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APIs, EXCIPIENTS, & MANUFACTURING 2015

SUPPLEMENT TO THE SEPTEMBER 2015 ISSUE OF2015C

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PharmTech .com

from the editors and publishers

s6 The PharmTech/CPhI Connection

regulatory compliance

s8 Lessons Learned from FDA Inspections of Foreign API FacilitiesLisa Tung and Maria Eng

excipient cgmp

s14 Certifying Excipient cGMPsAgnes Shanley

import testing

s18 Import Testing of Pharmaceutical Products Has Limited Safety Benefits Joerg H.O. Garbe, Karl Ennis, Guido M. Furer, Maria G. Jacobs, and Stephan K. Roenninger

regulatory correspondence

s27 Regulatory Considerations for Controlled Correspondence Related to Generic Drug ChemistryKristina Adams, Xiaochuan Yang, Min Li, Thomas O’Connor, Lane Christensen, Frank Holcombe Jr., Andre Raw, Susan Rosencrance, and Geoffrey Wu

process analytical technology

s33 PAT Paves the Way for Continuous ManufacturingSofia T. Santos, Francisca F. Gouveia, and Jose C. Menezes

protein stability

s35 Excipient Selection for Protein StabilizationCynthia A. Challener

process controls

s44 Utilizing Run Rules for Effective Monitoring in ManufacturingAaron Spence

cleaning Validation

s48 Cleaning of Dedicated Equipment:Why Validation is NeededCristina Baccarelli, Paola Bernard, Teresa Cortellino, Oscar Cruciani, Rita Pacello, Chiara Parisi, Luisa Stoppa, and Isabella Marta

cphi worldwide planning guide

s51 CPhI Worldwide Planning Guide

s66 Ad IndexIssue Editor: Rita Peters and Adeline Siew. Cover: Science Photo Library/ Science Photo Library-TEK IMAGE/Phil Ashley/Stockbyte Silver/Getty Images; Dan Ward

APIs, EXCIPIENTS, AND MANUFACTURING 2015

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Science Editor Randi Hernandez [email protected]

Art Director Dan Ward

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

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From the editors and Publishers

The editors and publishers of the Pharmaceutical Tech-nology brand of print and online publications are pleased to present our annual APIs, Excipients, and Manufactur-ing supplement, which includes a special CPhI World-wide 2015 Planning Guide. This issue combines tech-nical articles on leading pharma industry topics and a comprehensive preview of the upcoming CPhI World-wide trade show.

For almost 40 years, the Pharmaceutical Technologybrand has provided authoritative, technical, and highly respected articles, peer-reviewed research, news, analy-sis, and commentary for bio/pharmaceutical develop-ment and manufacturing professionals around the world.

Pharmaceutical Technology magazine provides readers in North America with similar content, while keeping a close watch on FDA regulatory concerns.

Pharmaceutical Technology Europe magazine, now in its 26th year of publishing, delivers monthly updates on the latest trends and practices in bio/pharma development and manufacturing, with a focus on the European markets.

Online, PharmTech.com provides daily updates of breaking news from the technical, scientific, regulatory, and business sectors of the bio/pharma industry. Read-ers around the globe stay informed through weekly and monthly newsletters on a range of topics.

The PharmTech brand’s strength in the bio/pharma arena and global audience proved a natural fit with the CPhI brand of trade shows—including CPhI Worldwide (Oct. 13–15, Madrid, Spain)—when UBM plc, organizer of CPhI, acquired Advanstar Communications, the par-ent company of the PharmTech brand, in 2014.

Our research reveals that bio/pharma professionals turn to different media channels—print, online, webcasts, trade shows, newsletters, content marketing, and more—to solve their most difficult drug development and man-ufacturing challenges. We believe the new relationship with CPhI is a prime opportunity to make PharmTech’s content available to a broader bio/pharmaceutical market.

We invite you to explore this supplement, view more content on PharmTech.com, subscribe to the PharmTech newsletters, and meet us in person at CPhI Worldwide at Stand 1A3. PT

the Pharmtech/

CPhi Connection

Rita Peters

Editorial Director

Adeline Siew, PhD

Editor

Michael Tracey

Publisher

Chris Lawson

Associate Publisher

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The number of poorly soluble new drugs or active pharmaceutical ingredients (APIs) entering development is

estimated to be 40% to 70%. The poor aqueous solubility of many APIs makes formulating them more difficult and

therefore are focusing attention on the solubility of new drug candidates to

understand the effect on clinical exposure.

Formulators can use Cytec’s Docusate as a solubilizer to overcome these

problems using several manufacturing techniques, such as granulation, nano

milling and hot melt extrusion (HME).

While solubility is certainly an important factor in granulation, surface

wettability during the granulation process is also critical however the

effectiveness of Docusate in wetting has been recognized for many years and it can address these needs.

In nano milling applications Docusate acts as a stabilizer

for the nanoparticles as well giving rapid wettability.

Docusate also significantly improves the dissolution

profiles of low solubility API compounds in HME.

Functioning as a solubilizing aid for poorly soluble APIs,

in a variety of techniques, Cytec Docusate can improve

the efficacy of your end product. We can provide

formulation examples of these various techniques with

BCS class 2 and 4 APIs.

Docusate sodium is a highly versatile and effective anionic surfactant, manufactured by

Cytec under cGMP and meeting current USP and EP monographs. As a pharmaceutical grade

surfactant Docusate is an exceptional excipient and aid to pharmaceutical formulation as it

possesses excellent solubilizing, wetting, dispersing and emulsifying properties.

DOCUSATEPROVIDING A SOLUTION TO YOUR SOLUBILITY CHALLENGES

To learn more about Cytec’s industry-leading pharmaceutical grade docusate sodium surfactant

visit cytec.com or contact us at [email protected] to discuss your specific pharmaceutical application

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MW: 444.6 g/mol

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0=S=0

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00

0

can lead to a reduction in the bioavailability of the drug. Many companies DOCUSATE SODIUM STRUCTURE

Su

rfac

e Te

nsi

on

(m

N/M

)

Concentration (mg/ml)

65

55

45

35

25

0.01 .01 1 10

CMC OF DOCUSATE SODIUM AT 25C IN PURIFIED WATER


s8 Pharmaceutical Technology APIs, ExcIPIEnts, & MAnufActurIng 2015 PharmTech .com

Regulatory Compliance

Since 2007, foreign drug inspections have increased three-fold, from 200 to 600 in 2013 (1, 2). As more drugs are produced overseas, particularly in areas where regulatory oversight may differ compared to

that in the United States or Europe, it is crucial to ensure that products entering the supply chain are safe, effective, and of high quality. FDA has been ramping up inspections of in-ternational drug manufacturers during the past decade to improve drug safety. The heparin recall of 2007–2008, which resulted when oversulfated chrondrotin sulfate was used to substitute for the active ingredient in heparin, illustrates the serious harm that substandard pharmaceutical drug products can cause to consumers. The contamination originated from pig slaughterhouses in China, affecting mostly the US market, but also citizens from 10 other countries worldwide (3).

To prevent situations like this, FDA regulates manufactur-ers of API and finished dosage form (FDF) drug products through standards, regulations, and guidelines promulgated from the Federal, Food, Drug, and Cosmetic Act. Through statutory law, authorities given to FDA allow for regulations known as current good manufacturing practices (cGMPs) to assure control of manufacturing processes. Throughout the drug process, manufacturers must meet minimum re-quirements for identity, strength, quality, and purity of drug products by monitoring system practices and operations (4). By ensuring quality control at each stage of the drug pro-duction, contamination, deviations, and failures are more likely to be prevented. Areas such as buildings and facilities, equipment, personnel qualification and training, starting materials, laboratory, packaging and labeling, and produc-tion units are all evaluated during a drug inspection (4). If manufacturers are not compliant with cGMPs, they can be issued a FDA Form 483 listing areas of noncompliance, in order of significance.

This project analyzed all FDA inspections performed out-side of the US from January through December 2013, to pin-point problem areas for compliance. The majority of inspec-tions were conducted in Europe, at 33.76% and Asia, at 63.39%. The International Conference on Harmonization’s (ICH’s) Q7, Good Manufacturing Practice Guide For Active Pharmaceutical Ingredients (5, 6) was utilized to categorize results.

Lessons Learned from FDA Inspections of Foreign API Facilities Lisa Tung and Maria Eng

The opinions expressed in this article do not

necessarily reflect FDA’s position on the matter

being discussed.

*Lisa Tung, PharmD, MPH, is a senior regulatory officer at

FDA, [email protected], and Maria Eng, Dr.PH and

MPH, is a Behavioral Epidemiologist and Adjunct Professor

at Johns Hopkins Bloomberg School of Public Health.

*To whom all correspondence should be addressed.

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Pharmaceutical Technology APIs, ExcIPIEnts, & MAnufActurIng 2015 s9

Between January 1 through December 31, 157 API plant inspections found 839 observations of noncompli-ance within ICH Q7. The five most problematic areas, in order of descending frequency, were found to be in ICH Q7 sections 11, Laboratory Controls; 12, Validation; 6, Documentation and Records; 5, Process Equipment; and 8, Production and In-Process Controls. Based on a Phar-maceutical Inspection Co-operation Scheme (PIC/S) ques-tionnaire, these data were analyzed to determine which operations were most prone to noncompliance in API facilities outside the US. The project’s overall goal was to determine which types of deficiencies API manufacturers were most commonly cited for during inspections. By un-derstanding the types and trends of violations found from inspectional outcomes, future resources and knowledge could be directed in specific areas, to help manufactur-ers improve quality control and assurance (QC and QA).

Materials and methods

Data for the project were compiled from an internal database known as the mission accomplishment and regulatory com-pliance services (MARCS) compliance management system (CMS). It is an internal, web-based enterprise architecture application that links to other FDA resources and is used to manage compliance-related work activities (7). Records and documents associated with inspections that were conducted by FDA are placed under work activities and case numbers in the MARCS–CMS. By utilizing the advanced work search function and the advanced output options, work ID, work type (CDER-Evaluate Foreign GMP Inspection), firms, in-spection profiles, work country, inspection start date, inspec-tion end date, and inspection initial classification were fields used to generate the data. The calendar year of January 1 to December 31, 2013 was used to assemble relevant data into an Excel spreadsheet. Formatting and sorting of cells was then completed to distinguish between API and FDF sites.

Through the class code filter, the following codes were defined as APIs—CBI (recombinant/non-recombinant protein drug substance of biologic origin), CEX (starting/intermediate derived from plant/animal extraction), CFN (non-sterile API by fermentation), CFS (sterile API by fer-mentation), CRU (non-sterile starting/intermediate [not plant/animal]), CSN (non-sterile API by chemical synthesis), CSS (sterile API by chemical synthesis), and CXA (puri-fied API derived from plant/animal extraction). Once API manufacturing sites were separated from FDF manufactur-ers, further grouping was used to distinguish between sites

that received a FDA Form 483 of objectionable conditions: voluntary action indicated (VAI) or official action indicated (OAI) from those not receiving one; no action indicated (NAI). The spreadsheet was further filtered to include VAI and OAI under the inspection initial classification column, and then each FDA Form 483 was pulled from the MARCS–CMS database.

Observations listed in the FDA Form 483 were categorized against the ICH Q7 guideline (6). In addition to the introduc-tion (Section 1), ICH Q7 features the following sections:

2. Quality Management3. Personnel 4. Buildings and Facilities 5. Process Equipment 6. Documentation and Records 7. Materials Management 8. Production and In-process Controls 9. Packaging and Identification Labeling of APIs and

Intermediates 10. Storage and Distribution 11. Laboratory Controls 12. Validation 13. Change Control 14. Rejection and Re-use of Materials 15. Complaints and Recalls 16. Contract Manufacturers (including laboratories) 17. Agents, Brokers, Traders, Distributors, Repackers, and

Relabellers 18. Specific Guidance for APIs Manufactured by Cell Cul-

ture/Fermentation 19. APIs for Use in Clinical Trials. Each section is further broken down into multiple sub-

sections that highlight more specific details. For example, under Section 6, Documentation and Records, further sub-sections include: 6.1 Documentation System and Specifications 6.2 Equipment Cleaning and Use Record 6.3 Records of Raw Materials, Intermediates, API Label-

ing and Packaging Materials 6.4 Master Production Instructions 6.5 Batch Production Records 6.6 Laboratory Control Records 6.7 Batch Production Record Review.

Documentation of each citation was recorded under each corresponding subsection of ICH Q7. Breakdown of data was evaluated in each section, subsection, geographic region, and country. Foreign API drug manufacturers in-cluded countries outside the US, in Asia, Australasia, Eu-rope, North America, and South America.

Results

Data were collected in mid-June 2014, using data from Janu-ary 1 to December 31, 2013. At this time, 581 foreign drug inspections were conducted. Of the inspected sites, 270 (46.47%) were performed at API drug manufacturing facili-

Process validation and controls

(lab and manufacturing) were

weak points.



ties, while the remaining 311 were at FDF sites. In addition, 157 sites were issued a FDA Form 483 and classified initially as VAI or OAI at 58.15%, compared to manufacturers that did not receive one and were considered as NAI.

A total of 839 observations were counted, ranging from 1 to 25 per site, with an average of 5.38 observations issued

per site. Within regions, the average number of observa-tions per site was 5.9 for Asia, 4.4 in Europe, 5 in North America, 3 in South America, and 1 in Australasia. Most of the violations, totaling 592, were found in Asian facilities; 233 violations were found in Europe; 10 in North America; three in South America and one in Australasia. Figures 1

and 2 show the percentage of observations in each country in Asia and Europe.

Overall, ICH Q7 Section 11, Laboratory Controls, was the most frequently cited section, with 167 observations (19.90%). This was followed by 12, Validation, at 120 ob-servations (14.30%); 6, Documentation and Records, with 109 (12.99%); 5, Process Equipment at 108 (12.87%); and 8, Production and In-Process Controls, with 62 observations (7.39%) (see Figure 3). A further breakdown into subsections revealed that the most common overall observation (n=839) cited in ICH Q7 was for 11.1, General Controls, with 84 ob-servations (10.01%). This subsection was followed by 5.2, Equipment Maintenance and Cleaning, with 61 observa-tions (7.27%); 6.5, Batch Production Records, at 45 obser-vations (5.36%); 2.2, Responsibilities of the Quality Unit(s), with 39 observations (4.65%); and 6.6, Laboratory Controls Records, with 36 observations (4.29%) (see Figure 4).

In Asia, the top observations noted were for 11, Labora-tory Controls, at 18.58%; 5, Process Equipment, at 14.19%; 12, Validation, at 14.02%; 6, Documentation and Records, at 12.84%; and 4, Building and Facilities, at 6.93%. Similar to Asia, in Europe, the most cited observation was for 11, Laboratory Controls, at 21.46%. This was followed by 12, Validation, at 15.02%; 6, Documentation and Records, at 14.16%; 8, Production and In-Process Controls, at 10.73%; and 5, Process Equipment, at 9.87%.

The majority of inspections and observations occurred in India and China. In India, 39 sites were issued an FDA Form 483 and had 299 observations. Across 41 inspections in China, 198 observations were issued to manufacturers. These two countries accounted for 80% of inspections in the Asia region, and 83.95% of observations. There were simi-lar situations with sections 11, Laboratory Control, and 12, Validation, which were the top two problem areas. Section 11 accounted for 17.39% of observations in India and 17.68% in China, and 12, Validation, for 14.38% of observations in India and 14.14% in China.

In India, section 5, Process Equipment came in at 13.38%, 6, Documentation and Records, at 12.70%, and 4, Building and Facilities, and 7, Materials Management, tied at 7.69%. In China, 6, Documentation and Records, was at 16.16%; 5, Process Equipment, at 15.15%; 2, Quality Management, and 4, Buildings and Facilities, tied at 6.57% (see Figure 5).

The volume in North America, South America, and Australasia regions combined was an extremely small fraction of the total calculation, and accounted for only 2.55% with four inspections (n=157) and 1.67% with 14 observations (n=839).


Figure 1: Number of observations in each country out of the total region number (n=592) of observations in Asia from January 1 – December 31, 2013.

Figure 2: Number of observations in each country out of the total region number (n=233) of observations in Europe from January 1 – December 31, 2013.

South Korea1%

Taiwan3%Malaysia

0%

Japan8%

China34%

India51% Israel

2%

Hong Kong1%

Netherlands2%

Norway2%

Sweden1%

Italy16%

Ireland2%

United Kingdom11%

France11%

Finland3%

Spain7%

Denmark2%

Switzerland1%

Bulgaria3%

Belgium2%

Austria4%

Germany33%

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Discussion

Across geographic regions of Asia and Europe and within China and India, deficiencies in section 11, Laboratory Con-trol, were most frequently cited during inspection. In this section, API manufacturers failed to follow testing standard operating procedures, establish appropriate specifications with accepted reference standards and did not have knowl-edge of testing methods or investigate out-of-specifications or discrepancies.

The next two cited sections for Asia and Europe had simi-lar findings in 12, Validation, and 6, Documentation and Records. Validation plays another critical area of API drug

manufacturing, because it is tied to production processes, cleaning proce-dures, analytical methods, in-process control procedures, and computerized systems. Manufacturers must set up critical process parameters during the development stage so that ranges are established and operations can be re-producible based on the data. With validation of procedures and pro-cesses connected to so many parts of the manufacturing process, validation failures can negatively affect the qual-ity of the API in every step to follow.

Documentation and Records was another place that manufacturers were cited on when there was a failure to re-cord data properly or retain records. Under subsections 6.5, Batch Produc-tion Records, and 6.6, Laboratory Con-trol Records, firms did not have com-plete records or were not completing documentation contemporaneously. Documentation of every phase during a batch production must be completed accurately and legibly, to be checked against the master batch record.

Differences within the top de-viations were noted in Asia, where a higher percentage of observations were for 5, Process Equipment, whereas in Europe, Section 8, Production and In-Process Controls, had a higher number of deficiencies when inspected. Manu-facturing sites in one region may have more challenges within a particular section of ICH Q7, and therefore, ap-pear to have a higher percentage of de-ficiencies. This finding, however, could be attributed to selection bias, because the number of inspections in a region can vary from year to year.

In Asia, subsection 5.2, Equipment Maintenance and Cleaning, was the area with the most de-ficiencies seen. Equipment used in the manufacturing of APIs was not properly cleaned or given adequate mainte-nance. Improper cleaning of equipment between production cycles could affect the next product to be used, and result in contamination issues.

