt to future changes quickly and easily. Flexibility, however, typically re-quires an investment in infrastructure. At their most extreme, these two ideas are at opposite ends of a facility-design continuum.

Anticipating the futureThe idea of “right-sizing,” when applied to design, is to create an optimal facility. An example is found in the best practice recommendation of designing for actual equipment loads instead of the traditional method of estimated loads (1). Without the data of real loads, the practice of esti-mating results in oversized systems that increase energy and operational cost. But at what point is the glove’s fit tailored too tight? Experience has established that—in the pharmaceutical industry—change is inevitable, making flexibility a necessary facility consideration. When building a facility, it is wise to build in some accom-modation for future modifications. An-ticipating the future can be daunting, but experience proves that it is prudent to try.

To effectively tailor a design for current needs, while at the same time planning for future potential, the different types of change that may occur must be consid-ered. The most obvious potential change is increasing the manufacturing capac-ity to meet demand for the current drug portfolio. This change will require more and/or larger equipment of the same type as already exists. Another consideration is how new products will be introduced to the facility. Over the long haul, the ability of a facility to adapt to changing market and business conditions ensures its value far into the future. Inevitably, this ability will require more than just adding similar equipment, and new and different tech-nologies will need to be accommodated.

Making spaceIn all cases, at a minimum, drug man-ufacturing facility owners need to allow for additional space. Planning for more space can be as simple as lay-ing out a facility so that the manufac-turing area has a direction in which to expand, such as into a warehouse or to the exterior into a future building addition. Key to effective growth, how-ever, is having a strategy for internal circulation, with a sound way for ma-terials and personnel to access the fu-ture area. Because continuity is harder to achieve if it has not been planned, a good place to start is ensuring that the current manufacturing circulation (i.e., the flow of materials and person-nel) can be extended directly into the future area. While the exact use of the future space may be unknown, the need to get personnel and materials in and out in a way that is operationally effective and compliant is certain.

Over time, the drive for greater manufacturing efficiencies and capa-bilities leads to new equipment. All equipment has a limited useful lifes-pan. In addition, drug reformulation can demand additional or modified equipment, and new products and their processes may be added to an existing portfolio. A facility design should allow for the removal of exist-ing equipment and the installation of new models. Dimensional clearances

Flexibility vs. Right-Sizing:

Determining the Right Facility Size

Eric Bohn

Eric Bohn is partner at Jacobs

Wyper Architects, 1232 Chancellor St.,

Philadelphia, PA 19107, tel: 215.985.0400,

www.jacobswyper.com.

Choosing the right facility size requires tailoring the design for current needs as well as anticipating the future.


and movement pathways need to be integrated into the design. Without such a mindful approach, equipment may become inaccessible, and changes may require major interruption of on-going operations.

Planning for utilities and servicesPlanning for additional space and new equipment is relatively easy to imple-ment. A greater challenge, with greater cost burden, is planning for future utili-ties and services. Again, smart strate-gies need to be applied. Near-term flex-ibility can be provided by a thoughtful approach to system distribution. For example, service mains can be installed and sized so that local distribution can be easily added in the future. If judi-ciously done, this oversizing of a system can, for little upfront cost, provide for relatively easy and efficient growth in the future. In some situations, however, extending the current system may not be the right approach. If not, a strat-egy for future utilities still needs to be developed. One strategy is to plan a pathway and space for new mains and distribution to be installed later. Another strategy is to make a decision to develop a separate system in the fu-ture. In any case, it is better to build in a strategy at the beginning than to be without options later.

The greatest cost potential is in the gen-eration of overall utility capacity, which is typically a longer-term consideration related to an expanded manufacturing footprint. Using modular equipment that can provide phased growth is a strategy that has found much success. Admittedly, this will not work for all systems, but it can work for many. Such an approach enables spending only what is required and delaying future capital expenditures until they are actually needed. Another option is purchasing extra capacity up-front by way of oversized equipment, thus anticipating the future need for increased capacity. You can ignore this possibility by rationalizing, “if we are that success-ful, we’ll deal with it then,” or you can develop a strategy that affords flexibility and a relatively quick and easy response when needed.

ConclusionRight-sizing is more than responding to the immediate, foreseeable requirements of a facility. To optimize a design, there needs to be a prudent investigation of the potential for growth. With right-sizing, as the phrase implies, one size does not fit all. An approach needs to be crafted appropriate for the situation and the po-tentials that exist for a facility. Right-siz-ing is about finding value, the sweet spot

where design, management, and opera-tional considerations are balanced and deliver a quality facility for an appropri-ate cost. Finding the “right size,” involves the creation of an efficient design with an appropriate amount of flexibility.

Reference 1. US Environmental Protection Agency, Lab-

oratories for the 21st Century Best Practice Guide: Right-sizing Laboratory Equipment Loads (Washington, DC, August 2005). PT

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TROUBLESHOOTING Equipment and Processing

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PharmTech.com/Troubleshooting

The benefits of adopting single-use technologies in the production of biopharmaceuticals, such as lower

capital investment and increased flex-ibility, are now well documented and widely recognized in the industry. But when building a new facility based on single-use technologies, or incorporat-ing single-use into an existing facility,how do companies ensure they fully realize the benefits?

Facility design is a complex, multi-faceted, multi-step process, and early de-cisions can cause unforeseen limitations as the project progresses or, later, when further development of the facility is re-quired. Asking the right questions at the outset and having the depth of experi-ence and knowledge to understand theconsequences of the answers are vital to establishing the right specifications dur-ing the design phase.

Identifying a partner or partners tosupport the design and build of a facility and the process that sits within it is the first key decision. Traditionally, an archi-tectural and engineering firm and one, or possibly multiple, single-use process-equipment supply partners are selected. Working with a single external point of contact can help drive efficiencies in project-management and delivery. To be successful, however, the lead partner will need an understanding of biomanufac-turing facility design, engineering, qual-ification, and validation, as well as the

operational aspects of combining process hardware, single-use consumables, and automation platforms.

Overall, there are four sets of re-quirements to consider: product(s) to be made, process technologies, facility design, and supporting services. In eachcase, a series of questions will help iden-tify objectives, design specifications, and potential constraints.

Considering the productProduct class. The first element that de-fines any biopharmaceutical manufac-turing facility is the product itself. Will the facility be manufacturing monoclo-nal antibodies, recombinant proteins,vaccines, antibody-drug conjugates, or fragment antibodies? Also, will theproducts be mammalian cell-derived or microbial cell-derived? While thesequestions are most pertinent for the se-lection of the bioprocessing technolo-gies required, they are also importantfor the design of the facility itself.

The promise of f lexibility and sim-plification are often major deciding fac-tors for choosing single-use technology. Removing the need for cleaning and sanitization, for example, means that switching between one product and an-other becomes quicker and easier. One way to take advantage of this flexibility is by making the facility multi-purpose(i.e., the manufacture of two or more products) to drive greater facility utiliza-tion. Deciding between a single- or multi-product facility impacts facility design considerations. Factors such as avoiding cross-contamination between products and ensuring that process-specific equip-

ment can be moved around efficiently or housed nearby for rapid changeover need to be built into the design.

Regulations. With the plethora of regulatory guidelines and associated compliance requirements to adhere to when building a facility, it must be clear whether the product is for re-search and development purposes (pre-clinical), clinical trials, or commercial scale, as this will define the relevantGMP requirements. Also, if producing at commercial scale, which regulatory standard is needed? Is the product ap-proved by FDA, the European Medi-cines Agency (EMA), the China FDA, Brazil’s National Health Surveillance Agency (ANVISA), or other agencies? In some cases, local requirements go be-yond global ones. For example, Chinese fire regulations demand a greater levelof fire resistance than is typical glob-ally, and in countries such as Korea and Japan earthquake-proofing measures may have to be implemented.

Capacity. To define the necessary ca-pacity of the facility, the primary ques-tion is how many batches per productper year are needed? However, thisnumber has not always been defined when the facility design stage is reached. Alternatively, it should be possible to consider what quantity (in kilograms) of the bulk API needs to be produced for each product within the facility per year to meet clinical trial or commercial market requirements, and then work back to the number of batches.

For example, one can consider 2 x 2000-L bioreactors running a typical 14-day incubation period staggered a

Peter Genest is global operations manager,

FlexFactory, tel: 1.860.670.3014, pete.genest@

ge.com, and John Joseph is engineering

project leader, both at GE Healthcare’s Life

Sciences business.

Asking the right questions is crucial.

Peter Genest and John Joseph

Designing a Biomanufacturing Facility Incorporating Single-Use Technologies

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Troubleshooting

week apart, which equates to one batch produced each week. A typical batch at 2 g/L with a 70% overall yield in down-stream processing and a 95% production success rate will therefore yield 138 kg/yr in total. The final yield here is deter-mined by the product titer of the pro-duction bioreactor, combined with the efficiency of the downstream purifica-tion steps, both of which will be driven by the details of the bioprocess itself.

Selecting process technologiesThe next step is to drill down into the discrete unit operations of the biomanu-facturing workflow. If the production pro-cess is already defined, it should be listed out, but if not, then the contracted partner may be able to provide an equipment list with flexible process capability. Figure 1 shows an example of a production process from cell culture to bulk drug substance.