With subsection 8.3, In-process Sampling and Controls, control procedures during manufacturing were deemed in-adequate, as firms failed to monitor process steps that could cause variability in the quality characteristics of the API. India and China shared all of the top five observations, which included sections 11, Laboratory Controls; 12, Valida-

Figure 3: Total number of observations (n=839) categorized across main sections of ICH Q7 (2 – 19) from January 1 – December 31, 2013.

Figure 4: Total number of observations (n=839) categorized across subsections of ICH Q7 (2.1 –19.9) from January 1 – December 31, 2013.

25.00%

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Subsections 2.1-19.9 of ICH Q7

12.00%

10.00%

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6.00%

4.00%

2.00%

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2.1

2.4

3.2

4.2

4.5

5.1

5.4

6.3

6.6

7.2

7.5

8.3

9.1

9.4

11.1

11.5

12.1

12.4

12.7

14.1

14.4 16

17.3

17.6

18.1

18.4

19.2

19.5

19.8



tion; 6, Documentation and Records; 5, Process Equipment; and 4, Buildings and Facilities.

Almost equal in the number of in-spections, Indian manufacturing sites were often cited more frequently. The average number of observations was slightly higher, with 7.7 compared to China with 4.8. The high number of inspections and observations found in India and China could be expected, since these two countries provide nearly 50% of APIs used in the US (8). Monitoring this number in the future can be useful to see if sites in India will continue to have more deviations with cGMPs, compared to China.

The project also showed how inspec-tion reporting could be standardized to facilitate trending and improve in-dustry response. Investigators wrote and formatted observations differently from one FDA Form 483 to the next. Depending on how the observation was written, the citation could be understood as a single or multiple count. For example, an observation may cite failure to follow a procedure in one unit, and then follow with another description stating failure in a different area. The two examples were listed under a single observa-tion, yet, they related to two different units within ICH Q7.

Another limitation in categorization of observations under ICH Q7 was when a single citation described the quality unit, laboratory, and documentation all in one ob-servation. Because the observation related to more than one section of ICH Q7, but was counted as a single observation, the classification of the observation could be placed in one section over another and subject to interpretation.

While data were pulled half way into 2014, not all inspec-tions that occurred in 2013 were included. If work activities were not entered into the MARCS–CMS database due to incomplete establishment inspection reports, missing FDA Form 483s would not be ref lected in the total count. Of foreign API manufacturing sites that were inspected from January 1 to December 31, 2013 and issued a FDA Form 483, the top areas of concern were for sections 11, Labora-tory Control; 12, Validation; 6, Documentation and Records; 5, Process Equipment; and 8, Production and In-Process Controls.

Today, most of the world’s APIs are manufactured in India and China, which were the countries with the most inspections as well as the highest number of observations. In 2013, Indian facilities received a higher number of observa-tions than their counterparts in China. As more APIs are produced there, a rise in observations is expected.

Steps could also be taken to standardize data collec-tion. Currently, FDA has an automated reporting system,

TurboEIR (Establishment Inspection Reports), which is used to standardize FDA Form 483. However, with API products, FDA Form 483s are manually prepared (9).

Having a program with the number and type of obser-vations in place would establish a baseline for trending, and help focus resources and training. It could also pro-vide insights to optimize control of API manufacturing, since any deviations from cGMPs could affect drug prod-uct integrity and potentially harm patients if they are not controlled. The manufacturing of APIs is a crucial point in the pharmaceutical drug process and all surrounding activities must be accurately performed in order to confirm the chemically active substance is safe and effective as it moves forward.

References 1. A.C. von Eschenbach, MD., Statement, “FDA’s Foreign Drug In-

spection Program,” House Committee on Energy and Commerce Hearing, Nov. 1, 2007.

2. FDA, Data pull from Mission Accomplishment and Regulatory Compliance Services (MARCS) Compliance Management System (CMS) on June 16, 2014.

3. J. Woodcock, MD, Statement, “FDA’s Ongoing Heparin Investiga-tion,” House Committee on Energy and Commerce Hearing, Apr. 29, 2008.

4. FDA, Guidance for Industry Quality Systems Approach to Phar-maceutical CGMP Regulations (Rockville, MD, September 2006).

5. ICH, “FAQs About ICH,” ICH.org (2014), www.ich.org/about/faqs.html, accessed July 29, 2013.

6. ICH, Q7, Good Manufacturing Practice Guide For Active Pharma-ceutical Ingredients (ICH, Nov. 10, 2000).

7. FDA, CMS Software Users Guide For Operations & Maintenance 3 (OM3) (2011).

8. A. Edney, Drug Quality in China Still Poses Risks for U.S. Market, (Apr. 4, 2014).

9. Inspection Observations, Fda.gov, (2013), www.fda.gov/ICECI/Inspections/ucm250720.htm, accessed July 30, 2014. PT

Figure 5: Observations categorized across sections of ICH Q7 (2 – 19) in India (n=299) and China (n=198) from January 1 – December 31, 2013.



20.00%

18.00%

16.00%

14.00%

12.00%

10.00%

8.00%

6.00%

4.00%

2.00%

0.00%2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Sections 2-19 of ICH Q7

India

China



Excipient cGMPs

Once upon a time, excipients were considered mere

“fillers,” necessary for drug formulation. Even though they make up most of any pharmaceuti-cal formulation, they were not included in original

pharmaceutical current good manufacturing practices (cGMP) regulations. The past few years, however, have brought increased awareness of how important their quality is to patient safety.

Both the European Union’s (EU’s) Falsified Medicines Direc-tive (FMD) and the United States FDA Safety and Innovation Act (FDASIA) require that drug manufacturers verify that their excipients are made according to cGMPs. In March 2015, the EU updated its guidance on excipient cGMPs, requiring systems for tracing starting materials, intermediates and excipients, and identifying risks all along the supply chain. The FMD set a dead-line of March 2016 for performing supplier risk assessments.

For years, excipient cGMP requirements were set forth in guid-ance published by the International Pharmaceutical Excipients Council (IPEC). At this point, three countries have established cGMP regulations for excipients, and a number of standards have been set, most recently, the American National Standards Insti-tute’s (ANSI’s) 363, launched in March 2015, which involved the efforts of IPEC, NSF International and a group of industry repre-sentatives and independent experts; the EXCiPACT GMP stan-dard, and the EXCiPACT GDP standard (published as an annex to the International Standard Organization’s [ISO] 9001:2008).

Given the cost of auditing suppliers, regulators in the United States and Europe have encouraged manufacturers to work with third-party auditors to certify that they are using raw materials that meet cGMPs. Options include: •The US Pharmacopeial Convention’s (USP’s) excipient

verification program, launched in 2006• EXCiPACT asbl’s certification scheme, established by

IPEC, the European Association of Chemical Distrib-utors (FECC) and the United Kingdom’s Pharmaceu-tical Quality Group (PQG)•NSF International’s program, enabled by the acquisi-

tion of International Pharmac• eutical Excipient Auditing (IPEA), IPEC’s inspection

and certification authority, in 2013, and certified against ANSI 363 • RX-360’s program, which uses various standards and

the auditing services of BSI Supply Chain Solutions. Pharmaceutical Technology interviewed directors of these

programs to get some idea of how the programs work and what sets each of them apart (for more detailed interviews, please visit www.PharmTech.com).

Certifying Excipient cGMPsAgnes Shanley

As EU supplier risk assessment deadlines

approach, a number of voluntary third-party

auditing and certification options are available.

Will more excipient suppliers, and drug

manufacturers, use them?

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Excipient cGMPs

John AtwaterSenior director, USP’s Excipient Verification Programs, Auditing and Certification Program

PharmTech: When did USP establish its program for excipi-ents verification and how does it work?

Atwater: We established the excipient verification program in 2006. It includes a triennial onsite GMP audit for compli-ance to USP general chapter <1078>, GMPs for Bulk Phar-maceutical Excipients. It also includes a thorough review of chemistry, manufacturing and control (CMC) product documentation, and lab testing of product samples for con-formance to standards in the United States Pharmacopeia and National Formulary (USP–NF).

As we perform this work, we come up with observa-tions that companies must correct. Once they do, they are awarded a certificate of standards compliance, and the use of the USP excipient verified mark to use on their bulk labels and certificates of analysis. We have similar programs for APIs and dietary supplements. We also offer an excipient supplier qualification program, a truncated version of the verification program that we launched in 2008.

PharmTech: How long does it take for certification, and how long does that certification last?

Atwater: Certification generally lasts for up to three years. After initial verification, we perform continuous change- control monitoring and annual surveillance testing of samples that have been verified. It’s a continuous process of monitoring excipient quality.

PharmTech: How long does initial verification take? Atwater: Generally it takes at least three months. Some

companies can take up to a year to get through the program.

PharmTech: What is the cost of excipient certification?Atwater: You’re typically looking at around $25,000-

$30,000 for three years. Costs depend on the complexity of the excipient that is involved.

PharmTech: Today, there are many different routes to cer-tification and auditing. What makes USP’s unique?

Atwater: Our program involves both the GMP audit and product documentation review and testing. For instance, we expect participants to provide complete CMC documenta-tion, in the form of the International Council for Harmoni-zation’s (ICH’s) Common Technical Document.

Patty BensonCo-chair, Audit Operations Group, Rx360, and director of quality operations, SAFC, US

PharmTech: What are the major developments in Rx360’s au-diting program?

Benson: Last year, we engaged BSI, one of the largest reg-istrars in the world. The company is now the primary sup-plier of audits to us. When we get a request for a joint audit, it goes out to BSI, which is a third-party contractor to us.

PharmTech: What is a joint audit?Benson: It refers to multiple manufacturers sponsoring an

audit of one supplier. This approach benefits manufacturers by providing high quality audits while minimizing costs. It also benefits suppliers, since they only have to host one audit instead of several different ones.

PharmTech: How many pharmaceutical manufacturers have used your audit approach so far? How much does cer-tification cost?

Benson: This year, we expect to complete around 100 audits. The figure for previous years has been in the 30-to-40 range.

The audit time varies based on the audit standard and the materials, or the supplier involved. The cost depends on the length of time it takes to do it plus the number of travel days involved, plus where BSI has auditors. Once the audit is completed, licensing costs $2500 for suppliers that are members of Rx360 and $5000 for non-members.

PharmTech: How many companies can share an audit? Benson: In theory, a limitless number, but, in reality, most

audits have an initial sponsorship of less than four. We use a database, in which a company enters a supplier and stan-dard wanted for an audit. Other companies can look up this information and join the audit if they wish. This way, we match up sponsors who are looking at the same supplier. Once the audit is completed, anyone can license it.

For raw materials that are not excipients, we developed our own standard in 2011. We also have audit standards for APIs and packaging materials, and do supply chains security audits to review facilities, controls, and transportation. In addition, we’re working on some new standards including current good distribution practices (cGDPs), medical device standards, and an audit standard for contract labs.

ES664589_PTsupp0915_016.pgs 08.28.2015 03:01 ADV blackyellowmagenta


Maxine FritzExecutive vice-president, Pharma Biotech, NSF Health Services, NSF International

PharmTech: Can you tell us about ANSI-363?Fritz: The standard has been a work in progress for several years.

It was developed by NSF with IPEC, with a panel that included representatives from industry, regulatory bodies, and academia, so it went through a rigorous standard-setting process.

PharmTech: Given the different audit and certification models available, how does your approach differ?

Fritz: We are actually accredited by ANSI, which is recog-nized by global regulatory agencies worldwide.

PharmTech: Should standards for excipient cGMP compli-ance be mandatory in the future?

Fritz: The whole purpose of standards is to apply a consistent approach to regulating a certain part of the industry, depend-

ing on what it is. From an excipient perspective, the standard is the best way to get a consistent approach to regulation.

It can be very difficult for regulators to implement new regulations, so a voluntary standard is often a very good way to get industry in compliance without having to go through the years and years that are required to set a new regulation.

PharmTech: What do you see as the key areas where education and guidance are needed in excipient cGMP assessment?

Fritz: Suppliers need to get a better understanding of how their excipient products fit in for pharma applications. They also need to understand how much rigor to apply, based on how each particular product will be used.

For instance, you might have food-based sugars that are also used as pharma excipients. The quality requirements and type of manufacturing process might change based on how that excipient is used. In addition, end users need to have a better understanding of where their excipients are coming from.

Tony ScottConsultant, EXCiPACT

PharmTech: Where do you see the greatest vulnerability today in the pharma excipients supply chain?

Scott: The greatest potential vulnerability is the varying level of commitment and the resource availability from within national authorities and industry to inspect and audit suppliers for compliance with appropriate cGMPs. This is particularly true for Asian manufacturers and suppliers of APIs, excipients, and final dosage forms.

Pharma companies will strive to secure the information they are legally obliged to obtain from their suppliers and others, proportionate to their evaluation of the technical and commercial risks involved in their supply of a particular prod-uct. The pharma company has the ultimate legal responsibility in this regard. In higher risk cases, I would expect companies to complete an audit themselves or via an assured third party.

The supplier will be more willing to accept a customer audit if a strategic business relationship exists. Overall, the audit burden is increasing as a result of new regulations, and this can be reduced for both suppliers and their customers if the supplier becomes certified in ways acceptable to the regulators.

PharmTech: Can you please bring our readers up-to-date on new developments in the EXCiPACT program?

Scott: The EXCiPACT third-party certification scheme is picking up speed globally, especially in the US, China, and India, with over 20 registered suppliers.

PharmTech: What makes the program unique, and what does certification cost?

Scott: EXCiPACT asbl was created as a non-profit asso-ciation in January 2014 with IPEC Europe, IPEC Americas, FECC and PQG as founding members, following a five-year development and a two-year pilot phase involving a team of over 40 industrialists and regulators.

Costs of certification vary, but participation typically costs 30,000 Euros over a three-year period; the savings for a supplier at 90,000 Euros over three years, and the savings for a pharma company at 180,000 Euros over three years, offer-ing a total industry benefit of 240,000 Euros over three years.

The EXCiPACT standards (EXCiPACT GMP/GDP or NSF/IPEC/ANSI 363) underpin the EXCiPACT Certification Scheme, which can use all of the above standards within a comprehensive, quality-assured process leading to sup-plier certification. Suppliers have the choice of being audited against the ANSI standard or the ISO 9001 and the EXCi-PACT standards in the EXCiPACT Certification Scheme.

PharmTech: What will be needed to get more pharmaceuti-cal manufacturers to be proactive in managing and oversee-ing ingredients suppliers?

Scott: More pharma companies are becoming more pro-active in managing their excipient suppliers when they see the business benefit from doing so. This has already hap-pened with API suppliers, where strategic relationships are now the norm especially for patented products.

Given the present huge difference in the value of APIs compared to excipients, I don’t expect a major shift any-time soon, but I feel sure that the trend will develop when pharma companies realize the profit potential from strategi-cally managing their excipient suppliers. PT

ES664591_PTsupp0915_017.pgs 08.28.2015 03:01 ADV blackyellowmagenta


To help ensure drug product quality and safety, health authorities in many countries have implemented, or are considering implementing, quality control (QC) testing requirements for pharmaceuticals, biologi-

cal/biotechnology, and/or vaccine products entering their countries—also referred to as import testing. A survey was conducted within the International Federation of Pharma-ceutical Manufacturers & Associations (IFPMA) to analyze data on import testing, other categories of re-testing (e.g., post-marketing surveillance), and applied waiver types. The findings suggest that import testing does not add significant quality or safety benefits to patients, provided that the prod-ucts are uninterruptedly controlled according to the glob-ally harmonized manufacturing, distribution, and storage standards (GMP, GDP, GSP). In fact, it was observed that import testing could potentially increase risks to the patient by causing delay in the supply chain and other complexities.

Historically, re-testing requirements may have been necessary to prevent the distribution of unsafe or non-conforming drug product. However, laws, regulations, and regulatory oversight have changed significantly. Today, the pharmaceutical, vaccine, and biotechnology industries have developed and implemented robust quality systems and control of the supply chain to ensure the identity, safety, purity, and potency of its drug products throughout their manufacture and international distribution channels. The requirement of import testing is, therefore, regarded to be redundant (1, 2). This perspective has been evidenced by data presented herein, analyzing quantitative figures on import testing collected from multinational pharmaceuti-cal companies.

Survey resultsThe presented data were received from six multinational pharmaceutical companies—Amgen, AstraZeneca, Bayer, F. Hoffmann-La Roche, Johnson & Johnson, and Pfizer—associated with IFPMA, unless otherwise specified. In total, 184 data sets of information on 149 countries, collected from September to November 2014, were analyzed. Data were collected from the six companies on:

Import Testing of Pharmaceutical Products Has Limited Safety Benefits and Can Add Risk to PatientsJoerg H.O. Garbe, Karl Ennis, Guido M. Furer, Maria G. Jacobs, and Stephan K. Roenninger

Findings from a study on import testing, based on

data collected from six multinational pharmaceutical

companies, suggest that import testing does

not add significant benefits to the quality or

safety of drugs, provided that the products are

uninterruptedly controlled according to the globally

harmonized manufacturing and distribution

standards. The authors, therefore, recommend

establishing more exemptions from import testing,

subject to well-defined conditions, and that

timely waiver procedures are employed where a

company has demonstrated appropriate controls

of manufacturing and distribution processes.

Joerg H.O. Garbe is global quality manager, In-Country

Testing, F. Hoffmann-La Roche Ltd., Pharma Global

Technical Operations, Basel, Switzerland; Karl Ennis

is in-country analytical testing project leader, Global

Analytical Development, GlaxoSmithKline, Hertfordshire,

United Kingdom; Guido M. Furer is commercial QA

manager, LA Region, AbbVie S.A., Buenos Aires,

Argentina; Maria G. Jacobs is director, Quality and

Regulatory Policy, Pfizer Inc., New York, US; and

Stephan K. Roenninger is head of external affairs

Europe, Amgen (Europe) GmbH, Zug, Switzerland.

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Import Testing


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Import Testing

• re-testing requirements• number of re-tests per year• number of out-of-specification (OOS) investigations

and batch rejections• the costs associated with the testing and related costs,

such as warehousing or blocked capital. Categories of re-testing in the country of destination. Apart

from re-testing associated with the import of pharma-ceutical products, other testing categories were reported. Re-testing may be performed by companies themselves, contractors, and/or governmental laboratories in each country. The different categories of local re-testing reported and their impact are described subsequently:Import testing

• QC testing (full or partial local re-testing against approved specifications) for medicines as part of the importation process.• Performed in governmental laboratories or under the

responsibility of the manufacturers/importers.• Causes prolonged storage of the goods in warehouse

upon import.• Increases complexity in chain of custody/supply chain.• Can lead to delayed supply of medicine to the patient or

product stock-out.• For small markets, the amount of required samples can be

a significant portion of the total importation.