Starting with upstream, the status of the cell line and whether the process should be batch, fed-batch, or perfusion needs to be decided. Details about the nature of the process also need to be captured, including the bio-safety level and lengths of culture time for the seed and production bioreactors.

Moving to downstream, the overall yield of the purification process from

post-cell culture harvest through to purified bulk API should be provided, along with an estimate of the step yield of each unit operation. If chromatog-raphy columns are used in the process f low, also specify the column volume and diameter required along with the desired number of cycles for each step.

Many single-use consumable supply partners now offer large customized sys-tem designs that can be tailored exactly to a specific workflow. Having an all-en-compassing single-use system for a unit operation may seem to be the most effi-cient option. However, manufacturing a large single-use system comes with chal-lenges. Packaging size and transportation integrity, sterility validation, component supply, handling and staging, installa-tion, and operational use can all become more difficult and lead to greater risk lev-els. In some cases, defining and selecting smaller and simpler single-use systems to function in a modular workflow can be beneficial for minimizing risks.

Another important consideration in selecting single-use consumables is ensur-ing the supply chain is robust. Switching out any element of a validated process re-quires significant additional work. There-fore, make sure the supply partner has a proven track record, a materials policy

in place, transparency on how they work with raw material suppliers, and a proac-tive communication program, and that they can provide examples of how they have dealt with previous situations of raw material changes. Also check the robust-ness of the qualification and validation package supplied, and make sure it meets all relevant regulatory requirements.

Breaking new ground or renovating?The crucial point in designing a new facil-ity is whether it will be a brownfield/reno-vation or a greenfield site. If it is brown-field, then designers and engineers will need to know if the footprint is fixed and whether there are any restrictions on the space, such as floor strength, ceiling height, or door and elevator sizes. When thinking about the layout, are there existing person-nel, product, or material flows already in place? Also, is there existing support infra-structure, such as utilities, warehousing, or laboratory space, that can be accessed? If possible, plans for future plant expansion at the site, or at other sites, should be taken into account, particularly if they will have an impact on the product requirements of the facility being built now.

If it is a greenfield site, then there is increased flexibility in what can be built. However, sourcing an engineering firm

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Troubleshooting

with the relevant experience for a stick-built biopharmaceutical facility design can be challenging in some parts of the world. In response to this, another op-tion that has emerged is the modular facility, made from standardized pre-built units delivered to the greenfield site. This approach can have benefits in ensuring consistent standards of quality and reduction of time to first batch. This modular approach to building allows site excavation to run in parallel with module construction and validation of unit operations to begin offsite.

For those on a brownfield site or those building a new facility adjacent to an existing one, any current cen-tralized automation platform for data archiving and process monitoring may need to be linked to the new facility. In other cases, a standalone automation platform will be appropriate.

Finally, the need for any additional support functions or buildings should be decided (e.g., fill and finish building, a black utility generation building, a ware-house, quality control [QC] laboratories, or a waste treatment plant).

The needs here can sometimes run counter to expectations. For example, when embarking on a first foray into single-use, many presume that the re-moval of the hard piping and utilities needed for clean in place of stainless steel will result in a reduced footprint require-ment. What is not always anticipated is the warehousing requirements for the stock of single-use consumables, which also need to be unpacked and prepared in a staging area. While having adjacent warehousing on a site may fulfill this need, more efficient tracking, set-up, and speed of changeover will be achieved if some consumables staging and storage sits within the facility itself, in close prox-imity to, or as part of the cleanroom en-vironment. In total, the footprint is likely to be reduced in switching from stainless steel to single-use, but the change is not always as significant as expected.

When adding a single-use train to complement existing stainless-steel production facilities, the flexibility of single-use can help reduce the need for additional utilities. In one case, when

designers and engineers looked at which existing underutilized utilities could be shared with a new single-use set-up, it turned out to be a significant amount. For example, the flexibility of single-use meant that single-use unit operations requiring a water supply could be sched-uled for the downtime or periods of low water consumption of the stainless-steel process. The reduced consumption of utilities required to operate the single-use process allowed for easier integration of additional capacity into the existing in-frastructure of a production site.

Safety and time considerationsThe ability of operators to safely work with biologic and potentially hazardous materials at any stage during the pro-cess is a key facility design consideration. Knowing where to place biosafety cabi-nets, if aseptic connections are required, and knowing any special design modi-fications to the single-use system (e.g., extra clamps, material selection, han-dling of highly toxic excipients) is vital.