Registration testing

(a) Testing in conjunction with initial registration• Regarded as part of the initial “validation” by law in some

countries.• Often implemented to establish innovative test methods/

techniques in a country.• Can result in a significant delay to availability of new

innovative medicines to patients.(b) Testing in conjunction with post-approval changes and/

or license renewal• Results in administrative and financial (high sample costs)

burdens.•Does not usually impact supply during the commercial

phase.Surveillance testing

• Represents an independent control of medicines on the market.•Opportunity to detect counterfeit/falsified medicine (3)

or unauthorized imports. These data may also help to understand these threats and to define appropriate measures.•No delay in access of medicines to patients.•An accepted practice to monitor the quality of marketed

medicines.Re-testing requirements by country. Data on requirements

from 129 countries (the European Union [EU] market was counted as one country) were collected and assessed. Table

I provides an overview of the countries with such require-ments by categorizing them in terms of the extent of testing. Table II outlines the testing requirements by country. The countries are subsumed by regions: Asia Pacific, Eastern Europe, Western Europe, Commonwealth of Independent States (CIS), Middle East, Africa, North America, Central America and the Caribbean (CAC), and South America.

Multiplication of tests along the global supply chain. Multina-tional manufacturers manage global product supply chains. One drug product batch may be dispatched to several coun-tries (i.e., batch splitting) after country-/region-specific packaging. Accordingly, the same batch may undergo sev-eral re-tests. Table III provides examples for a recombinant interferon and a chemical product.

A special situation exists in Chile, where two local sets of re-tests are required for the import of biological products (4). In addition to the partial re-test under the responsibility of the importer/manufacturer, the products are subject to testing at governmental laboratories, referred to as “series control.”

Delay to supply. The local re-testing process takes signifi-cant time. Information from 29 operations in 18 different countries was received. The average supply-chain delay is summarized in Figure 1 and ranges from two to 19 weeks. The maximum absolute delay was reported as 22 weeks (biologics testing in China). It is noted that re-testing can be further prolonged in case of OOS investigations or other delays (e.g., if required materials/reagents are temporarily not available due to import procedures).

Table I: Number of countries by requirement (testing category)*. Status as of November 2014.

Number Category Definition/Extent of Testing

5 YImport testing required; causing delay in

the supply chain.

30 (Y)

Import testing required (only for specific

products or with reduced frequency);

causing delay in the supply chain.

9 (N)Import (or surveillance) testing may be

required; without delay in the supply chain.

85 N

Import testing not required; however,

registration testing may be required

(20 countries).

129

Countries represented in the survey

(with the European Union market

counted as one country).

*It is noted, that as of the request, the compilation focuses

on import testing. Data on quality-control re-testing in the

scope of market authorization/renewal/post-approval changes

(registration testing) as well as surveillance testing is reflected

as complementary information only. Additional countries

might require import, registration, or surveillance testing.

Accordingly, the present overview of testing requirements

is not comprehensive but rather an attempt to give an idea

about the complexities in global supply and trade of medicines

caused by import regulations.

ES663800_PTsupp0915_020.pgs 08.27.2015 05:53 ADV blackmagentacyan


Table II: Testing requirements by country. This table considers testing requirements that could cause delay in the supply chain (refer to Table I). The extended version of this table, which includes testing requirements from all 129 countries, is available online at www.pharmtech.com/pt/importtesting.Who performs the testing: Governmental laboratory (Gov), companies laboratory (Comp), company could use certified laboratory (Gov/Comp). Requested testing for product categories: active pharmaceutical ingredients (API), API biological/biotech (API/B), drug product (DP), drug product sterile (DP/S), combination product/medical device (Comb), vaccine (Vac), others (O). Status as of November 2014.EDQM is European Directorate for the Quality of Medicines & HealthCare; EEA is European Economic Area; EFTA is European Free Trade Association; MOU is memorandum of understanding; MRA is mutual recognition agreement; N/A is not applicable; N/I is no information available; OMCL is Official Medicines Control Laboratories; Reg. is registration testing at governmental laboratories; Surv. is surveillance testing at governmental laboratories.

Region Country

Import testing

Further

testing

requirements

Comments

Extent by

category

Who

performs

the testing

Product

categories in

scope

Reg. Surv.

Asia

PacifcChina Y Gov

DP, DP/S,

Comb- -

For biological products also clinical material to

be retested (one batch)

India (Y) Gov N/I - -Waiver possible in case of adequate

compliance status of the manufacturer

Pakistan (Y) GovDP/S, Vac,

others- -

Import testing for certain products (i.e.,

vaccines, sera, interferons)

South Korea Y CompDP, DP/S,

Comb- - Waiver for orphan drugs/indications

Thailand (Y) GovDP/S, Vac,

others- -


vaccines, sera, blood products and derivatives)

Vietnam (Y) Gov Vac, others - -Import testing for certain products (i.e.

vaccines, biologic material-derived antibodies)

Japan (Y) Gov Vac, others - -Import testing for certain products (i.e.,

vaccines, sera, blood products)

Western

EuropeEU (Y)

Comp

(Gov for

Vac)

API, API/B,

DP, DP/S,

Comb.

- X

Waiver possible for EEA member states (28 EU

member states, Norway, Iceland, Lichtenstein)

and mRA countries (Australia, Canada, Israel,

Japan [non-sterile products only] and Switzerland)

Surveillance testing by OmCL as part of EDQm

Switzerland (Y) CompDP, DP/S,

Comb- X

Waiver possible for countries with comparable

control of medicinal products (PIC/S countries,

EEA member states [EU and EFTA], Japan [mOU],

Canada [mRA])


Eastern

Europe

Bosnia and

Herzegovina(Y) Gov N/I X X

Import testing of packaging only

Registration testing during DP registration and

license renewal


Israel (Y) Gov DP X -

Waiver possible, EU QP release practice;

waiver for EU countries according to Agreements

on Conformity Assessment and Acceptance of

industrial products (ACAA)

Registration testing during DP registration and

license renewal

macedonia (Y) Gov/Comp N/I - X

Waiver possible for products fled under the

simplifed CADREAC procedure

Surveillance testing by OmCL as part of

EDQm



Import Testing

Table II: (Continued)

Region Country

Import testing

Further

testing

requirementsComments

Extent by

category

Who

performs

the testing

Product

categories in

scope

Reg. Surv.

montenegro (Y) Gov N/I - X

Import testing of packaging only

Verifcation of leafet and CoA, if imported from

EU or agreement-holding countries


Serbia (Y) Gov N/I - X


vaccines, sera, toxins, allergens and other

blood products)


CIS Azerbaijan (Y) Gov N/I - -Waiver possible in case of adequate


Belarus (Y) Gov N/I - -Waiver possible in case of adequate


Kazakhstan (Y) Gov N/I - -Waiver possible upon certifcation (inspection)

of the manufacturing site (usually 3 years)

moldova (Y) Gov DP, DP/S - - Import testing of packaging components only

Russia (Y) Gov/CompDP, DP/S,

Comb- -

Waiver possible upon certifcation (inspection)

of the manufacturing site (usually 3 years)

Ukraine (Y) GovDP, DP/S,

Comb- X

Import testing, no routine procedure for the

majority of product classes


middle

East

Iraq Y Gov N/I - -

Jordan (Y) Gov N/I - X

Import/surveillance testing, after 24 months

and successful testing of 7 consecutive

commercialized batches, the testing frequency

is reduced to 3 random tests per year

Kuwait (Y) Gov DP, DP/S X -

Import testing, the authority performs random

tests to check on quality (even less frequent

testing for expensive drugs); if no QC test

occurs, a batch gets certifed based on visual

control

Registration testing (rarely)

Oman (Y) Gov N/I - - Import testing required for generics only

Saudi Arabia (Y) Gov DP/S - -Import testing required for biological products

only

Yemen (Y) Gov N/I - - Import testing required for generics only

Africa Algeria Y Gov

API, API/B,

DP, DP/S,

Comb.

- -Governmental laboratory decides on the tests

performed per batch

Egypt (Y) Gov DP - -

Routine procedure (each received batch) for

biological products. No routine procedure

(random testing) for chemical products.

South Africa (Y) Comp DP, DP/S - -

Import testing (identity and assay testing only)

Waiver possible if temperature data available

or testing cannot be performed locally



Quality-control figures. The survey collected annual data on the number of re-tests (full or partial), OOS investiga-tions, and batch rejections. Six companies reported a total of 18,616 re-tests performed per year. Of these, one re-test resulted in a batch rejection. The overall figures are shown in Table IV.

Associated resources for testing. The following costs (per year) were queried in the survey: (a) costs of local QC analytics (e.g., for testing, samples, contract laboratories) and (b) loss by blocked capital due to longer storage duration of the in-ventory (e.g., warehoused at customs). The responses were aggregated in subsets according to the reported cost figures, as follows:• Subset 1: Nine in-country operations reported both fig-

ures (a + b). Countries reported are Argentina (1 oper-ation), China (1 operation), EU (3 operations), Israel (1 operation), Mexico (2 operations), and South Korea (1 operation). The resulting annual costs associated with import testing accumulate to $66,143,060, calculated from costs of local QC analytics ($22,970,651) and blocked capital ($43,172,409).

• Subset 2: Thirteen in-country operations reported just one of the requested figures (a or b). The total re-ported annual costs from all 22 in-country operations (including Subset 1) add up to $101,198,383.• Subset 3: A second survey within the European Federation

of Pharmaceutical Industries and Associations (EFPIA), conducted January to February 2015, was performed fo-cusing on material subjected to import testing in the EU after import from the United States. Fifteen multinational pharmaceutical companies reported 8495 product batches for 2014 (5). Considering $3381 as the average cost per re-test (see below), the costs add up to $28,719,047.

Reported costs per re-test. Costs per re-test were deduced from the data sets, where in-country operations reported the number of re-tests and costs (at least the costs of local QC analytics). Twenty two in-country operations reported 17,164 re-tests and associated costs of $58,025,974. The re-sulting average costs per re-test are $3381.

Hidden costs. Companies provided details of additional re-sources required for local re-testing even if the testing is not performed under their responsibility. To support re-testing at the government laboratories, costs arise, for example for:• analytical method implementation (including training

activities)

Table II: (Continued)

Region Country

Import testing

Further

testing

requirementsComments

Extent by

category

Who

performs

the testing

Product

categories in

scope

Reg. Surv.

North

AmericaCanada (Y) Comp DP, DP/S - -

Import testing required (identity testing only).

Waiver possible if manufactured, tested and

packed in an mRA country (EEA member states

[EU and EFTA], Switzerland, Australia)

CAC mexico (Y)

Comp

(Gov for

Vac)

API, DP,

DP/S, Vac- -

Import testing required; waiver possible

in case of certifcation (inspection) of the

manufacturing, analytical and/or packaging site

(biological products)

South

AmericaArgentina Y Comp DP, DP/S - -

Brazil (Y) Comp DP, DP/S - -

Reduced testing possible (assay/content,

degradation products) in cases where

temperature/humidity monitoring data are available

Additional requirement for local analytical method

validation

Chile (Y)Comp

(and Gov)

API/B,

DP, DP/S,

Comb, Vac

- -

Import testing required for selected quality

attributes (e.g., identity, assay/content,

selected impurity, dissolution); special

requirements for biological products, which are

additionally tested in governmental laboratories

(“series control”)

Uruguay Y CompAPI/B, DP,

DP/S, Comb- -

Import testing required for selected quality

attributes (e.g., identity, assay/content,

selected impurity, dissolution)

Editor’s Note: €1 = $1.146 as of Aug. 25, 2015.



Import Testing

• equipment (e.g., chromatographic columns) and devices (e.g., method-specific apparatus)• critical reagents and reference standards (including

qualification)• importation and customs requirements for these materials.These additional costs are typically not monitored and

may not be reflected in the reported figures accordingly.Types of waivers implemented. Global re-testing requirements

were presented in Table II. Responding companies also reported that local regulations permit waivers from local re-testing, where different approaches were identified:• legal

- formation of an union (e.g., EU member states) - mutual recognition agreement (MRA) (e.g., EU-Switzer-

land, Australia-Canada) - Agreements on Conformity Assessment and Acceptance

of Industrial Products (ACAA), which is a specific type of MRA based on the alignment of the legislative system and infrastructure of the country concerned with those of the EU (e.g., EU-Israel)

• regulatory

- for specific product categories (e.g., chemical products, Egypt or orphan drugs/indications, South Korea)

- for products filed under a simplified procedure (e.g., Collabo-ration Agreement of Drug Regulatory Authorities in Euro-pean Union Associated Countries [CADREAC] in Turkey)

• compliance

- countries with comparable control of manufacturing/transport (e.g., Switzerland)

- transport validation: temperature data available from shipment (e.g., Brazil)

- compliance status evaluated through certification (inspec-tion) of the manufacturing, analytical, and/or packaging site (e.g., India, Mexico, most CIS states)

• practical

- testing cannot be performed locally (e.g., South Africa) - import of small quantities for selected patients or groups

of patients (e.g., South Africa).

DiscussionImport testing adds limited quality or safety benefits to patients.

Companies reported 18,616 re-tests were conducted per year, which resulted in one batch rejection. This result equates to a batch rejection rate of 0.005%. This low batch rejection rate indicates that firstly, there is no significant difference between the results of the original certificate of analysis (CoA) results (manufacturing site) and the import testing (local re-testing); and secondly, distribution following good distribution practices (GDP) is under control. Accordingly, import testing does not seem to add verifiable value for supply-chain security and patient safety.

Delay to market increases risk for drug shortage. The average delay in releasing the drug to the market caused by the local re-testing is approximately four weeks and varies from two to 19 weeks. It is not always predictable when the final re-lease to the market can occur. OOS investigations or other testing issues (e.g., if needed materials/reagents are tempo-rarily not available due to import procedures) may result in delayed release of product into distribution. Accordingly, import testing may lead to interrupted supply of important medicines to patients.

Remaining shelf-life period can limit product availability. The maxi-mum reported absolute delay caused by import testing was 22 weeks or approximately five months (China). According to the Chinese drug importation regulations (6), the minimum re-maining shelf-life (RSL) should be at least 12 months. For drugs with a shelf-life less than 12 months, the RSL should be at least six months. This example indicates that import testing can significantly reduce the RSL of a medicine, and consequently increase the risk of interruptions in the supply of the medicine.

Increased supply chain complexity does not benefit patients. At the time of importation, the materials often have to be stored under quarantine in customs (bonded) warehouses for a certain pe-riod, which may be prolonged due to import testing. These warehouses are to a certain extent not under the control of the importer/manufacturer and, therefore, may not be quali-fied according to the standards applied and enforced in the

Table III: Potential multiple analyses for globally supplied products. The examples are based on the requirements listed in Table II.

Definition/extent of testing

Number of re-tests

Interferon

(recombinant

production)

Chemical

product

Release testing at the

manufacturing site1 1

Full or partial re-test upon import

in a country23 21

Additional analyses for

surveillance testing8 9

Total number of tests 32 31

Figure 1: Assessment of the reported data: Average delay to supply (in weeks) per country.

China

Costa Rica

Bosnia and Herzegovina

Saudi Arabia

Iraq

Russia

European Union

Mexico

Argentina

South Korea

Jordan

Algeria

South Africa

Egypt

South Korea

Chile

Japan

Brazil

0 2 4 6 8 10 12 14 16 18 20

FIG

UR

E 1

IS

CO

UR

TE

SY

OF

TH

E A

UT

HO

RS

.



pharmaceutical industry. Accordingly, the storage in these warehouses may increase the risk for temperature deviations.

Moreover, a less stringent chain of custody for test samples may increase the risk for samples to be lost or diverted, and material to be contaminated/soiled/violated as security/tamper-evident seals need to be broken for these operations. These risks are reduced when robust GDPs are not interrupted (7).

Import testing vs. surveillance testing. The test samples are generally taken directly after customs clearance upon im-port and straight from the imported batches. After the batch is produced under good manufacturing practice (GMP) at the manufacturing site, its integrity is maintained through adherence to GDP and good storage practices (GSP). Con-sidering transport controls and possible monitoring data, it can be expected that re-testing results would not be sig-nificantly different from the manufacturing site’s CoA. The reported rejection rate of one in >18,000 batches supports this conclusion and also shows no evidence that import test-ing detects counterfeited products (also see Table IV). Accord-ingly, testing upon import does not add value, if all relevant good practice quality (GxP) guidelines and regulations are applied. Furthermore, conducting re-testing at the point of entry into a country does not reflect additional, or greater, risk related to local distribution channels.

Although not comprehensive, post-marketing surveillance testing is much better suited to monitor independent control of medicines on the market nearer to the direct supply to the patient. Samples taken from wholesalers, pharmacies, or hospitals could also provide the opportunity to verify compliance of the medici-nal product with approved specifications, detect counterfeits (3), unauthorized imports, or manipulations reflecting the entire sup-ply chain. In addition, such data may help to understand these threats and to define appropriate measures for their mitigation. Serialization requirements (8), currently implemented across many the supply chains, make even surveillance testing obsolete for the detection of counterfeits. Furthermore, this risk-based approach would not cause any delay in access of medicines to patients.

Reported costs may underestimate actual costs. Significant costs are associated with import testing. Because of the limitations of the survey (data from only six companies); however, it is believed that the actual expenditure by the industry is much greater than that reported due to the difficulty in fully accounting for the impact of import testing. In many cases, these costs will feed through into the costs of the medicines and consequently im-pact costs to the public healthcare systems and patients.

Recognizing the high costs connected to the product import, some countries established waivers from import testing for or-phan drugs/indications (e.g., South Korea) and high price/low turnover products (e.g., Chile, Ukraine). For small markets, the number of samples required can be a significant portion of the total imported quantity into the market.

Several countries have implemented waivers from local re-test-

ing. In total, 13 countries reported waiver procedures (see Table II). The different types of waivers have been described in this article. Waiver procedures provide the opportunity

for the legislators to grant exemptions from secondary test-ing, where the importing country’s health authority has con-fidence that the product is safe, efficacious, and complies with registered specifications.

Elimination of import testing is justified based on (1):• Evidence that the product manufacturing, testing, and stor-

age/distribution systems are well controlled and validated.•An effective quality system is in place to assure compliance.•Oversight by regular audits and inspections performed

by regulatory authorities (9, 10). Even if import testing is required by laws/regulations, waiver

processes may be defined in the corresponding guidelines with-out violating overarching laws. If any legal possibility for waivers is lacking, it is suggested that the legislative requirements should be amended to enable exemptions from import testing under well-defined conditions.

Increasing international convergenceModern product development ensures comprehensive process understanding and well-characterized products. Nowadays, pharmaceutical manufacturing is highly regulated and con-trolled. The modern pharmaceutical industry together with regulatory authorities and global organizations (e.g., PIC/S, WHO, ICH, ASEAN, APEC) have established appropriate controls of the manufacturing process through substantially advanced process understanding, in-process controls, valida-tion of the manufacturing process and transportation as well as release testing complying with international globally recognized GxP standards: GMPs (11–14), GDPs (7, 15–17), and GSPs (18).

Recognizing the consequence of the successive controls across the entire supply chain, several global health authorities, including ANVISA in Brazil (19), the United States Food and Drug Administration (20, 21), and the Ministry of Health of Ukraine (22), have eliminated import testing for certain biologi-cal products. Likewise, China (SFDA) has eliminated secondary testing for chemical products (e.g., clinical-trial materials).

The increasing international convergence on this topic is also reflected in statements of the World Trade Organization (WTO) and the EU. The WTO regards the “burdensome practices for certification and testing of products” as non-tariff barriers

“which adversely affect the distribution trade.” Accordingly, a country will benefit from “the removal of barriers caused by differences in national product regulations and the elimination of border controls” by enhanced international trade (“interna-tionalization of distribution”) (23). The EU stated that one of

Table IV: Number of re-tests and out-of-specification (OOS) investigations/batch rejections per year.

Number Figure Occurrence

18,616 Re-tests for import N/A

23 OOS investigations 0.338%

1 Batch rejections 0.005%



Import Testing

the goals of the EU–US Transatlantic Trade and Investment Partnership is to “reduce redundant and burdensome testing and certification requirements” (2).

ConclusionWith a reported batch rejection rate of 0.005%, it was ob-served that import testing does not add additional quality or safety benefits to patients if appropriate controls can be demonstrated and provided products are controlled accord-ing to GxP standards through the entire supply chain. In fact, import testing introduces potential for increased risks to the patient associated with supply chain delay and com-plexity.

This study reports approximately four weeks delay to supply (22 weeks maximum reported delay) and potential significant loss of product shelf life. Patient risk is poten-tially increased due to less controlled storage conditions and less stringent chain of custody.

Import testing may lead to additional complexity in the overall supply chain, repeated tests along the global supply chain (i.e., a drug product batch may be analyzed up to 32 times), increased local inventory/warehouse capacity, and considerable increase in costs (on average, approximately $3438 per batch imported). These costs triggered waiver processes in some countries for orphan drugs/indications and high price/low turnover products, respectively.

For these reasons, it is recommended the regulators es-tablish exemptions from import testing under well-defined conditions and that timely waiver processes are employed where appropriate manufacturing and distribution controls have been demonstrated. Where the legal framework does not allow for waivers, it is suggested that the legislative re-quirements should be amended to enable exemptions from import testing.

It is acknowledged that import testing could offer value, for example, if the abovementioned conditions are not met. In the case of the single batch rejection reported in this sur-vey, a discrepancy in the upstream processing of the product (e.g., transportation) could be the cause and secondary test-ing may have prevented an inefficacious or harmful medi-cine reaching patients. However, the 18,615 released batches indicate that the controls, discussed in this publication, are comprehensive and highly effective. Moreover, these control processes are subject to continual improvement as part of a modern pharmaceutical quality system (24).

Post-marketing surveillance testing offers the possibil-ity to execute risk-based quality checks and is much better suited to detect counterfeits or unauthorized imports as it includes local distribution channels.

AcknowledgementsThe authors thank Ivana R. Antonacci (Merck & Co., Inc., Kenilworth, New Jersey, USA) and Angela McGillivary (Bio-gen Idec Ltd, Berkshire, United Kingdom) for constructive discussions.

References 1. IFPMA, “Appropriate Control Strategies Eliminate the Need for Re-

dundant Testing of Pharmaceutical Products,” www.ifpma.org/up-loads/media/IFPMA_Position_Paper_on_Redundant_Testing_05.pdf, accessed July 6, 2015.

2. European Commission, “Technical Barriers to Trade,” Initial EU TTIP Position Paper, July 16, 2013.

3. K. Outterson and R. Smith, Alb. L.J. Sci. & Tech. 16, 526–43 (2006). 4. Ministry of Health of Chile, “Reglamento del sistema nacional de con-

trol de productos farmacéuticos de uso humano (Regulation of the na-tional system of control of pharmaceutical products for human use),” DS 03/10, 2010.

5. S.K. Roenninger and J.H.O. Garbe, “Import Testing: Limitation of Pa-tient Access to Medicines,” in publication.

6. China State Food and Drug Administration (SFDA), “Medical prod-uct import regulation. Administration of import drug,” SFDA Order No. 4, 2004.

7. WHO, “Good distribution practices for pharmaceutical products,” WHO Technical Report Series, No.957 (Annex 5) 2010 (Geneva).

8. EC Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products, Official Journal of the European Union, L 174/74, 1/7/2011, 2011.

9. IFPMA, “Global GMP Inspection Landscape—Industry Point of View and the Way Forward,” www.ifpma.org/fileadmin/content/Quality/Inspections/Foreign inspections IFPMA presentation 2010.pdf, accessed 6 July 2015.

10. EFPIA, “Enhanced Good Manufacturing and Good Distribution Practices (GMP/GDP) Inspection Efficiency,” www.efpia.eu/uploads/documents/EFPIA_Enhanced Inspection Practice - Final_v8a_19May2014.pdf, accessed 6 July 2015.

11. WHO, “Good Manufacturing Practices for Pharmaceutical Products: Main Principles,” Technical Report Series, No. 961 (Annex 3) 2011.

12. EC Guidelines EudraLex, Vol. 4, Good Manufacturing Practice Medici-nal Products for Human and Veterinary Use (Brussels, 2010).

13. Code of Federal Regulations, Title 21, Current Good Manufacturing Practice for Finished Pharmaceuticals (Government printing Office, Washington, DC) Part 211.

14. PIC/S, ÒGuide to Good Manufacturing Practice for Medical Products,Ó PE 009-11, 2014.

15. PDA, ÒGuidance for Good Distribution Practices (GDPs) for the Phar-maceutical Supply Chain,Ó Technical Report No. 52, 2011.

16. EC Guidelines 2013/C 343/01, Good Distribution Practice of medicinal products for human use (Brussels, 2013).

17. PIC/S, ÒGuide to Good Distribution Practice for Medical Products,Ó PE 011-1, 2014.

18. WHO, ÒGuide to Good Storage Practices for Pharmaceuticals,Ó Techni-cal Report Series, No. 908 (Annex 9) 2003.

19. ANVISA, ÒQuality Assurance Requirements for Non-Biological Im-ported Products,Ó Resolution RDC No. 10/2011 (2011).

20. FDA, “Reinventing Regulation of Drugs Made from Biotechnology,” Press Release, Nov. 9, 1995.

21. FDA, ÒInterim Definition and Elimination of Lot-by-Lot Release For Well-Characterized Therapeutic Recombinant DNA-Derived and Monoclonal Antibody Biotechnology Products,Ó Fed. Reg. 60 (236), 63048-63049 (Dec. 8, 1995).

22. Ministry of Health of Ukraine, “About approval of the Procedure of control of compliance of the immunobiological preparations applied in hospital practice, to requirements of the state and international standards,” Command No. 698 (Oct. 1, 2014).

23. World Trade Organization (WTO), “Distribution Services,” Note S/C/W/37, June 10, 1998.

24. ICH, Q10: Pharmaceutical Quality System, Step 4 version (2008). PT



Regulatory Correspondence

Controlled correspondence provides a crucial com-munication mechanism between FDA and the ge-neric pharmaceutical industry. Such a mechanism allows the industry to seek for the agency’s input

prior to the submission of an abbreviated new drug appli-cation (ANDA). On average, FDA has received more than 1000 controlled correspondences every year since the agency began responding to inquiries in 1992.

Controlled correspondence is defined as “a correspondence submitted to the agency, by or on behalf of a generic drug manufacturer or related industry, requesting information on a specific element of generic drug product development” (1). An effort has been made to data-mine correspondences related to generic-drug chemistry that were submitted in the past 10 years with the goal of identifying major categories of interest and determine areas where FDA can improve communication with the industry. This effort is expected to increase efficiency and thereby assure the fulfillment of the agency’s Generic Drug User Fee Amendments of 2012 (GDUFA) commitment to the industry, as elaborated below.

Under the GDUFA commitment (2), FDA will respond to:• 70% of controlled correspondence in four months

from date of submission in fiscal year (FY) 2015 • 70% in two months from date of submission in FY

2016• 90% in two months from data of submission in FY

2017.If the controlled correspondence requires input from the

clinical division, one additional month will be added to the goals outlined above.

Several years ago, FDA established a webpage (3) and provided instructions to better guide the industry in sub-mitting controlled correspondence. To further improve the efficiency of processing controlled correspondence, a draft guidance for industry entitled Controlled Correspondence Related to Generic Drug Development (1), was published in August 2014. In this guidance, controlled correspondence is defined and criteria are given for what correspondence is acceptable for submission to FDA. Pre-ANDA meeting

Regulatory Considerations for Controlled Correspondence Related to Generic Drug ChemistryKristina Adams, PhD; Xiaochuan Yang, PhD; Min Li, PhD; Thomas O’Connor, PhD.; Lane Christensen,

PhD; Frank Holcombe Jr., PhD; Andre Raw, PhD; Susan Rosencrance, PhD; and Geoffrey Wu, PhD

An analysis of controlled correspondence

between generic-drug manufacturers and FDA

reveals patterns in questions about specific drug

chemistry topics and the response to information

provided in FDA guidance documents. Strategies

to improve communication between generic-

drug manufacturers and FDA are offered.

The authors are with the Center for Drug Evaluation and

Research, FDA. Contact: Geoffrey Wu, PhD, Geoffrey.

[email protected]. Disclaimer: this article reflects the views of the authors and should not be

construed to represent fDA’s views of policies.

ImA

GE

So

uR

CE

/GE

TT

y I

mA

GE

S




requests, questions related to pending ANDAs under review, inquiries not directly related to generic-drug development, or general, open-ended, or insufficiently detailed questions will not be considered as controlled correspondence. Request-ors inquiring on matters under consideration by FDA (e.g., approval standards for complex products) will be notified, but no conclusive information will be given until the matter is settled by the agency. Moreover, the guidance states that requests for review of clinical protocols for in-vivo bioequiva-lence studies will remain excluded from GDUFA goal dates as these recommendations are covered by individual guid-ances. These well-defined limits are anticipated to reduce the volume of inquiries and allow allocation of FDA resources to providing timely answers to appropriate inquiries.

This retrospective analysis of chemistry-related con-trolled correspondence is another tool to aid in improving the agency’s response to the industry. Understanding trends in the content of these correspondences will allow FDA to improve communication, address gaps in guidance interpre-tation, and inform future guidance development. Increased clarity from FDA will further increase efficiency by reduc-ing the volume of correspondences each year, thereby reduc-ing strain on the agency’s resources.

Methods

The agency’s correspondence database was data-mined to identify chemistry-related correspondence received between January 2004 and May 2014. Preliminary search identified 754 correspondences labeled as chemistry related; among these, 173 were sub-labeled as meeting requests, biowaiv-ers, bioequivalence, and citizen petition. However, they were not included in the further data analysis because they are not considered as chemistry-related correspondences under the new definition. Therefore, the final sample size was 581.These correspondences were reviewed and assigned one of 15 categories and a number of relevant keywords. The ques-tions and answers provided by the agency were summarized in a master spreadsheet based on receipt dates. The most

Figure 1: Number of chemistry-related controlled correspondence (CC) received every year between 2004 and 2014.

0

20

40

60

80

100

120

140

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Nu

mb

er o

f C

C

Figure 2: Number of chemistry-related controlled correspondences (CC) per category.

0

50

100

150

200

Combin

atio

n pro

ducts

Contain

er-clo

sure

system

Diss

olutio

n

Form

ulatio

n

Inac

tive

ingre

dients

Ove

rage

Stab

ility

Spec

ifca

tions

505(

j) el

igib

ility

Post-a

pprova

l chan

ges

Pre-

appro

val c

hanges

Nu

mb

er

of

CC

Category

Figure 3: Breakdown of the categories of specifications (A), post-approval changes (B), and stability (C). CC is controlled correspondence.

0 5

10 15 20 25 30 35 40

Resid

ual so

lven

ts

Iden

tity

Lim

its

DM

F

Test M

ethod

Valid

atio

n

Impurit

y

Nu

mb

er o

f C

C

0

5

10

15

20

25

30

35

40

45

Support documentation Reporting category

Nu

mb

er o

f C

C

0

10

20

30

40

50

60

70

80

Gu

ida

nce

cl

ari

fca

tio

n

Bra

cke

tin

g/

Ma

trix

ing

Ba

tch

siz

e

Ba

tch

nu

mb

er

Tra

nsd

erm

al

Te

st p

ara

me

ters

Pa

cka

gin

g

Nu

mb

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f C

C

(A)

(B)

(C)

Al

l F

IGu

RE

S A

RE

Co

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frequently asked questions were identified and are discussed in this publication. A Python-based natural language pro-cessing tool (4) was then used to count keywords for further analysis of the categories and to generate a lexical dispersion plot to determine the location of each category within the text in a chronological order. In addition, review outcomes and commonly seen issues have been summarized and sug-gestions for improvement are provided.

Discussion and resultsOn average, the agency receives approximately 1200 cor-respondences yearly. Approximately 5–10% are related to generic-drug chemistry. The number of chemistry-related correspondences has increased steadily since 2011, as shown in Figure 1. Topics in these correspondences can be loosely grouped into 11 categories: • Combination products• Container closure system•Dissolution• Formulation• Inactive ingredients•Overage• Stability• Specifications• 505(j) eligibility• Post-approval changes• Pre-approval changes. Each correspondence was assigned to one category, and

the number of correspondences under each category was counted and summarized in Figure 2. Categories with the highest number of counts include formulation, stability, specifications, and post-approval changes.

Formulation is a broad category, but generally consists of inquiries about API-related topics such as allowable particle size, salt stoichiometry, or synthetic route deviations from the reference listed drug (RLD); the presentation of the dos-age form; and other allowable deviations from the RLD.

The specifications, post-approval changes, and stability categories were broken down into sub-categories to further elucidate trends.

Specifications is a broad topic, which includes questions related to residual solvents, identity, limits, drug master file (DMF), test method, validation, and impurity (see Figure 3A). While the counts in many of the subcategories were distributed relatively evenly, test method and impurity stood out as major topics. Test method questions were highly varied and case-specific. These questions sought specific recommendations on the procedure and/or data requirements for stability testing; API/excipient characterization and compatibility; in-process testing; quality requirements; and ANDA submission data requirements.

Inquiries about residual solvents or impurities generally requested advice on the limits or the types of solvents/impuri-ties found with a particular API. The limits category catches all other inquiries regarding limits that are not pertaining to residual solvents or impurities; these questions largely re-quested advice on the setting of assay limits for the API.

Inquiries regarding post-approval changes (see Figure 3B) revolved almost exclusively around questions about which post-approval reporting category was most appropriate, fol-lowed by requests for advice on any other information or data that should be filed with the supplement(s). Questions in this category will no longer be considered as controlled correspondence; the draft Guidance for Industry: Controlled Correspondence Related to Generic Drug Development A

ll

FIG

uR

ES

AR

E C

ou

RT

ES

y o

F T

hE

Au

Th

oR

S.

Table I: Common questions and answers in controlled correspondences. PAS is prior approval supplement; CBE is changes being effected; ANDA is abbreviated new drug application; RLD is reference listed drug.

Category Question Answer

Stability We ft the criteria; can we submit a reduced batch size?yes, please provide suffcient justifcation for the batch

size in your submission.

Formulation What if there are two sources for the API?

Equivalency between the sources should be

demonstrated in the application. For instance,

comparative stability and release data from one batch

of the drug product manufactured using the API from

alternate source(s) against the primary source are

recommended.

Post-approval

Changes

Should a (major) change be reported as a PAS, CBE-

30, CBE-0, or in the annual report?Guidance was given on a case-by-case basis.

overage Is it acceptable to have an overage of the API?

In general, overage is discouraged and a review issue.

In most cases, the frms were directed to include

suffcient justifcation (if overage is used) in their ANDA

submission for review. In rare cases, the agency might

concur based on the information available.

FormulationIs it acceptable to submit a tablet or capsule size larger

than that of the RlD?

This is not recommended; if it is deemed necessary,

suffcient justifcation should be provided in the ANDA

submission for review.




( August 2014) considers any questions related to a pending or approved ANDA as a review issue and outside the scope of controlled correspondence (1). However, the agency is trying to establish some mechanism to address general ques-tions for approved ANDAs during the post-approval phase.

Stability questions were divided into subcategories (see Figure 3C) and pertained to requirements for batch size and re-quests for approval of bracketing or matrixing protocols. Batch number questions generally seek to clarify how many primary stability batches are required for supporting the ANDA submis-sion given the requirements set forth in the June 2013 Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products (5). Because the release of this guidance and the sub-sequent May 2014 Guidance for Industry, ANDAs: Stability Test-ing of Drug Substances and Products Questions and Answers (6) generated many questions and represents a relatively major shift in FDA’s approach, further analysis of these controlled corre-spondences will be elaborated in a future publication.

Most frequently asked questionsThe most commonly posed questions across all categories were compiled in Table I. The most popular question was about reduced batch size(s): Firms requested for the agency’s concurrence on reduced primary batch sizes compared to the established pilot-scale size according to the International Conference on Harmonisation (ICH) definition. The cri-teria for an exception to the recommendations regarding minimum size for pilot scale for ANDA submission batch size reduction were established in the agency’s guidance (6): •The RLD has an orphan drug designation.•Use of a controlled substance allocated by the Drug

Enforcement Administration.

•The test batch size is the same as the commercial batch size with the commitment that a prior approval sup-plement (PAS) will be provided when there is scale-up.

FDA did concur with the proposals for reduced batch sizes when they met one of the above criteria; however, in cases where the proposals used the high API cost or other financial/logistical constraints as justifications, the agency normally denied concurrence.

The second most popular question was regarding mul-tiple API sources. The specific questions were broad, but generally related to whether different routes of synthesis are acceptable from two API sources in the same ANDA submission, whether it is acceptable to have different speci-fications and test methods for different sources of API, and how many exhibit/stability batches should be manufactured using the API from the alternate source(s). For the first two scenarios, FDA typically concurs with the proposals while recommending sufficient justifications to be included in the ANDA submission(s). Regarding the number of batches, the agency recommends comparative stability and release data from at least one batch of finished drug product produced from each alternate API source. It should be noted that the APIs in discussion are limited to small molecules; recom-mendations for complex drug substances or products (e.g., peptides, low molecular weight heparins, and biologics) can be different and would require considerations on case-by-case basis.