Next, if known, specify the buffer and media requirements of each unit opera-tion step in the production process, in-cluding whether any solutions require special handling (e.g., 70% ethanol), if steps are time-constrained (e.g., a highly-labile product that must be processed in a specified period), or if temperatures other than room temperature are required (e.g., temperature-sensitive media for upstream or cold purification processing).

The buffer preparation schedule for downstream purification can have a sig-nificant impact on facility design. Whether it is just-in-time preparation, one day in advance of use, or before any purification is started, will influence how much space is required for buffer storage or whether a system of built-in piping is required.

Planning for the futureFacility design is a multifaceted, inter-locking web of needs, wants, and risks, and it must be properly managed from the outset to accommodate and account for all requests. Management includes being able to step back and take a holis-tic view. The prime driver and desired outcome, whether it is shortest time to

market, lowest overall cost, or capital preservation, will significantly direct the decisions made at all stages of the design and building process.

For example, for a small biotech that was particularly concerned about reduc-ing capital expenditure, the ultimate rec-ommendation was to buy-in ready-made buffer and media in single-use liquid delivery bags. The overall scale and out-put of the facility was relatively low, and therefore the additional infrastructure re-quired for in-house preparation was not going to drive significant savings in the longer term. This change in processing methodology minimized both footprint and utility needs.

Another element to consider at this point is how much “future flexibility” to account for during the design and build phase. Do you want to allow for the possi-bility of adding more production bioreac-tors to expand manufacturing capacity? Do you want to add 10% more communi-cation drops for the integration of future equipment? The balance to be struck is between too much and not enough.

One reason such flexibility is impor-tant is that future manufacturing needs are always uncertain. Factors such as in-creased productivity and titer, coupled with increased market competition due to products coming off patent, has led to some stainless-steel facilities becom-ing underutilized and ending up shut down or sold.

The facility itself is only the beginning. Operational training will be required, as a minimum, but many supply partners can offer a much wider range of services. Vali-dation requires significant experience and know-how and has the potential to con-sume significant internal resources. Out-sourcing this element to an experienced partner can be a cost-effective option.

Ultimately, of course, budget is a cru-cial factor, along with when production needs to commence. But these should be considered alongside a close appraisal of the experience and depth of knowledge of the team that will be delivering the project. By mapping skills against re-quirements, it is possible to identify key attributes external partners need to have to make a project a success, first time. PT

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Engineering the Mechanical

Properties of Amorphous

Spray-Dried Dispersions

EVENT OVERVIEW:

Drug candidates with low oral absorption potential in the crystalline state are

frequently converted to the amorphous form to increase solubility, prevent

precipitation, and increase dissolution rate, thereby improving the extent of

absorption and bioavailability. Spray drying drug from a solution containing an

amphiphilic polymer is one of the most common and scalable methods used to

achieve these enabling properties. The resulting powder contains the amorphous

drug molecularly suspended or solubilized within the polymer matrix. Typical

crystalline drug properties, often unfavorable for downstream processing, are

masked by the amorphous state of the drug and matrix polymer. In addition,

unlike many crystalline drug substances, spray-dried dispersion (SDD) particles

are tunable, even within the spray drying process. Given this tunability, SDD

composition and physical properties can be co-optimized for absorption potential,

physical and chemical-state stability, mechanical and powder flow properties, and

spray drying throughput. This is a departure from traditional development, where

drug substance and drug product are progressed somewhat independently, with

drug substance form and morphology often changing during the development

and scaling processes. This often results in constraining the oral dosage formulation

and process to overcome undesirable crystalline drug properties.

In this webinar, experts will discuss:

■ How particle engineering by spray drying can be used to co-optimize several

facets of SDD development with a specific focus on optimization of SDD

mechanical properties

■ Reduction of SDD tableting scale up risks and pill burden through identification

of the primary mechanismof compaction and rational formulation design

■ Development case studies highlighting SDDs whose primary mechanism of

compaction is plastic flow versus brittle fracture.

Key Learning Objectives:

■ The mechanical properties of SDDs can be tuned by changing the degree of

atomization and drying rate in the spray dryer.

■ A review of typical SDD mechanical properties, including stress stain

behaviors, and how these can be exploited to optimize tableting.

■ Engineering SDD particles provides opportunities to reduce pill burden

by maximizing SDD loading in the dosage form through rational excipient

selection and SDD physical property design.

ON-DEMAND WEBCASTOriginally aired Feb. 23, 2016

For questions, contact Daniel Graves at [email protected]

Presenter

Aaron Goodwin, Ph.D.