Another common question is the reporting mechanism for post-approval changes. Nearly all questions in the post-approval changes category were related to reporting category or what data should be submitted in support of the change. These questions have been addressed using a risk-based

Figure 4: Popularity of categories over time. The publication time points of three guidance documents: A. CMC Postapproval Manufacturing Changes to be Documented in Annual Reports (March 2014); B. ANDAs: Stability Testing of Drug Substances and Products (June 2013); C. Stability Testing of Drug Substances and Products: Questions and Answers (May 2014) are indicated in the figure.

combination products

container closure system

dissolution

formulation

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specifcations

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postapproval changes

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approach following the general principles prescribed by the agency’s guidances on post-approval changes (7, 8).

Questions on overage were almost exclusively related to whether or not the firm could produce a drug product with an overage of the API. In most circumstances, the overage proposal was not approved. As set forth in the Guidance for Industry: Q8(R2) Pharmaceutical Development (January 2009) (9), the use of an overage to compensate for degradation during manufacture or a product’s shelf life, or to extend shelf life, is discouraged. Many firms claim to have found an overage in the RLD; however, this may not be a sufficient justification for overage because the RLDs may have used a different product design and/or manufacturing processes. Given that only a limited amount of information is typically provided in these correspondences, FDA typically considers the use of overage as a review issue to be evaluated within the full context of the ANDA(s); therefore, the firms should provide sufficient justifications in the ANDA submission(s) if overage is used.

The fifth most popular question was whether it is accept-able to formulate a tablet or capsule size larger than that of the RLD. It is generally recommended to formulate generic solid oral dosage forms to be similar in size to the RLD to increase patient compliance and reduce the risk of dysphagia. Further details are discussed in the Guidance for Industry: Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules (10). Somewhat similar to the use of overage, the agency typi-cally states in the responses that deviations (especially when larger) should be justified in the ANDA submission. Proper justifications should at least include why a larger size is neces-sary, and how the firm will circumvent dysphagia and patient-compliance issues. Arguments based on patent infringement or manufacturing limitations are not considered appropriate.

Chronological correlationIt is helpful to visualize when a topic becomes popular in time. These time points can signal when guidances have ac-curately conveyed information or may alert the agency about unclear guidance language or recommendations. A lexical dispersion plot (Figure 4) displays words in sequential order within a text to visualize the location of keywords within the text. Each stripe represents the instance of a word (the cate-gory) and each row represents the entire text. Simultaneously identifying the location of the years 2004–2014 within the text allowed for correlation between the occurrence of each category to the date that the correspondence was submitted.

This type of chronological correlation shows a height-ened interest in specification, formulation, and overage questions beginning in 2012. Questions regarding post-ap-proval changes have remained fairly steady. The Guidance for Industry: CMC Postapproval Manufacturing Changes to Be Documented in Annual Reports (8) was published in May 2014; correspondences will be monitored using such a chorological correlation to assess how well such a guidance document would guide the industry. Figure 4 shows a sharp increase in stability-related controlled correspondence beginning in late 2012, which loosely correlated with the publication of the stability guidance document (5) and its companion question and answer document (6). Given that many questions were about the number and sizes of primary stability batches, FDA may use this information to guide further policy/guidance development or updates.

Furthermore, the evaluation of the frequency of inqui-ries on a topic over time can indicate how well the agency’s guidance/policy addressed the related topics. For example, questions regarding acceptable limits for and test methods

Figure 5: Breakdown of specifications category and popularity over time. The publication time points for the guidance documents: A. Residual Solvents in Drug Products Marketed in the United States (November 2009); B. ANDAs: Impurities in Drug Substances (June 2009); and C. ANDAs: Impurities in Drug Products (November 2010) are indicated in the figure.

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of residual solvents (see Figure 5) were most popular in 2008 and 2009 and then decreased after 2009, corresponding to the release of the Guidance for Industry: Residual Solvents in Drug Products Marketed in the United States (11) in November 2009. From 2012, no more residual solvents inquiries are recorded. Similarly, the number of questions on impurities dramatically dropped in 2009 and 2010, concurrent with the publication of two impurity-related guidance documents (12, 13).

Observations and recommendationsBased on the observations during the review of these cor-respondences, commonly seen submission issues include:•Vague, general, or poorly-worded questions • Imprecise language and/or misused terms•Questions that make incorrect assumptions•Too much unnecessary information provided.The agency strongly recommends the firms:• Provide clear, concise questions•Thoroughly research the question before drafting the

controlled correspondence, including visiting the FDA website for published guidances and materials• Provide relevant information clearly in the letter, in-

cluding, at a minimum, dosage form

•Do not assume that the agency will correct any incor-rect assumptions/information.

With these recommendations considered, a general work-flow for proper assembly of controlled correspondences is provided in Figure 6.

ConclusionControlled correspondence is a crucial route of communica-tion between FDA and the generic-drug industry to facilitate the development of generic-drug products. Therefore, the agency has agreed to specific program enhancements and performance goals for addressing these correspondences, as set forth in the GDUFA Commitment Letter (2). As part of the effort, this data-mining exercise was conducted to identify gaps and potential continual improvements in chemistry-related correspondences. The findings and ob-servations here can provide valuable reference to both FDA and the generic-drug industry. From these observations, the agency can gain better understanding of how its guidances and policies are received and further gauge the needs and concerns of the industry. Further interpretation of certain guidances and policies are provided here so that the indus-try can be more efficient in submitting correspondences and developing generic-drug products.

References 1. FDA, Guidance for Industry: Controlled Correspondence Related to

Generic Drug Development (Draft). (Rockville, MD, August 2014). 2. FDA, Generic Drug User Fee Act Program Performance Goals and

Procedures (Rockville, MD, 2012) online, www.fda.gov/ForIndus-try/UserFees/GenericDrugUserFees/ucm282513.htm, accessed July 15, 2015.

3. FDA, Recommendations for Improving Submissions of a “Con-trolled Correspondence” to the Office of Generic Drugs (Rockville, MD, 2012) online, www.fda.gov/aboutfda/centersoffices/officeof-medicalproductsandtobacco/cder/ucm120610.htm. accessed July 15, 2015.

4. E. Loper et al., Natural Language Processing with Python Analyz-ing Text with the Natural Language Toolkit. 1st ed. (Sebastopol, CA, 2009).

5. FDA, Guidance for Industry: ANDAs: Stability Testing of Drug Substances and Products (Rockville, MD, June 2013).

6. FDA, Guidance for Industry: ANDAs: Stability Testing of Drug Substances and Products Questions and Answers (Rockville, MD, May 2014).

7. FDA, Guidance for Industry: Changes to an Approved NDA or ANDA (Rockville, MD, April 2004).

8. FDA, Guidance for Industry: CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (Rockville, MD, March 2014).

9. FDA, Guidance for Industry: Q8(R2) Pharmaceutical Development (Rockville, MD, Nov. 2009).

10. FDA, Guidance for Industry, Size, Shape, and Other Physical At-tributes of Generic Tablets and Capsules (Rockville, MD, June 2015).

11. FDA, Guidance for Industry: Residual Solvents in Drug Products Marketed in the United States (Rockville, MD, Nov. 2009).

12. FDA, Guidance for Industry: ANDAs: Impurities in Drug Sub-stances (Rockville, MD, June 2009).

13. FDA, Guidance for Industry: ANDAs: Impurities in Drug Products (Rockville, MD, Nov. 2010). PT

Figure 6: Recommendations on how to assemble a controlled correspondence (CC).

Your formal contact information

Name, title, address, phone number, email address, and

entity (e.g., corporate affliation) of the person submitting

the controlled correspondence

A recommendation of the appropriate review discipline to

review the CC

Example: We recommend Division of Chemistry to review

this controlled correspondence

Information on the product that you are interested in

developing

Include key information such as dosage form, reference

listed drug, and the application number you are

referencing

Relevant background information and reference to any

previous related CC and FDA’s response

Example: We propose the commercial batch size will be

the same as the exhibit batch size. Please see previous

controlled correspondence number 12345.

Provide clear and concise questions

Provide additional information if necessary

Relevant prior research, formulation, and manufacturing

materials



Process Analytical Technology

The pharmaceutical and biotechnological industries face unprecedented challenges as a consequence of increased competition and difficulty in bringing innovative products to market. Therefore, signifi-

cant efforts are being made to improve product quality and productivity through technological innovation and cross-industry best practices.

In 2004, FDA published its process analytical technology (PAT) guideline, which promotes the adoption of innovative technologies to perform timely measurements on critical qual-ity attributes of raw and in-process materials, allowing better process understanding and control (1). The PAT concept is embraced in the quality-by-design (QbD) framework, which endorses a control strategy that considers not only risk assess-ment, prior knowledge, and enhanced process understanding, but also how unit operations affect the quality and stability of the product (2, 3).

QbD/PAT-based strategies provide the cornerstone to move toward continuous manufacturing in pharmaceutical and bio-pharmaceutical production. There is a global interest in adopting cleaner, safer, shorter, and more flexible and efficient manufac-turing processes through science and data-driven approaches. Continuous processing, however, requires a different mindset and implementation strategy from development up to commer-cial manufacturing, aligned with regulatory expectations. Today, health authorities have a clear view on the definition of batch/pro-duction lot (4, 5), and no other requirements are imposed. In that sense, the regulatory standpoint should not be a reason to avoid continuous manufacture. Yet, to foster continuous processing adoption, regulatory agencies, industry, and academia must col-laborate to develop approaches and a roadmap for implementation.

Using PAT to set control strategiesTo implement a control strategy in a continuous process, it is crucial to understand and minimize incoming material variation, perform timely in-process measurements, define representative sampling (depending on the dynamics of the system), set ap-propriate acceptance criteria, and characterize the propagation of changes and disturbances through the system (4). In contrast

PAT Paves the Way for Continuous ManufacturingSofia T. Santos, Francisca F. Gouveia, and Jose C. Menezes

Process analytical technology is crucial

for understanding a pharmaceutical or

biopharmaceutical process. Thorough process

knowledge is needed to develop process

control strategies and select process equipment

configuration for continuous manufacturing.

Sofia T. Santos, Francisca F. Gouveia, and José

C. Menezes are with 4Tune Engineering, Av. António

Augusto Aguiar 108, 4, 1050-019 Lisbon Portugal.

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Process Analytical Technology

to batch processing, in which local control of each piece of equip-ment is in many occasions considered sufficient, in continuous manufacturing not only is local control is mandatory, but also the entire process flow must be coordinated and equipped with second-level control systems that supervise and align the work of individual unit operations (6).

The selection of appropriate PAT tools is a crucial step to-ward setting efficient control strategies in continuous processes. Spectroscopic technologies have been widely applied in pro-cess analysis and increasingly for on-line process monitoring in both pharma and biopharma. Features such as easy-to-use instrumentation, high measuring frequencies, and the ability to monitor multiple process parameters in whole samples that more faithfully capture the real process state, allow PAT tools to surpass the limitations of traditional chromatographic tech-niques not suited to cope with high process dynamics (7, 8).

As reported in industrial case studies, various PAT tools have been used for reaction monitoring purposes, such as simultaneous use of mid-infrared and Raman probes to monitor early API synthesis, the combination of on-line analytics with Raman process analyzers for real-time de-tection of steady state in continuous flow reactors, and the employment of in-line, near-infrared monitoring tools to control the synthesis of API intermediates (8–11).

In an industrial scenario, the implementation of a successful end-to-end control strategy in continuous processing requires setting up a multidisciplinary team, thus integrating different types of knowledge (e.g., reaction chemistry, kinetic models, en-gineering principles) to establish performance requirements for the commercial process. The workflow from the implementa-tion stage until validation of the control strategy is the limiting step, as it is technically demanding and the object of regulatory oversight. The use of a standard platform for continuous manu-facturing (i.e., with equivalency of scale and equipment for pilot, clinical, and commercial production) can, however, minimize the challenges of scale-up and tech-transfer activities, facilitate training and validation procedures, and enhance collection of substantial amounts of data to enhance process understanding.

Continuous biopharmaceutical manufacturingEven though continuous manufacturing is better established for bulk chemicals, there is growing interest as well as invest-ment in realizing the benefits of continuous manufacturing for biopharmaceuticals. Moreover, the biopharmaceutical industry is particularly dominated by stringent regulatory and quality requirements, and the increasing pressure to reduce costs and growing competition from biosimilar products impacts devel-opment time. Thus, the benefits of continuous bioprocessing include steady-state operation, reduction of facility and equip-ment footprint (e.g., small bioreactors, single-use equipment), high-volumetric productivity, a streamlined process flow (e.g., elimination of hold tanks and non-value unit operations), low cycle times, a high degree of automation (minimizing manual operations and subjective decision making), the opportunity to implement standardized procedures, and more flexibility

not only in terms of rapid capacity adjustments, but also to modulate the process duration based on product demand.

There are different process configurations in continuous biomanufacturing: hybrid systems with continuous upstream and batch mode downstream (or the opposite), and fully inte-grated continuous unit operations for the entire process train. Continuous upstream (i.e., perfusion cell culture) with batch downstream is widely used for commercial manufacturing of complex and labile proteins, providing short residence times and enabling the production of unstable proteins with minimal degradation. On the other hand, batch upstream with continu-ous downstream has been explored at development and pilot scales with economic benefits, because smaller chromatogra-phy columns result in significant cost savings. A fully inte-grated continuous bioprocess reduces equipment size, costs, and residence and cycle times. Even so, not all the necessary unit operations are commercially available, and additional ef-forts are required to develop interfaces between unit operations, which opens an opportunity to employ single-use technology. Continuous operations also have the potential to positively in-fluence the supply chain, because shorter cycle times, reduced inventory, and the fact that scaling is defined by time extension offers greater flexibility in meeting variable market demands.

Selecting the appropriate process configuration requires reflect-ing on the different technological requirements when considering continuous upstream and/or downstream processing. Although continuous perfusion bioreactors have been broadly applied for commercial manufacturing of biopharmaceuticals, there are many necessary improvements, such as the development of robust and stable cell lines able to maintain high productivity, the design of media formulation to support high cell density, and the optimi-zation of bioreactor conditions (e.g., cell-density control, efficient oxygenation and ventilation, and foam control, among others).

Experience with continuous operations in downstream pro-cessing is limited, and until recently, equipment for continuous protein purification was not available. An important design re-quirement for continuous downstream processing is the abil-ity to intertwine several purification steps to operate over pro-longed periods and under strict bioburden control conditions. Ultimately, significant experience needs to be accumulated in process scale-up, and the adoption of such tools for routine use will take some time to be evaluated, validated, and implemented.

Even though regulatory agencies are increasingly sup-portive of this new manufacturing paradigm, a partial or complete integration between upstream and downstream has not yet been commercially demonstrated. To motivate companies to adopt these approaches, regulatory authorities are currently promoting the benefits of continuous process-ing, and agency experts are available to discuss approaches and the operationalization roadmap. However, low tolerance of risk, management concerns about implementing new tech-nologies, and overinvestment are some of the reasons that hold back the penetration of new processing methodologies.

Contin. on page 39



Protein Stability

Biopharmaceuticals, while highly effective medicines, are susceptible to aggregation upon manufacturing, distribution, and storage, which can result in im-munogenicity and/or reduced efficacy. Stabilization

of proteins and other biologic drugs is, therefore, crucial for ensuring both safety and efficacy.

The molecular structures of therapeutic proteins and the critical sites within these proteins that are prone to oxidation, deamidation, hydrolysis, etc., and can result in aggregation and fragmentation, are well known. The development pro-cess, therefore, begins with efforts to stabilize therapeutic proteins using protein engineering. However, the improve-ment in stability is generally limited because of the unstable nature of proteins; the stabilization energy for the native state is typically between 5 and 20 kcal/mol, which is equivalent to that of a few hydrogen bonds. Because the folded state is only marginally more stable than the unfolded state, any changes in the protein environment may trigger protein degradation, aggregation, and or inactivation.

The use of excipients is, therefore, common during the en-tire manufacturing process and in the final formulation to achieve protein stabilization through retardation of chemical degradation processes and prevention of aggregation, accord-ing to Kristina Kemter, project leader in the Research and Development department of Leukocare. Selection of appro-priate stabilization agents, however, is challenging, and made more so by the limited choice of substances that have been approved for this use.

Aggregation and other stability issuesProtein stability is a result of achieving a balance between de-stabilizing and stabilizing forces. The destabilizing forces are mainly due to the large increase in entropy of unfolding; the stabilizing forces are provided by intra-protein and protein-solvent interactions. Disruption of these interactions will shift the balance and destabilize a protein, and many stress factors are known to disrupt this delicate balance and affect protein stability.

These stress parameters include temperature, pH, ionic strength, metal ions, surface adsorption, shearing, shaking, additives, solvents, protein concentration, purity, morphism, pressure, and freeze/thaw-drying, according to Kemter. As a

Excipient Selection for Protein StabilizationCynthia A. Challener

The complex task of stabilizing proteins

is made more challenging due to the

limited number of approved excipients.

Cynthia A. Challener, PhD, is a contributing

editor to Pharmaceutical technology.

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Protein Stability

result, a variety of physical and chemical processes can lead to aggregation of proteins. She also notes that there are significant differences between freeze-dried and liquid protein products in terms of the stress exposures upon manufacturing (freeze drying) and during storage of the final products.

Liquid formulations in general have a higher risk for physical and chemical instability during storage than dried formula-tions due to their high mobility and the increased likelihood of chemical reactions and physical instability. For liquid-protein preparations, stability can be enhanced by selection of pH-buffering salts, and often amino acids can also be used. It is often interactions at the liquid/air interface or liquid/solid interface (with the packaging) that lead to aggregation follow-ing adsorption and unfolding of the protein, according to Jens T. Bukrinski, a formulation scientist with Novozymes. Shear stresses during spray drying can also lead to exposure of hydro-phobic protein regions upon spray drying that allow initiation of aggregation, according to Kemter.

Stability, particularly thermal stability, can be increased greatly when the protein is dried. For example, lyophilized formulations are generally more shelf-life stable than liquid formulations; however, protein molecules can potentially form large amounts of aggregates during the lyophilization process, according to Jay Kang, director of analytical and formulation development at Patheon. In the freezing phase, the formation of numerous ice crystals creates a large water/solid surface, a highly concentrated solution, and often an altered pH envi-ronment. All these conditions can cause protein aggregation. During drying, removal of water puts significant stresses on protein molecules and can induce aggregate formation.