Principal Investigator,

Research & Development

Bend Research

Bend Research is a division of

Capsugel Dosage Form Solutions

Moderator

Rita Peters

Editorial Director

Pharmaceutical

Technology

Register for free at www.pharmtech.com/pt/spray_drying

Who Should Attend:

■ Large pharma, mid-size pharma, biotech

companies

■ Product development group leaders and

formulators, technical, and engineering

positions involved in scale-up and

manufacturing of oral solid dosage forms


OUTSOURCING OUTLOOK

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PharmTech.com/ptoutsource

Pharmaceutical and biopharmaceuti-cal companies will continue to use outsourcing services, especially drug

manufacturing, due to cost concerns and mergers and acquisitions, according to a market survey of drug manufacturers by ISR Reports. The survey showed that the top five activities that drug companies outsource are drug product manufactur-ing, packaging and labeling, distribu-tion, small-molecule manufacturing, and holding and storage, according to Kate Hammeke of ISR Reports (1).

The ISR survey suggests that the majority of companies are outsourcing their small-molecule manufacturing. ISR’s 2016 small-molecule outsourcing survey also showed that other popular outsourced activities include packaging and labeling, distribution, and holding and storage. Respondents to ISR’s survey indicated resources, an increased product demand, cost, and mergers and acquisi-tions as some of the reasons small-mole-cule companies outsource these activities.

For large-molecule companies, distri-bution was the number one outsourced activity indicated by ISR’s survey, with packaging and labeling coming second. Cost was the number one reason large-molecule companies indicated as the reason for outsourcing.

Service providers are expanding their services and capabilities to keep up with the high demand. The following are some examples of the growth the outsourcing industry is experiencing.

Company developments, expansions, and acquisitionsThe first few months of 2016 has seen an array of investments, expansions, and acquisitions in the pharmaceutical

outsourcing market. Outsourcing com-panies appear to be looking to the early-phase development and clinical trial mar-kets to increase their portfolios.

MPI Research, an early-stage drug de-velopment contract research organization (CRO) based in Michigan, is investing more than $5 million in a facility renova-tion to begin in 2016. The company plans to renovate more than 55,000 square feet of facility space.

Ed Amat, executive vice-president of global sales and marketing, said in a press release that the expansion reflects the in-creasing demand for investigational and preclinical pharmaceutical and medical device studies (2). In the upcoming year, MPI hopes to increase the company’s workforce by approximately 10%.

LabConnect, a Seattle-based provider of laboratory services to biopharmaceu-tical, medical device, and contract re-search firms, has built a new 5000-sq-ft biorepository in Johnson City, TN, that includes space for ambient, refrigerated, cold (-20 °C), and ultra-low temperature (-70 to -80 °C) storage as well as liquid nitrogen vapor phase storage (-190 °C) (3).

The facility includes storage capac-ity for more than eight million samples, validated and mapped backup freezers and generators, redundant HVAC sys-tems, building and biorepository security systems, and a temperature monitoring system for freezers and refrigerators with a 21 Code of Federal Regulations Part 11 compliant audit trail. LabConnect also tracks sample locations and consolidates data within a centralized database.

Catalent Pharma Solutions announced on Feb. 2, 2016 (4) an investment of $4.6 million to expand its Singapore clinical supply facility by building GMP space

for secondary packaging. The invest-ment doubles the ambient storage space and quadruples cold-storage capacity, the company reports. The site provides clini-cal supply services including project and supply-chain management, comparator sourcing, clinical label printing, second-ary packaging, clinical storage, import/export management, importer of record service, and returns and destruction management services. It has served as a regional hub for studies in Australia, Singapore, Korea, Hong Kong, and other countries in Southeast Asia.

Onyx Scientific, a UK-based CRO and small-scale API manufacturer, has announced an investment in an addi-tional site located adjacent to its existing facility in North-East England to increase its laboratory facilities, GMP suites, and storage of GMP materials (5). In addition, the company has recruited several more chemists to support clients’ pre-clinical, development, and early-stage API manu-facturing projects. In 2015, the company grew its GMP space following an increase in demand for its small-scale API manu-facturing services.

Vetter announced on Jan. 28, 2016 that the company’s Schuetzenstrasse multi-functional building in Ravens-burg, Germany, has been completed on schedule and departments critical to its operation have started to move in (6). The $32 million (€29 million) investment is part of a $331 million (€300 million) total investment strategy announced by the company in September 2015 for further development to its manufacturing sites.

The continued demand by large and small customers for enhanced drug de-velopment services, as well as the need for ever-more future-oriented sophisticated

Pharma Outsourcing Market Expands

The pharma outsourcing market starts 2016

with expansions, acquisitions, and new offerings.

Susan Haigney


Outsourcing Outlook

IT systems to protect their data, created the need for the new facility, the company reported in a press statement.