Mechanisms of destabilizationTemperature and pH have the greatest influence on both physi-cal and chemical protein stability. High temperatures can lead to thermal denaturation and subsequent aggregation as well as accelerate chemical degradation pathways (i.e., side chain oxidation, hydrolysis, and deamidation) that may result in ag-gregation. In addition, most proteins are generally stable only in a narrow pH range, and physical and chemical pathways to aggregation are possible outside of that window, according to Kemter. Furthermore, the effect of pH on the chemical stability of a protein can be altered in the presence of excipients.

For instance, the effect of salts strongly depends on the pH of the solution, which dictates the charged state of ionizable groups in the protein. “Salts may stabilize, destabilize, or have no effect on proteins depending on the type and concentra-tion of salt, the nature of ionic interactions, and the presence and amount of charged residues in proteins on fully exposed surfaces and/or in fully or partially buried interior sections,” Kemter says.

Depending on the type and concentration, metal ions may also stabilize or destabilize a protein because their interactions with proteins are highly protein-dependent. Metal ions may also significantly affect protein stability without affecting much of its secondary structure. “Trace amounts of metal ions in

protein formulations may catalyze the oxidation of proteins, namely via the Fenton pathway, targeting in particular the residues methionine, cysteine, histidine, tryptophan, tyrosine, proline, arginine, lysine, or threonine. The catalysis depends on the concentration of the metal ions, and the metal-catalyzed reaction can be facilitated in the presence of reducing agents such as ascorbate or sulfhydryl (RSH) compounds,” Kemter explains. Oxidation of proteins by metal ions, oxygen, or reduc-ing agents can lead to aggregation.

Similarly, chelating agents such as ethylenediaminetetraace-tic acid (EDTA) and citric acid can bind and destabilize pro-teins or bind harmful metal ions and prevent oxidation. The net effect depends on the metal ions, oxidation mechanism, and the type of chelating agent, according to Kemter.

Protein concentration can also influence aggregation and in some cases chemical degradation, depending on the mecha-nism. “More biopharmaceuticals are being formulated at very high concentrations today. Higher concentrations create more chances for unwanted self-association, and consequently high viscosities, which can make both processing and injection more difficult,” Bukrinski observes. High pressure can also cause protein unfolding during freeze-drying or spray-freeze drying.

Chemical degradation pathways include not only oxidation, hydrolysis, and deamidation, but also isomerization, succinimi-dation, disulfide bond formation and breakage, non-disulfide crosslinking, and deglycosylation, and often occur simulta-neously, according to Kemter. She notes that deamidation of asparagine and glutamine residues is most common, and the rate, mechanism, and location of deamidation are all pH-de-pendent. Oxidation is another important chemical degradation mechanism, particularly the oxidation of the thio groups in methionine and cysteine residues. The formation of disulfide bond linkages or thio-disulfide exchanges can result in protein aggregation or polymerization.

“All of these influences can occur—either simultaneously or separately—when different types of stresses are applied to a protein, such as during isolation and purification of a protein; drying of a protein by lyophilization, spray-drying, spray-freeze drying or foam drying; storage of a protein in solution; after drying; as well as reconstitution after drying,” states Kemter.

Types of stabilizing excipientsStabilizing excipients are added to formulations to slow down or prevent protein aggregation through different mechanisms, including strengthening of protein-stabilizing forces, destabili-zation of the denatured state, and direct binding to the protein, which are applied during isolation and purification, drying (ly-ophilization, spray-drying, spray-freeze drying, foam-drying), storage in solution or after drying, and reconstitution after dry-ing, according to Kemter.

Six categories of excipients are commonly used to stabilize proteins against aggregation, according to Kang: buffers, salts, amino acids, polyols/disaccharides/polysaccharides, surfac-tants, and antioxidants. These excipients prevent aggregation through several mechanisms. “First, pH is critical to protein



stability and must be controlled to an optimal value through the use of appropriate buffers. Salts and amino acids increase the ionic strength of solutions while minimizing electrostatic interactions between protein molecules.”

Polyols/disaccharides/polysaccharides, on the other hand, stabilize protein molecules through preferential hydration or preferential exclusion, in which the excipient is excluded from the protein surface, allowing the rearrangement and stabiliza-tion of a stabilizing hydrate shell around the protein surface and preventing protein molecules from interacting. Surfactants, meanwhile, protect proteins against interaction with hydro-phobic surfaces such as air/water interfaces and container sur-faces, and antioxidants protect proteins against oxidation.

Specific examples include trehalose and sucrose (disaccha-rides); mannitol and sorbitol (sugar alcohols); histidine, gly-cine, and arginine (amino acids); polysorbate 20, polysorbate 80, and proteins like human serum albumin (surfactants); sodium chloride (salt); and dextran and polyethylene glycol (polymers). Each type has a completely different stabilizing mechanism.

Alkylsaccharides as alternatives to polysorbatesThe quality of the excipients can have a dramatic impact on protein stability. For example, common surfactants such as polysorbates are well known to contain trace amounts of per-oxides that can become significant during storage and con-sequently compromise protein stability through oxidation of susceptible amino acids, particularly exposed methionine, ac-cording to Kang. “A good practice is to use compendial excipi-ents in the development study and control the quality/storage of the excipients from the very beginning, so no surprises are encountered in GMP manufacturing and subsequent long-term storage,” he says.

The issues with polysorbates have been a focus of Aegis Therapeutics. “The oxidative damage to biotherapeutic pro-teins can directly reduce their efficacy, but perhaps more im-portantly introduce unwanted immunogenicity, which can give rise to neutralization of activity and in more serious cases, neutralization of any residual biological activity associated with the patient’s own corresponding proteins,” observes Edward T. Maggio, president and chief executive officer of the company.

The polysorbates do an excellent job of preventing aggre-gation and permitting the creation of high-concentration for-mulations of biotherapeutics, but even though they are ideally highly purified when first incorporated, Maggio notes that formation of chemically reactive species occurs immediately upon any contact with oxygen during manufacturing or stor-age of the final product.

Aegis has shown that alkylsaccharides are as effective, and in some cases, more effective than the polysorbates for the prevention of aggregation, and they are completely free of any oxidative damage problems. Comprising a sugar attached to a long chain fatty acid, alkylsaccharides break up rapidly in the body into a sugar, typically glucose, and a fatty acid. They are essentially nontoxic food components, and are considered gen-erally recognized as safe (GRAS) for food purposes. Both Big

Pharma and smaller biotech companies (e.g., Roche and Biodel) are investigating the use of alkylsaccharides as replacements for polysorbates, according to Maggio. He also notes that there is extensive safety and toxicity study data in the drug master file covering the alkylsaccharides to which licensees of the tech-nology receive a right of reference for their regulatory filings.

A blending approachTo assist formulators of biologic drugs with the stabilization and protection of therapeutic proteins in dry and liquid for-mulations, Leukocare developed its Stabilizing and Protecting Solutions (SPS) platform of excipient formulations. The pro-prietary SPS platform has been proven to stabilize different biological macromolecules during freeze drying and spray dry-ing, during storage at increased temperature in dry or liquid formulations, and even during sterilization processes, accord-ing to Kempter. She adds that the modular concept of the SPS facilitates the possibility to adjust excipient compositions to the specific requirements of the biomolecule to protect from various types of stress exposures.

SPS formulations solely comprise excipients (mainly based on amino acids) listed in pharmacopeia that are also in gen-eral listed by FDA as inactive ingredients. Interactions between multiple functional groups of the excipients in solution and particularly during drying result in a strong amorphous char-acter of the dried product, according to Kemter. The osmolytic excipients of the compositions may also support stabilization of the hydration shell around proteins in liquid formulations according to the preferential exclusion theory. In dried formu-lations, and according to the theory of water replacement, the excipients may substitute the stabilizing hydrogen bonds be-tween proteins and water through the formation of stabilizing electrostatic interactions or hydrogen bonds with the proteins upon drying.

Recombinant human serum albumin (rHSA)rHSA is the most common protein found in human plasma and is known for ligand binding and colloidal stabilization, prop-erties that are also ideal for the stabilization of proteins and other biologics. In addition, because rHSA is a natural protein in the body, it is safer than other alternative surfactant excipi-ents, such as synthetic polymers, because it has a low risk for immunogenicity and there is a natural pathway for its elimina-tion from the body.

In addition to preventing protein aggregation by blocking undesired adsorption onto vial surfaces or air/liquid interfaces, rHSA has also been shown to prevent self-association of protein drugs through preferential hydration or preferential exclusion effects and to prevent the formation of micrometer-sized par-ticles to increase the solubility of poorly soluble peptide-based drugs. Furthermore, rHSA exhibits antioxidant properties used for the stabilization of radiolabeled drugs. “As a result of this multifunctionality, in some cases, it is possible to reduce the number of excipients required to stabilize a biologic drug,” Bukrinski says. He also notes that through covalent linking of

ES663666_PTsupp0915_037.pgs 08.27.2015 05:24 ADV black


Protein Stability

a biologic API to rHSA or through encapsulation in albumin particles, it is possible to extend the circulatory half-life and control the release of drugs. Novozymes offers recombinant HSA products specifically produced for the biopharmaceuti-cal industry.

Choosing the right stabilizing excipientsBecause every protein is different and reacts differently with different types of excipients, the selection of the proper ex-cipients for a given formulation is a complex and challenging task. Some excipients may be effective in one formulation and cause protein degradation and aggregation in another.

“For instance, commonly used polysorbate detergents often disrupt the protein complexes in virus-like particles, and therefore an alternative such as recombinant human serum album or a carbohydrate-based polymer is needed,” Bukrin-ski comments.

The choice of the right excipients for stabilization of a desired protein must take into account the very complex physical and chemical degradation behaviors and the potential multifunc-tional influences that each excipient can have on protein stabil-ity, according to Kemter. “The formulation scientist must have a thorough knowledge of several factors: how to optimize the physical and chemical stability of the active ingredient; how, rationally, to include specific excipients in the formulation; how to obtain the optimum conditions for stability; how to prevent stability issues during up-scaling; and, finally, how to design a formulation that is suitable for the intended route of administration, that is, one that allows the absorption barrier to be overcome.”

Unfortunately, the structural differences among different proteins are so significant that generalization of universal sta-bilization strategies has not been successful to date. In addition, while it is desirable to keep the number of functional excipients as low as possible, the vast amount of potential destabilizing effects often necessitates the addition of several excipients.

Many scientists select excipients empirically, which takes a long time and puts a strain on resources, according to Kang.

“It is more effective to perform a preformulation study to iden-tify degradation pathways and stability-indicating analytical methods before testing major categories of excipients for their ability to protect protein molecules against specific degrada-tions. Further study using a design-of-experiment (DoE) ap-proach enables determination of the optimal levels of the most effective excipients and their interactions for the final formu-lation,” he asserts. In fact, Patheon has been able to shorten the development timeline by designing formulations based on scientific rationale and the screening of large quantities of ex-cipients using DoE.

Even so, Kemter believes that there remains a significant need for improved methods for the folding of proteins and the prevention of unfolding during production and storage and that can be generally applied to the majority of biopharmaceu-ticals. “Such technology would eliminate the need for so many individual investigations,” she notes.

Evaluation of stabilityTypical studies for determination of the stability of biophar-maceutical formulations include determination of the level of aggregates and insoluble particles of various sizes; detection of increased immunogenicity; determination of the level of amino acid oxidation, in particular, methionine and tryptophan; and evaluation of the fragmentation of polypeptide chains, all for samples subjected to both stressed and unstressed conditions, according to Maggio.

Most of the tests are accelerated aging studies, such as heat-ing at elevated temperatures for 1 to 4 weeks, shaking at high temperature with an air/liquid interface for several days, and freezing and thawing for multiple cycles. Temperature ramping experiments are also common for determination of the melting and aggregation temperatures under different conditions, but Bukrinski has on several occasions observed that results from such studies do not always correlate well with shelf-life stability.

A whole host of advanced techniques are employed to an-alyze the results obtained in the above tests. Some examples include polyacrylamide-gel electrophoresis (PAGE), parti-cle-size analysis using micro-flow imaging (MFI), dynamic and static light scattering, size-exclusion chromatography (SEC), ion-exchange chromatography (IEX), and reversed-phase (RP) high-pressure liquid chromatography (HPLC), liquid chromatography/mass spectrometry (LC/MS), pep-tide and glycan mapping, circular dichroism (CD), Fourier transform infrared spectroscopy, and other advanced MS methods.

A newer method that, according to Bukrinski, is increasingly used as an orthogonal method for the validation of SEC results is field flow fractionation (FFF). Instead of passing through a packed column, the fluid passes through a narrow channel and a force applied perpendicular to the channel causes separation of the particles based on their different mobilities.

Not all methods will work equally well for each biologic API. Therefore, the first step in any study is to determine which methods provide accurate results for the protein in question.

“It is very important to first determine the appropriate meth-ods for stability evaluation, followed by optimization of the pH and ionic strength for the formulation. It is only at that point that screening for appropriate excipients can be effective,” Bukrinski says.

Because so many stability tests must be performed for the development of an effective biopharmaceutical formulation, he also notes that the ability to perform rapid, high-throughput screening is imperative. “We perform as many analytical meth-ods as we can using robotics systems that can evaluate small quantities of samples in microplates. Often times, however, tight timelines will dictate a less optimal formulation devel-opment process,” notes Bukrinski.

“Two of the most efficient screening tools include biophysical characterization and high-throughput degradation analysis under stressed conditions,” adds Kang. “Biophysical tools, such as differential scanning calorimetry (DSC) and CD, directly measure the effect of excipients on the higher order structure of



the proteins, which is often a good indicator of protein stability. High-throughput methods such as plate-based dynamic light scattering (DLS) can screen a large amount of excipients in a short period time.”

Compared to small molecules, however, protein degradation involves multiple pathways, and a simple Arrhenius equation is generally not applicable, according to Kang. It is, therefore, dif-ficult to predict long-term real-time stability through stressed and accelerated stability studies. “New mathematical models are currently being developed to establish a correlation between protein stability at different storage temperatures, and if suc-cessful, will greatly enhance formulation development and shelf-life prediction for protein drugs,” he states.

Automated stability determination using chemical denaturationBecause temperature has such a significant influence on pro-tein aggregation, it is important to obtain accurate thermody-namic data on proteins. However, temperature denaturation is often irreversible and accompanied by aggregation and precipi-tation and, therefore, not suitable for thermodynamic analysis.

On the other hand, isothermal chemical denaturation is gen-erally a reversible process for most biologic drugs and has been proven to provide reliable thermodynamic data of use for the evaluation of protein stability. AVIA Biosystems has developed an automated protein denaturation system for protein stability analysis that uses intrinsic (or extrinsic) fluorescence to moni-tor the protein conformational changes associated with protein unfolding (denaturation). Using the instrument, the identifica-

tion of solvent conditions that maximize the structural stabil-ity of biologics can be completely automated, according to the company. Proteins and other compounds can also be ranked by their stability and propensity to aggregate.

Few approved excipients creates challengesAlthough the large number of stability tests and analyses required for the development of stable protein formulation present difficulties for biopharmaceutical companies, one of the biggest challenges for formulators is the limited number of known and approved excipients for protein stabilization, according to Kemter. In addition, many biopharmaceutical manufacturers will only use excipients that are approved in-ternally, and generally only consider other excipients that are approved but have not been previously used by the company if no solution is possible with the existing choices, according to Bukrinski. “New excipients—whether just new to the company or compounds that have not been used as excipients before—will only be used if they have significantly high value and can compensate for the extended approval process. There must be a justification for the additional cost and risk,” he says.

Kang agrees that the biggest challenge in developing new stabilizing excipients for biologics is the additional safety data required to introduce a novel excipient to a pharmaceu-tical product, particularly a parenteral formulation, which is the form in which most protein drugs are formulated. “The resources and time associated with this requirement makes formulation scientists hesitant to try new excipients,” he ob-serves. PT

ConclusionThe business strategy of both pharmaceutical and biophar-maceutical companies can benefit from the implementation of continuous manufacturing, because it enables more respon-sive and efficient supply-chain management. Lower produc-tion costs motivate smaller companies to start manufacturing earlier in their lifecycle, thus reducing their dependency on CMOs. Additionally, smaller plants permit establishing multi-purpose facilities, and a standard production platform enables producing different products in the same unit, increasing op-erational flexibility, and allowing a better control of costs (6).

The coming years will certainly be exciting in the pharma-ceutical industry, especially for those involved in manufacturing sciences and technologies, as the transformation from batch to continuous manufacturing takes root and allows faster and safer supply of new and more affordable drug products to patients.

References 1. FDA, Guidance for Industry: PAT—a Framework for Innovative

Pharmaceutical Development, Manufacturing, and Quality As-surance (Rockville, MD, Sept. 2004).

Process Analytical Technology — contin. from page 34

2. C. Schaefer et al., J. Pharm. Biomed. Anal. 83, 194-201 (2013).

3. S. Kozlowski et al., “The CMC Strategy Forums, Celebrating a

Decade of Collaborative Technical and Regulatory Interaction,

Part 1: QbD and Risk Management,” BioProcess International

Special Report (2015).

4. FDA, “FDA Perspective on Continuous Manufacturing,” www.

fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedi-

calProductsandTobacco/CDER/UCM341197.pdf, accessed 21

July, 2015.

5. EMA, Guideline on Process Validation for Finished Products—

Information and Data to Be Provided in Regulatory Submissions

(London, Feb. 2014).

6. K.B. Konstantinov and C.L. Cooney, J. Pharm. Sci. online,

DOI:10.1002/jps.24268, 21 Nov. 2014.

7. Z. Chen, D. Lovett, and J. Morris, J. Process Control 21 (10)

1467-1482 (2011).

8. R. Chen et al., Pharma. Outsourcing 12 (4) 1-7 (2011).

9. M. Roberto et al., Processes 2 (1) 24-33 (2013).

10. M.J. Pedersen et al., Org. Process Res. Dev. 17 (9) 1142-1148

(2013).

11. A.E. Cervera-Padrell et al., Org. Process Res. Dev. 16 (5) 901-914

(2012). PT


Earlier this year CPhI Pharma Insights reports revealed

that 70 per cent of the pharmaceutical industry is actively

investing in manufacturing techniques and technologies,

and 41 per cent is outsourcing more of their manufacturing

to other organizations. The market continues to become

increasingly complex and segmented as these changes

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

to reduce costs while improving product quality and safety

standards in order to remain competitive. Considering this,

efficiency in moving forward and the development of trusted

partnerships have become increasingly essential in achieving

success.

CPhI Worldwide, together with co-located events ICSE,

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

to specific sectors of the pharmaceutical manufacturing

market, covering the entire supply chain. The expanded

exhibition makes the event the most effective and efficient

place to make valuable business connections.