The 91,500-sq-ft, six-story building contains non-cGMP laboratories for development support, laboratory space for mi-crobiological analysis, office workplaces for Vetter Development Service and IT, and a data processing center with enhanced security systems, including a safety cell that protects technol-ogy and data from external physical hazards in the event of an emergency.

Novasep is building a new synthesis laboratory and adding kilogram-scale production at its existing US facility in Booth-wyn, PA (7). This extension will allow Novasep to offer both chemistry and purification services and to produce the initial kilogram-scale batches of synthetic molecules that are needed for biological testing and preclinical trials.

The investment is in response to increasing demand from US customers for closer proximity to Novasep’s con-tract manufacturing services for early-stage development and production scale-up. Novasep has provided purifica-tion development services to North American customers for more than 15 years at this location. The new laboratory, equipped with reactors up to 50 L in size, will start operation in May 2016. It will offer cryogenic capacities and standard chemistry, as well as preparative purification chromatog-raphy processes.

PBOA expands membershipThe Pharma & Biopharma Outsourcing Association (PBOA), founded in 2014, has been advocating for the pharma outsourc-ing industry as the global market changes and expands. “We’re focused on working on the reauthorization of the Generic Drug User Fee Amendment (GDUFA), while keeping an eye on FDA’s Quality Metrics initiative, and helping make sure that CMO/CDMOs [contract manufacturing organizations/contract de-velopment and manufacturing organizations] are prepared for track-and-track/serialization regulations as they roll out in the US and the EU in the next few years,” says PBOA President Gil Roth.

In February 2016, PBOA expanded its membership (8). IDT Bi-ologika and Ei SolutionWorks joined the PBOA as general mem-bers; 3M Drug Delivery Systems (DDS) joined as a sustaining member. Diego Romeu, manufacturing and supply chain director at 3M DDS, was also voted to a three-year term on the board of trustees, along with Rajan Puri, director of business development at Therapure, and Lee Karras, CEO of Halo Pharmaceutical.

“As we continue our mission to represent the CMO/CDMO industry before FDA, Congress and other stakeholders, it’s criti-cal that we increase our membership and provide a true voice for our industry,” said Roth. “We’ve been successful in bringing the CMO/CDMO perspective to issues such as GDUFA, quality metrics, and serialization, and we’re delighted to bring in new member companies and add fresh points of view to our Board of Trustees.”

References 1. A. Shanley, “Surveys Examine Outsourcing Trend,” Pharmaceutical

Technology, Supplement: Partnerships in Outsourcing, 40 (13), 32-33, www.pharmtech.com/surveys-examine-outsourcing-trend

2. PharmTech Editors, “MPI Research Invests in Upgrades and Depart-ment Expansions,” PharmTech.com, Feb. 11, 2016, www.pharmtech.com/mpi-reasearch-invests-upgrades-and-department-expansions

3. LabConnect, “LabConnect Builds New Biorepository, Expands Ser-vices, Offers Absolute Sample Protection,” Press Release, Feb. 3, 2016, www.labconnectllc.com/Documents/New%20Biorepository%20PR%2022016%20-%20New%20Biorepository%20Expands%20Ser-vices%20Offers%20Absolute%20Sample%20Protection.pdf, accessed Feb. 16, 2016.

4. Catalent, “Catalent Invests $4.6M to Further Expand Asia-Pacific Clinical Trials Hub in Singapore,” Press Release, Feb. 2, 2016, www.catalent.com/index.php/news-events/news/Catalent-Invests-4.6M-To-Further-Expand-Asia-Pacific-Clinical-Trials-Hub-In-Singapore, accessed Feb. 16, 2016.

5. Onyx Scientific, “Facility Expansion at CRO Following Record Year,”Press Release, Jan. 29, 2016, www.onyxipca.com/facility-ex-pansion-cro-record-year/, accessed Feb. 16, 2016.

6. Vetter, “Vetter Announces Completion of Multi-Functional Building for Development Service and State-of-the-Art IT,” Press Release, Jan. 28, 2016, www.vetter-pharma.com/en/newsroom/vetter-news/news-l-vetter-announces-completion-of-multi-functional-building-for-development-service-and-state-of-the-art-it, accessed Feb. 16, 2016.

7. Novasep, “Novasep Adds Synthesis and Kilo Lab Extensions at US Facility,” Press Release, www.novasep.com/home/about-novasep/media-events/press-release/novasep-adds-synthesis-and-kilo-lab-extensions-to-us-facility.html, accessed Feb. 16, 2016.