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

from more than 140 countries will converge at CPhI

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

will take place at the Paris Nord Villepinte in France from

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

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

pharmaceutical industry.

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

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

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

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

achieving business goals.

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

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

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

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

at www.cphi.com after the event.

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

complete with hors d’oeuvres, cocktails and entertainment. This event will take place in the luxurious

InterContinental Paris Le Grand, overlooking the world famous Paris Opera and providing an

exclusive opportunity to network with top industry professionals.

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

Mix with the world of pharma products, people & solutions

CPhI Worldwide Event Preview 2015— World-Class Content

CPhI Worldwide returns to Madrid in 2015,

where the world’s most prominent pharma

executives will gather to learn, exhibit, and

network with the leading decision makers and

innovators across this industry. Following the

success of the 25th Anniversary in 2014, this

year promises to be another record-breaking

show with an expanded conference platform,

increased content sharing, and greater

networking opportunities across the event’s

huge range of diverse platforms.

From 13–15 October, the entire pharma

community will return to IFEMA (Feria de

Madrid, Spain) for three days of networking,

informative conferencing, and meetings that

will help shape the industry over the next year.

In total, over 36,000 attendees are expected at

IFEMA (Feria de Madrid, Spain) to engage with

some 2500 exhibitors from over 150 countries.

But CPhI Worldwide is much more than a

meeting platform, it provides an unrivalled

melting pot of ideas and innovations, all

designed to maximize business benefit,

networking, and sharing. More than 20

dedicated zones covering ingredients, APIs,

excipients, finished dosage, contract services, packaging, biopharm, machinery, and many

more will be present at CPhI Worldwide, delivering world-class, industry-wide content.

Running alongside the pharmaceutical ingredients halls are three other sister brands, which help

visitors to quickly identify the right halls for their needs. ICSE is an outsourcing focussed area

designed to connect the pharmaceutical community with contract providers from clinical trials,

CROs, logistics providers, data management firms, and CMOs. InnoPack brings together buyers

and specifiers from the packaging and pharmaceutical industries. Finally, P-MEC Europe features

exhibitors from traditional large-scale capital equipment to companies focussed on instrumental

analysis, measuring and testing technologies, materials testing, quality control, and laboratory.

CPhI Worldwide 2015 officially begins with the CPhI Pre-Connect Congress (12th October), where

senior executives and influential speakers gather to discuss the latest innovations, trends, and

market developments from across the industry in a series of market-led educational modules.

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Complete Supply Chain Sourcing in at One Event

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

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

packaging, and technology & equipment.

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

excipients, fine chemicals & intermediates, and more, co-located show ICSE is a dedicated

outsourcing event designed to connect the pharmaceutical community with contract service

providers including specialist CRO & (pre)clinical trial companies, logistics & cold chain

providers, and bioservices companies. P-MEC delivers innovative pharmaceutical machinery,

equipment and technology to a worldwide forum of decision makers and incorporates

LABWorld for laboratory, analytical and biotechnology instrumentation. The final co-located

event is InnoPack which offers the pharma community innovative and diverse packaging

solutions to satisfy the changing way we package and deliver medication.

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

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

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

to source suppliers for their latest needs.

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

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

business for the short and long term. CPhI is the networking event for any business in the

pharmaceutical supply industry.

Conferences and seminars

In addition to attending the exhibition, CPhI worldwide

offers conferences and seminars, introducing attendees

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

Connect Congress and new InnoPack Conference both

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

pre-exhibition events offer the exclusive opportunity to

join senior executives and influential speakers from across

the pharma industry in networking and strengthening

your knowledge base on a variety of key topics such as

packaging innovation, strategic partnerships, and drug

delivery systems.




It is organised along two main tracks, with sessions in track one including ‘Formulation & Drug

Delivery’; ‘Biologics, Biosimilars & Biobetters’; and ‘API Sourcing & Manufacture’. Track two

features modules across ‘Generics’; ‘Pharmaceutical Packaging’; and ‘Mergers and Acquisitions’.

Additionally, the main exhibition also includes key content features including the Innovation

Gallery, Exhibitor Showcases, and Innovation Tours—details of which can be found below.

Another major event feature, new for 2015, is the CPhI Pharma Forum—a dedicated content

village—that will provide a central hub to examine thought leadership from media partners and

the CPhI Pharma Insights Reports. The Pharma Forum will also be the location for the exhibitor

and visitor party, and will include exhibitor Innovation Galleries, the CPhI Pharma Awards, and the

Pharma Insight Innovation Briefings—offering impartial, in-depth sessions on regional updates and

specialist topics covering regulation, QC, traceability, sustainability, and health to name but a few.

Again returning in 2015 are the revamped CPhI Pharma Awards (with five new categories) and

free sessions in Speaker’s Corner, which provides exhibitors a forum to deliver first-hand

presentations to senior pharma attendees from across the globe. To help attendees tailor their

time at the show, CPhI Worldwide Global Meetings is a custom matchmaking programme that

enables attendees to find and connect with specific companies tailored to their business needs.

Summary Highlights for CPhI Worldwide 2015

CPhI Pharma Awards:Now in their 12th consecutive year, the CPhI

Pharma Awards will honour companies and

individuals driving the pharma industry forward

through new innovations, approaches, and

strategies. The addition of five new categories in

2015 allows for a broader range of recognition to

all the great advances coming out of the Pharma

industry. The CPhI Pharma Awards jury panel

will review all the entries before announcing the

winners during the show.

Global Angels:CPhI has partnered with Global Angels—a charity that connects with innovative projects to

deliver tangible, life saving results in developing countries. CPhI has already worked with a

charity in Kenya and strongly encourages the pharmaceutical community to get involved with

this amazing cause. No matter how big or small the donation, every penny received goes directly

to Global Angels and will make a substantial difference, so please do have a look at the range of

charitable packages we are offering.

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The Pre-Connect Congress offers eight modules across

both commercial and technical tracks, including three

new modules on Excipients, Biopharmaceuticals,

and Trends in Oncology. Whilst the new InnoPack

Conference focuses on design trends, innovation,

security, and compliance in pharma packaging and

labelling. Thought leaders will discuss topics including

global serialisation & traceability requirements and their

effects on supply chain security, as well as innovative

packaging designs that assist with patient usability and

adherence.

Taking place throughout the 3-day exhibition, the

new CPhI Pharma Insight Briefings offer in-depth

sessions on specialist topics, such as Drug Discovery

Partnerships and Cool Chain & Temperature Logistics,

and regional updates on specific markets including

Brazil, Turkey, India, and the US. Designed for

individuals and suppliers who would like to understand

the challenges and opportunities in these niche areas,

these briefings provide valuable insights for improving

business methods or developing market entry

strategies.

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

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

to hear first-hand from exhibitors across the globe about the latest trends within the pharma

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

CPhI Global Meetings Programme- facilitating high-

quality business meetings

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

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

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

attendees with direct access to individual contacts- targeted to synergise their respective

businesses needs.

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

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

geographical location. Additionally, this service allows for pre-arranged one-to-one meetings,


Exhibitor Showcases:The Exhibitor Showcases are an invaluable

opportunity for exhibitors to educate the industry

across the expertise and services. Showcases

last approximately 25 minutes and provide an

opportunity for companies to present forward

thinking perspectives on their key products,

innovations, services, and more to visitors and

the press. It also provides an open platform for

speakers to directly interact with attendees and

increase their networking contacts.

Innovation Gallery:After its successful launch in 2014, the

Innovation Gallery has returned to CPhI

Worldwide for a second year. This unique

opportunity enables companies to showcase

their latest innovations on an international

platform. This forum presents the latest

innovations and newest products on the market

to top pharma executives in attendance.

Innovation Tours:Across each of the three days at CPhI, top

industry experts will guide attendees through free-of-charge Innovation Tours. These hour-

long bespoke tours give a brief overview of industry trends and recent innovations within the

pharmaceutical industry. Starting from the Innovation Gallery, the tours travel throughout CPhI,

ICSE, and InnoPack providing perspective across the entire pharmaceutical supply chain.

Mobile App:CPhI Worldwide will once again feature its hugely successful mobile app, providing exhibitors

and attendees with a timetable of the day’s activities, a list of exhibitors attending and their

location and many more. In addition, this advanced service will allow for your company to

directly promote its main messages, products, and services.

Pharma Forum:The Pharma Forum is a dedicated content village, which will be the central hub for thought

leadership from industry players, media partners, and the CPhI Pharma Insights Briefings. Across

the expansive space, event attendees will have free access to in-depth, industry-focus materials

and insights. This new addition to CPhI Worldwide 2015 will also include the Exhibitors’ Innovation

Galleries, Global Angels, and CPhI TV.

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ensuring a full diary that suits your schedule.

Women’s Networking Breakfast

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

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

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

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

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

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

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

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

women.

CPhI Pharma Awards- celebrating tomorrow’s

innovations today

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

distinguished thought leaders within the industry. In addition

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

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

debuts this year. Supported by Pharmaceutical Outsourcing

magazine, this award honours partnering methods, use of

technology, unexpected outcomes and unique partnering practices.

Open to the entire pharma industry, the awards celebrate the most

innovative and dynamic areas across the global pharma community. Shortlisted company entries

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

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

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

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

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

Bienvenue à Paris

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

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

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

theatres and 1,800 historical monuments, attendees are certain to find The City of Lights enchanting.


Pharma Insight Briefings:Taking place over the course of the three show

days in our new Pharma Forum, the Pharma

Insight Briefings are a series of 45-minute

seminars on specialist topics and regional

updates, allowing you to build your schedule

around high value content that’s relevant to

you. All seminars are free to attend.

Tweet Chat:Returning for its second year, the second

day of CPhI Worldwide will host an industry-

wide tweet chat broadcasting a conversation

between the CPhI Expert Panellists and the

attendees. With the release of the annual

report, attendees will be able to analyse the contributions of the panellists and contribute to a

live discussion displayed throughout the screens at the show.

VIP & Exhibitor Party:On the first day, the new addition of the Pharma Forum will house an exclusive VIP & Exhibitor

Party. At this event, the industry’s leading figures, thought leaders, innovators, and exhibitors will

meet together to network and discuss the latest developments across the industry. Additionally,

the party will host the CPhI Pharma Awards Ceremony, with the winners announced.

Women’s Networking Breakfast:Uniting female executives from the global

pharmaceutical network, this event will

celebrate female leadership and encourage

empowerment within the industry. Hear from

senior level female executives on how to

advance through the pharma industry and

widen networks.

CPhI Worldwide holds a unique position in

hosting the largest number of traditional

pharmaceutical buyers, alongside an array of

top pharmaceutical companies.

Register now for CPhI Worldwide 2015 at:

www.cphi.com/europe/visit

Or book exhibition space at: www.cphi.com/europe/exhibit

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Process Controls

To maintain a state of control and comply with regulatory authorities, many pharmaceutical, bio-tech, and medical-device companies have adopted continued process verification (CPV) initiatives

for manufacturing processes (1). By adopting a proactive approach to monitoring, life-science manufacturing com-panies can identify changes in their manufacturing process-ing prior to a quality event such as a batch failure. Control charts are the predominant monitoring tool used to monitor parameter data across batches with control limits defined for the normal manufacturing process. Control chart run rules generate signals when non-random processes occur and flag potential process issues. The maximum partial pressure of CO2, for example, may have an undesired upward trend due to a machine calibration issue, and a signal would prompt a process engineer to investigate before drug potency was affected. Valid signals can reduce costs, improve process understanding, and enhance operational reliability (2).

Despite the well-defined benefits of run rules, many life-science companies misuse them due to lack of guidelines and/or statistical expertise regarding statistical process control, which may lead to incorrect signals (i.e., the in-ability to differentiate between signals and random noise) and, ultimately, failure of the monitoring system. Essentially, the goal when using run rules is to ensure that valid signals are generated, correct signals are not overlooked, and false signals are not created.

This article discusses the life-science manufacturing in-dustry’s current use of monitoring techniques and provides guidance on how to improve the value obtained from moni-toring programs and run-rule signals.

Current industry practicesLife-science manufacturing companies with mature CPV initiatives apply run rules to critical/key process parameters and quality attributes for trending purposes (3). Despite small variation among companies, run rules are typically applied to parameters based on risk assessments (e.g., pro-cess failure mode and effects analysis, estimated process ca-pabilities, etc.). Two common issues life-science companies often face in the early stages of adopting a CPV initiative are over-alerting (e.g., generating false, non-value-added signals) or under-alerting (e.g., overlooking valid signals).

Utilizing Run Rules for Effective Monitoring in ManufacturingAaron Spence

To enable efficient monitoring

systems, life-science companies need

to effectively apply run rules.

Aaron Spence is manager of analytic consulting,

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Over-alerting is often the result of monitoring every pa-rameter with every run rule. Conversely, under-alerting can occur when companies only evaluate if critical release parameters fall within specification limits and adequate monitoring is not performed. The objective of run rules in a mature CPV program is to generate valid signals that pro-vide useful information for engineers and process experts.

One of the principal benefits companies receive from using run rules is the enablement of a monitoring-by-excep-tion solution. Instead of manually reviewing control charts on a regular basis, selected software programs can automati-cally alert users to run-rule signals (i.e., when a run rule is violated). Then, resources may be allocated appropriately to evaluate parameters with signal violations. A monitoring-by-exception solution that can scale up to multiple sites and products is essential to a CPV model.

Regardless of their specific practices, companies should clearly document the proper use of run rules in their moni-toring procedures to avoid significant regulatory risk, and responsible individuals should be assigned to create and maintain these crucial documents. Implementation will also likely require ongoing evaluations and support from the company.

Getting the right signalsGenerating valid run-rule signals provides a variety of ben-efits, primarily through cost reductions and deployment of an early-warning system to prevent product quality issues. Obtaining valid signals to drive these business benefits, however, is dependent on five mathematical assumptions: parameters must be baselined from an in-control process, baselined on an acceptable sample size, detailed regarding data precision, normally distributed, and independent.

Receiving correct value-added signals requires the use of historical data to establish baseline control limits for ongoing monitoring. Many companies overlook the criticality of base-

lining parameters, which results in inflated control limits and missed valid signals. To ensure the process is in control, special cause variation needs to be identified and removed during the baseline process. Special cause variation results from variability caused by events outside of the normal man-ufacturing process, such as operator error, power failure, etc. Eliminating special cause variation provides limits that more accurately reflect nominal manufacturing processes. Base-lining should occur after a known process change occurs (e.g., equipment change, supplier change, etc.) or on a regu-lar basis (e.g., annually or semi-annually) depending on the availability of staff, the number of batches produced in a year, and other parameters. When one is baselining parameters, at least 25–30 batches should be available to generate targets that accurately reflect the manufacturing process. The moni-toring system should allow engineers to differentiate valid signals from random process noise, as well.

To produce valid signals that generate value, an organiza-tion needs to measure and record process variability accu-rately with sufficient data precision. This is especially im-portant when the decimal precision for parameters results in a small number of unique values—an issue that often plagues the life-sciences manufacturing industry. For ex-ample, if pH is reported at a single decimal precision and values are always 6.7, 6.8, or 6.9, run rules cannot be appro-priately applied and false signals may be generated or valid signals may be overlooked.

For an organization to effectively use control charts and run rules, parameters need to follow a normal distribution. The assumption of a normal distribution relies on the fact that only 1 out of 370 observations will fall beyond control limits just by chance (4). Abnormal data results in an inflated likelihood that data will fall beyond control limits (e.g., a one out of 40 chance) (5). Non-normal distributions are highly prevalent in life-science manufacturing processes, and they are often expected when processes have lower or upper

Table I: Monitoring assumptions checklist.

AssumptionAssessed?

Typical assessments Suggested correction(s)

In-control process Process knowledge, outlier

identificationremove special cause for baseline

Sample size ≥ 25 or 30 batches availableObtain additional batches, limit run rules,

k-factor corrections (6)

data precision≥ 5 different parameter values

(excluding outliers)

Improve data collection procedures, limit run

rules, revise data agreements with contract

manufacturing organizations

normalityShapiro-Wilk, Anderson darling,

Q-Q plot

transformations, non-parametric limits,

rational subgrouping

Independence

dubin-Watson, ljung Box Q,

autocorrelation function/partial

autocorrelation function (ACF/

PACF) plots

long-term standard deviation for limits,

regression methods (e.g., autoregressive

integrated moving average [ArImA],

generalized least squares [GlS]), rational

subgrouping

ES664677_PTsupp0915_045.pgs 08.28.2015 03:48 ADV blackmagenta


bounds (e.g., yield, hold time, etc.). Not correcting for this as-sumption violation, however, may lead to false signals, which have the effect of devaluing the significance of a violated control limit. Over-alerting by generating false signals can result in employees simply ignoring the monitoring system.

Non-independent parameters have narrower control lim-its and are more likely to generate false signals, resulting in wasted resources and an inefficient monitoring system. The assumption of independence assumes that previous batches do not affect subsequent batches, and non-independence often indicates there is a pattern in the data. It is crucial that CPV and monitoring plans provide directions on how to test as-sumptions and correct for assumption violations so that mon-itoring-by-exception solutions generate appropriate signals.

To achieve the most value from a monitoring system and generate valid signals, one needs to continuously evaluate and correct the assumptions underlying a system. Without these corrections, false signals will waste company resources and valid signals may be overlooked. Table I provides assessments and suggested actions for the aforementioned assumptions.

Proper response to signalsLife-science companies with mature CPV models derive value from run-rule signals by implementing appropriate follow-up practices. When a monitoring system is configured correctly, incorporating all the steps defined in Table I, signals should

be valid and indicate that the process has changed in some way. Thus, when a run-rule violation occurs, it is impor-tant to appropriately follow up on the signal. Conversely, life-science manufacturing companies with immature CPV initiatives spend a lot of non-value added time chasing false signals, or they revert to the other extreme of not following up on signals at all. Limited resources and statistical exper-tise can make following up on violations a struggle for many life-science manufacturers.

It is crucial to understand that run-rule signals should be treated differently than out-of-specification quality events. Quality events require immediate corrective and preventive actions and investigations, whereas not every run-rule signal should be investigated. If a parameter has been relatively stable with infrequent and inessential signals for example, it is ac-ceptable to take no immediate action. However, it is important to track parameter signals over time so that multiple violations or problematic patterns are not overlooked. If a signal does require follow-up, it is crucial to identify the type of violation and follow-up with appropriate investigative techniques to detect a root cause. Although a multitude of process changes can occur, run rules are designed to detect some of the more common signals: single events, shifts, trends, oscillations, in-creasing/decreasing variability, and cycles (see Figure 1).