8. PBOA, “PBOA Welcomes New Members and Trustees,” Press Re-lease, Feb. 10, 2016, www.pharma-bio.org/news/pboa-welcomes-new-members-and-trustees/, accessed Feb. 16, 2013. PT

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The use of hot melt extrusion (HME) for formulating active

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Presenter:

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Technical Marketing,

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Thermo Fisher Scientific

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Moderator:

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Stay Current on Drug Development

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Attend panel discussions and presentations,

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PharmTech/BioPharm Keynote Sessions in the

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The Contract Services Market: 2016 Update

How will consolidation in the bio/pharmaceutical and contract services market, a changing financial market, and an active politi-cal and regulatory year shape the fortunes of the contract servic-es market? In his annual presentation, industry expert Jim Miller will offer his perspectives on the contract services landscape for the next few years.

Presenter: Jim Miller, president of PharmSource Information Services, Inc.

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INTERPHEX 2016 PLANNING GUIDE AND INDUSTRY PIPELINE

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Admix sanitary mixing equipment complies

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overcome this challenge, process automation data and data from the laboratory information system have to be shared with the information technology (IT) systems for batch re-cording, reviewing, and releasing. Furthermore, scheduling systems are a key part aligning all production steps and ensuring planning principles like first-in/first-out priori-tization rules. Extensive integration of these data sources by IT and automation systems will allow production costs to be lowered by at least an order of magnitude.

Another case that presents some challenges is transform-ing a batch pharmaceutical process into a continuous pro-cess. A continuous process requires a robust process design and continual monitoring, typically using online analyz-ers. Multivariate analyzer data and other process param-eters from simple sensors must be combined and treated by statistical engines to give the operators a clear view of the process so that they can ensure that the process always stays within the quality boundaries. In the next genera-tion of continuous production processes, it will become important to use these quality parameters to automatically adjust the process, thus closing the loop. The core of such an advanced process-control system is a data platform han-dling a large quantity of multivariate and univariate data in real time and applying statistical methods like principle

component analysis. The easy integration of multivariate analyzer data (e.g., spectral data) following open standards is an important requirement. An equally important feature is the real-time integration to the control system for adjust-ing the set-point dynamically. Advanced process control methods, especially model predictive control strategies, can add the benefit of controlling the overall quality at the low-est variance within the lower and upper limits. PT

Process Control

Visit PharmTech.com for more articles on process control, such as:

t� Reducing False Out-of-Control Signals, PharmTech.com/reducing-false-

out-control-signals

t� Model-Predictive Design, Control, and Optimization, PharmTech.com/

model-predictive-design-control-and-optimization

t� Flowsheet Models Modernize Pharmaceutical Manufacturing Design

and Risk Assessment, PharmTech.com/flowsheet-models-modernize-

pharmaceutical-manufacturing-design-and-risk-assessment

t� Incorporating Process Analytical Technology Data into Process Control,

PharmTech.com/incorporating-process-analytical-technology-data-

process-control.

More on process control

Process Control — contin. from page 55

Data Integrity — contin. from page 53

As regulators continue to tighten their inspection ap-proaches, it is crucial for managers and scientists in regu-lated GXP laboratories to understand these criteria for data integrity and to assess and improve laboratory data manage-ment processes to ensure compliance with current regula-tions. Only after all these points have been addressed can data integrity truly be achieved.

References 1. C. Rosa, “Current Regulatory/Inspection Issues Related to Supply

Chain,” Food and Drug Law Institute (FDLI), Conference Un-derstanding cGMPS–What Attorneys Need to Know, Washing-ton DC, July 15, 2014, www.fdli.org/docs/cgmps/carmelo-rosa.pdf?sfvrsn=0

2. MHRA, Guidance for Industry on Data Integrity (MHRA, March 2015), www.gov.uk/government/uploads/system/uploads/attach-ment_data/file/412735/Data_integrity_definitions_and_guid-ance_v2.pdf

3. FDA, “Glossary of Computer System Software Development Terminology,” 1995, www.fda.gov/iceci/inspections/inspection-guides/ucm074875.htm

4. European Commission, EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Chapter 4 Documentation (June 2011), http://ec.europa.eu/health/files/eudralex/vol-4/chapter4_01-2011_en.pdf

5. European Commission, EudraLex, The Rules Governing Medici-nal Products in the European Union, Volume 4, Good Manufac-turing Practice, Annex 11 Computerised Systems (January 2011),

http://ec.europa.eu/health/files/eudralex/vol-4/annex11_01-2011_en.pdf

6. US Electronic Code of Federal Regulations, 21 CFR 211.194(a). 7. FDA, FDA Warning Letter to Trifarma S.p.A, July 2014, www.fda.gov/

ICECI/enforcementactions/warningletters/2014/ucm404316.htm 8. FDA, FDA Warning Letter to Ipca Laboratories Ltd., January

2016, www.fda.gov/ICECI/enforcementactions/warningletters/ucm484910.htm

9. FDA, FDA Warning Letter to Micro Laboratories Ltd., Janu-ary 2015, www.fda.gov/iceci/enforcementactions/warninglet-ters/2015/ucm431456.htm

10. FDA, Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance–Records and Reports, www.fda.gov/Drugs/GuidanceComplianceRegula-toryInformation/Guidances/ucm124787.htm

11. EMA, GCP Inspectors Working Group publication, Ref lec-tion paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials (London, June 2010), www.ema.europa.eu/docs/en_GB/docu-ment_library/Regulatory_and_procedural_guideline/2010/08/WC500095754.pdf

12. R.D. McDowall, LCGC 27 (9) (September 2014), www.chromatog-raphyonline.com/role-chromatography-data-systems-fraud-and-falsification

13. FDA, FDA Warning Letter to RPG Life Sciences Ltd., May 2013, www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm355294.htm

14. FDA, FDA Warning Letter to Wockhardt Ltd., July 2013, www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm361928.htm PT


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ASK THE EXPERT

Q: Our company covers the entire lifecycle for our drugs, from

R&D through clinical trials to commercial product. The quality

management system covers good clinical practice (GCP) and cur-

rent good manufacturing practice (cGMP). In a recent client audit,

we received an observation: “You do not apply the same level of

cGMP to clinical-trial material manufacture as you apply to com-

mercial product.” Is this a new regulatory expectation?

A:It is not a regulatory expectation to apply the same level of

cGMP to investigational new drug (IND) and marketed prod-

ucts. Although it is correct that you need to apply cGMP to all your

clinical-trial supplies (referred to as investigational medicinal prod-

ucts [IMP] in the European Union [EU] and IND in the United States)

and to commercial operations, the level of cGMP differs. The rea-

sons for this are practical constraints as well as regulatory require-

ments. Under FDA regulations, the manufacture of most INDs used

in Phase I clinical trials is exempt from cGMPs (1) (i.e., 21 Code of

Federal Regulations Part 211 is not applicable). For INDs for clinical

Phases II and III and for commercial product, cGMP applies (2, 3).

In the EU, the relevant regulations are in EudraLex Vol. 4, Part x

I (drug product) and Part II (drug substance/API), and IMPs are

covered specifically in Annex 13 “Manufacture of Investigational

Medicinal Products,” which was last updated in 2010 (4).

EudraLex, and any laws and regulations laid down by EU memberx

states, are based on Commission Directive 2003/94/EC, which

applies to both IMP and marketed products (5).

Paragraph 17 in Annex 13 summarizes the differences in

cGMP for IMP and marketed product: “Production processes

for investigational medicinal products are not expected to be

validated to the extent necessary for routine production but

premises and equipment are expected to be qualified. For

sterile products, the validation of sterilizing processes should be

of the same standard as for products authorized for marketing.”

Though these guidances are useful, they will not necessarily

answer all questions. The common adage supported by the

majority of regulatory agencies is to apply a scientifically sound

risk-based approach to compliance. More information can be

found in several publications, including a widely publicized

technical report by the Parenteral Drug Association (6).

The regulators do understand that product and process

knowledge will continue to grow during the lifecycle from

clinical Phase I to launch and beyond. With increased

understanding, companies can and need to apply more

controls and move towards a fully validated process. You may

wish to discuss the observation with the auditor in light of the

regulations and guidance documents mentioned above.

References

1. FDA, Guidance for Industry: cGMP for Phase 1 Investigational Drugs (Rockville, MD, July 2008).

2. FDA, Draft Guidance for Industry: INDs for Phase 2 and 3 Stud-ies of Drugs, Including Specified and Therapeutic Biotechnology Derived Products (Rockville, MD, February 1999).

3. 21 CFR Parts 210 and 211, www.ecfr.gov. 4. European Commission, EudraLex-Volume 4 Good manufactur-

ing practice (GMP) Guidelines, http://ec.europa.eu/health/docu-ments/eudralex/vol-4/

5. Commission Directive 2003/94/EC on the principles and guide-lines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use, http://ec.europa.eu/health/files/eudralex/vol-1/dir_2003_94/dir_2003_94_en.pdf

6. PDA Technical Report 56 Application of Phase-Appropriate Qual-ity System and cGMP to the Development of Therapeutic Protein Drug Substance (PDA, 2012). PT

Ad Index

Siegfried Schmitt, principal consultant, PAREXEL, discusses the regulatory

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Phase-Appropriate GMP

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