Identifying the type of signal and appropriate follow-up techniques will bring significant value to a business by

Process Controls

Table II: Common run rules used in the manufacturing industry. Control limits = 3 standard deviations (SD) from mean; warning limits = 2 SD from mean; inner limits = 1 SD from mean.

Signal Signal type

Western

electric

rule

Nelson rule Follow-up

1 point outside of

control limitsSingle event rule 1 rule 1

examine other issues or events (e.g., operator error,

machine calibration) or any other abnormal observations

from other parameters within the batch.

2 out of 3 points outside

of warning limits

Shift

rule 2 rule 5Investigate process or supplier changes; utilize group

difference tests (e.g., t-tests, analysis of variance models

[AnOVAs]) for categorical process variables such as

machines, cleanrooms, etc.; conduct correlations with

parameter that displays shift.

4 out of 5 points outside

of inner limitsrule 3 rule 6

9 points on the same

side of the central linerule 4 rule 2

6 points in a row

increasing/decreasing

decreasing

variabilityn/A rule 3

Investigate correlations with the parameter that displays the

trend; determine if machine maintenance or calibrations are

required.

14 points in a row

alternating in direction

(increasing/decreasing)

Increasing

variabilityn/A rule 4

Investigate correlations with parameter that displays

oscillation; conduct group difference tests if multiple

populations are represented.

15 points in a row all

within the inner limits

In-control

process n/A rule 7

Investigate correlations with parameter that displays

decreased variability; examine process improvements.

8 points in a row, none

of which are within the

inner limits

In-control

process n/A rule 8

Investigate seasonality effects or non-random cycles (e.g.,

changing suppliers, using different machines, etc.); conduct

group difference tests; conduct correlations with parameter

that displays cycle.

ES663614_PTsupp0915_046.pgs 08.27.2015 05:23 ADV blackmagenta


reducing resource and time requirements. Each signal in-dicates that a different process change/event occurred, and investigations should be tailored based on the signal (see Table II). Once a signal has been detected and a decision has been made to pursue it, typical follow-up steps include:• Confirm the value is correct andnot a data entry

error.

• Determine if there is a readily apparent root cause

orifotherissuesoccurredintheprocess.

• Discussthesignalwithsubjectmatterexperts.

• Examine the lot traceabilityand reviewparameters

relatedtotheparameterofinterest.

• Escalatetoothergroupsforfurtherstatistical inves-

tigation.

While run rules provide a useful tool for detecting some non-random processes, not all patterns can always be flagged. Additionally, signals can be overlooked for param-eters that are being trended with few run rules. Thus, it is vital to review all parameters regularly (e.g., annually) to en-sure that trends are not missed. Individuals responsible for configuring, maintaining, and reporting on the monitoring system should be clearly identified in company documents. Properly responding to signals will result in more efficient use of resources and time. Additionally, investigating signals can enhance process understanding, which should improve process monitoring and operational reliability.

Conclusion

Proper CPV monitoring is a crucial business value invest-ment for a company. A monitoring-by-exception system that generates valid signals can reduce resource require-ments, proactively identify issues prior to a quality event, and create a regulatory compliant environment. Today’s life-science industry can improve productivity and com-pliance by developing more mature CPV initiatives and adopting practices to ensure that they get the right signals. Furthermore, performing appropriate follow-up on valid signals is vital to an effective and continuously improving monitoring solution.

References 1. FDA, Guidance for Industry: Process Validation: General Prin-

ciples and Practices (Rockville, MD, January 2011). 2. BioPhorum Operations Group, Continued Process Verification: An

Industry Position Paper with Example Plan, BPOG–Biophorum Operations Group (2014).

3. J. M. Juran, Juran on Quality by Design: The New Steps for Plan-ning Quality into Goods and Services (Simon and Schuster, New York, NY, 1992).

4. D. Montgomery, Introduction to Statistical Quality Control (John Wiley, Hoboken, NJ, 5th ed., 2005).

5. S. Steiner, B. Abraham, and J. MacKay, Understanding Process Capability Indices (University of Waterloo, Ontario, 1997).

6. R.J. Seely, L. Munyakazi, and J. Haury, BioPharm Int. 14 (10), pp. 28–34 (2001). PT

Figure 1: Examples of signals denoting process events/changes.

Single event

Nelson rule 1

Cyclical pattern

Nelson rule 2,5,6,8

Oscillation

Nelson rule 4

Increasing variability

Nelson rule 8

Shift

Nelson rule 2,5,6

Trend

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Cleaning Validation

Cleaning of pharmaceutical equipment is essential to re-duce the risk of product contamination and, as stated in relevant guidelines and as recognized by the pharma-ceutical sector, this can be achieved only if the cleaning

procedure has been validated. International Conference on Har-monization (ICH) guidance ICH Q9 (1) encourages that a quality risk management approach be considered and that, based on the level of risk, cleaning processes may be subject to different levels of validation or verification. This article covers cleaning validation of equipment dedicated to the production of a single API; equipment used for manufacturing a class of products (e.g., penicillins) should be considered as shared equipment and is not addressed here.

When one thinks of cleaning validation, the first thing that comes to mind is “prevention of cross-contamination”, which ob-viously applies only when equipment is used for manufacturing more than one product. So why is cleaning validation talked about with regard to dedicated equipment? Section 12.70 of the guide-line ICH Q7 states that, “Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality…” (2). Table I

highlights the differences between the approach to clean shared and dedicated equipment. As indicated in Table I, most points apply to both cases, meaning that great care needs to be given also when planning cleaning validation activities of dedicated equipment.

For dedicated plants/equipment, there is no risk of cross-con-tamination among different active substances; nevertheless, a wide range of possible contaminants must be evaluated on a case-by-case basis (3), taking into consideration the type of process (i.e., chemical synthesis, extraction from natural sources, fermenta-tion, physical steps, etc.), the final product, and the materials used during the manufacturing process (i.e., starting and raw materi-als, solvents, and reagents). As for cleaning validation of shared manufacturing plants, even for dedicated plants/equipment, it is necessary to identify all possible sources of contamination. Some key points to be considered are summarized in Table II.

Only cleaning procedures that have been validated ensure that any undesirable residues have been effectively removed below a level that has been demonstrated to be acceptable and that does not pose a risk to patients. Cleaning validation is time and resources consuming; however, some companies might prefer not to use shared facilities and, instead, dedicate an entire building, manu-

Cleaning of Dedicated Equipment: Why Validation is NeededCristina Baccarelli, Paola Bernard, Teresa Cortellino,

Oscar Cruciani, Rita Pacello, Chiara Parisi, Luisa Stoppa, and Isabella Marta

This article discusses cleaning validation of

equipment dedicated to the production of

a single API.

Cristina Baccarelli, Paola Bernard, Teresa Cortellino,

Oscar Cruciani, Rita Pacello, Chiara Parisi, Luisa

Stoppa, and Isabella Marta are all inspectors at the

Italian Medicines Agency.

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facturing line, or piece of equipment for the manufacture of a single product. If they use disposable equipment, such as single-use bioreactors, compatibility of the disposable equipment with the pro-cess should be assessed.

Companies manufacturing only one product use dedicated equipment by de-fault. In addition, companies must use a dedicated facility, line, or equipment, if:• The calculated limits of undesirable

residues are too low and therefore the potential residues would not be detectable with the available analyti-cal methods (2).

• The acceptance criteria are too low and cannot be achieved (i.e., for some high potency active sub-stances).

• The data to calculate safe threshold levels for toxic or sensitizing sub-stances are not yet available or not sufficient (4).

Planning for cleaning validationVisual examination is not acceptable as the only test to check residue during initial validation studies. Even if some literature data report proposed visual limits, this test does not meet ICH Q7 expectations, as it may depend on too many variables that are difficult to standardize (5) and vali-date. After the cleaning validation has been performed, visual examination could be used to detect “gross contamination” of the equipment immediately before use (2).

As for non-dedicated facilities, equipment should be of ap-propriate design and adequate size and suitably located for its intended use, cleaning, and sanitation (2). Design and technical aspects of equipment are covered by good engineering practices (6) and some technical references; practical guidelines for equip-ment design are also provided by food industry regulation (7). Equipment can be considered as “cleanable” if it is constructed using adequate materials such as stainless steel or polymeric materials that are compatible with the process to be carried out. Finished surfaces should be smooth and properly polished, and equipment should be appropriately designed and assembled in a way that facilitates cleaning and prevents microbial growth (i.e., no dead legs, not too many horizontal pipelines or exces-sive instrumentation, and ancillary components such as shafts, bearings, and agitators should be easy to disassemble). Finally, the equipment should be easy to inspect.

Sampling method selection (swabbing and/or rinsing or other means [8]) is essentially related to type and design of the equipment, nature of the residues, residues acceptance limits, and the analytical methods used for residues quantification; the approach to sampling is the same for dedicated and shared facilities.

Cleaning validation of dedicated production equipmentThere are three main aspects to consider when performing clean-ing validation of dedicated production equipment: campaign length, clean hold time (CHT), and dirty hold time (DHT).

If cleaning of equipment dedicated to one API production is not carried out after each batch but on a campaign basis, it is necessary to validate the maximum campaign length (in terms of duration, number of batches, and batch size) by demonstrating that manufacturing consecutive batches with no cleaning between them does not lead to a build-up of undesirable residues that cannot be properly removed at the end of the campaign with the selected cleaning procedure.

Recent inspection results show that lack of cleaning validation related to the maximum campaign length is still an issue that is worth clarifying. During an inspection of a dedicated manufac-turing facility, conducted by the Italian Medicines Agency, Agen-zia Italiana del Farmaco AIFA in 2015, it was observed that no validation studies were performed to determine an appropriate campaign length (i.e., duration and/or number of batches that can be manufactured before having to clean the equipment). Moreover, the company failed to put in place intra-campaign controls aimed at verifying that during a production campaign the level of poten-tial degradation residues in the equipment was maintained to a minimum and below pre-established specifications.

CHT is defined as the time between the completion of cleaning and the beginning of the next manufacturing operation. Clean equipment will not remain clean indefinitely depending on the length of the storage period and the condition of the storage en-vironment. Cleaning validation studies, therefore, should dem-onstrate that storage conditions do not contribute to growth

Table I: Differences between cleaning of dedicated and shared equipment.

Points to consider Dedicated Shared

cleaning validation

equipment design

Identification of sampling points

selection and validation of sampling methods

cross-contamination

Identification of potential contaminants

Acceptance criteria (for chemical and

microbiological residues, as applicable)

cleaning procedure

clean/dirty hold time

(if applicable)

(if applicable)

Validation of analytical method

Validation protocol/report

campaign length validation

(if campaign

production

approach is applied

by the company)

cleaning verification



of microorganisms. Evaluations need to be performed on a case-by-case basis; a CHT might not need to be defined if, for example, the equipment is always cleaned just prior to use.

The CHT also must be determined for dedicated equip-ment/facility. During an inspection conducted by FDA, it was observed that tanks used for the manufacture of a single API, carried out a few months before, were not cleaned since the last campaign. The interior of the equipment had accumu-lated approximately half an inch of a white substance and contained a shallow pool of liquid at the bottom.

DHT is defined as the time between the end of manufactur-ing and the beginning of cleaning procedure. A residue easy to remove, if cleaned immediately after use of equipment, could maybe be difficult to remove when applying the same cleaning procedure if the cleaning was not performed immediately after use. This could occur, for example, for the residues in a crys-tallization tank; the “wet” residues might be easy to remove while the “dried” residues could require a different cleaning procedure. As for CHT, evaluations need to be performed on a case-by-case basis. A DHT might not need to be defined if, for example, the equipment is always cleaned right after use.

For the reasons mentioned previously, it can be concluded that it is crucial to conduct cleaning validation for dedicated equipment. The quality of an API is intrinsically related to the cleaning procedure employed; therefore, this aspect needs to be adequately addressed by the manufacturers and deeply reviewed by regulatory authorities during GMP inspections.

References 1. ICH, Q9 Quality Risk Management (ICH, Nov. 9, 2005). 2. ICH, Q7 Good Manufacturing Practice Guide For Active Phar-

maceutical Ingredients (ICH, Nov. 10, 2000). 3. A. Walsh, Pharmaceutical Engineering (November/December 2011). 4. EMA/CHMP/ CVMP/ SWP/169430/2012, “Guideline on setting

health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”

5. PDA, Technical Report No. 29 (Revised 2012), Points to Con-sider for Cleaning Validation (PDA, 2012).

6. ISPE, Good Practice Guide: Good Engineering Practice (ISPE, 2008) 7. BS EN 1672-2:2005 Food Processing machinery–Basic concepts. 8. EDQM, EudraLex, Volume 4, EU Guidelines for Good Manufac-

turing Practice for Medicinal Products for Human and Veteri-nary Use, “Annex 15: Qualification and Validation” (in force from October 1, 2015).

9. ICH, Q3C (R5) Impurities: Guideline for Residual Solvents (ICH, Feb. 4, 2011).

10. M. C. Killilea, “Cleaning Validation: Viracept, 2007” IVT Net-

work (Dec 3, 2012). PT

Editors’ Note: This article is based on a topic addressed during the 6th

Pharmaceutical Inspection Co-operation Scheme (PIC/S) Expert Circle

on APIs meeting, held in Rome in May 2014 and hosted by the Italian

Medicines Agency (AIFA). PIC/S is a co-operative arrangement between

46 regulatory authorities worldwide active in the field of GMP for me-

dicinal products for human or veterinary use. It aims at harmonizing

inspection procedures globally by developing common GMP standards,

training inspectors, and facilitating exchange of information and mutual

confidence between regulators.

Cleaning Validation

Table II: Possible sources of contamination.

Potential contaminants Control strategies

Residues of processed materials (raw and starting

materials, intermediates)

contaminants could be reduced below acceptable levels if appropriate

in-process controls monitoring reaction completion is in place and the

process has been validated.

Residues of by-products Residues of toxic by-products generated during a manufacturing process

must be monitored. In the Thalidomide case, one of the two enantiomers

was later discovered to be teratogenic; in other cases different

enantiomers can have different pharmacological or toxicological profiles.

Residues of degradation products Adequate studies (e.g., forced degradation studies) should be conducted

in case the residues of the product are not stable throughout the whole

length of the production campaign.

Residues of solvents used during manufacturing

process

Acceptable limits level of contaminants should be established based

on toxicity calculation (9). The impact will depend on the stage of the

production process; the closest to the final product, the biggest the impact.

Residues of detergents or solvents used for cleaning

during a production campaign or between different

campaigns

Potential reactions between the solvents used for cleaning and the

reagents/starting materials should be evaluated (e.g., contamination of

antiretroviral drug Viracept [nelfinavir] with ethyl mesylate (10)).

Residues of sanitizers sanitizers could be used to sanitize the equipment at the end of a production

campaign. When the active substance has to meet microbiological

specification they could be used more often during a production campaign.

Microbiological contamination, endotoxins These factors should be considered in case of active substances with

microbiological or endotoxin content requirements.

Materials used during manufacturing (e.g., filtering aids,

charcoal, plastic particles from gasket, glass particles from

glass-lined tanks, paper particles from filters, lubricants

from motors and bearings, fibers from personnel garments,

diatomaceous earth, small slivers of stainless steel, etc.)

Many materials used during production could represent a source of

contamination if not removed or if maintenance and/or assembling of the

equipment are not performed correctly.


Pharmaceutical Technology APIS, EXCIPIENTS, & MANUFACTURING 2015 s51

2015

PLANNING

GUIDE

52 Welcome Message

53 Events and Highlights

54 Event Schedule

55 Pre-Connect Conference

59 Exhibition Overview

60 Exhibition Floor Plan

61 Technical and Business Insights

65 CPhI Pharma Awards

66 Registration and Travel

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s52 Pharmaceutical Technology APIS, EXCIPIENTS, & MANUFACTURING 2015 PharmTech .com

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Planning ahead is the key to a successful visit to CPhI Worldwide 2015.

Get Ready for CPhI Worldwide

For pharma industry professionals

heading to CPhI Worldwide 2015

in Madrid, Spain on Oct. 13–15,

navigating the 11 exhibit halls, attending

educational sessions, and making

networking contacts can be daunting.

Pharmaceutical Technology interviewed

Rutger Oudejans, Brand Director Pharma

at UBM EMEA—the organizer of CPhI—

to gain insight into the activities at CPhI

Worldwide 2015 and best practices

attendees can apply to accomplish

business objectives at the event.

Advice for first-time visitorsPharmTech: Describe CPhI for a first-time visitor.

Oudejans: The first thing that strikes everyone when they arrive

at CPhI Worldwide is its huge size and the wealth of opportunities

on offer. The brand consists of four co-located shows—CPhI,

P-MEC, Innopack, and ICSE—featuring some 20 specific zones. But

beyond the exhibitors, content sessions, and networking events,

it’s the people that make the show. Nowhere else, no other time

of the year, are there this many pharma executives in one place.

It provides an unrivalled melting pot of ideas and innovations,

all designed to maximize business benefit, networking, and

sharing. For a first-time visitor, without a preset agenda, it can be

overwhelming, so I would advise arriving early in the morning and

familiarizing yourself with the exhibition’s layout. We also encourage

all attendees to download the mobile app, as it provides a useful

tool for easy navigation and a quick reference to find any exhibitor.

The best way to experience CPhI is to plan ahead, pick a

couple of zones you are keen to visit, and set the meetings.

Also, spend a little time exploring your opportunities, as

there is a wealth of companies out there that are able to

transform your business. People report that some of the best

meetings are completely unplanned and occur spontaneously.

Madrid is a great venue and city, and much of the excitement

and innovation spills out into the city after closing, so try

to get out to some of the many evening events planned

and make the most of the networking opportunities.

Educational opportunitiesPharmTech: What educational opportunities are offered and

what special events and activities are highlights of CPhI?

Oudejans: CPhI presents visitors with a great swath of

educational and insightful material, starting the day before the

main event during the CPhI Pre-Connect Congress (Oct. 12). Here,

senior executives and influential speakers discuss the

latest innovations, trends, and developments from across the

industry in a series of market-led educational modules.

The Pre-Connect Congress is organized along two main

tracks. Sessions in track one include Drug Delivery & Design,

Biologics, Biosimilars & Biobetters, and API Sourcing &

Manufacture. Track two features modules across Generics,

Pharmaceutical Packaging, and Mergers and Acquisitions.

Additionally, the main exhibition also includes free

sessions open to all attendees in the Exhibitors’ Showcase,

a forum for exhibitors to deliver first-hand presentations

to senior pharma executives from across the globe.

New for this year is the CPhI Pharma Forum—a dedicated

content village—which will provide a central hub to examine

thought leadership from leading industry players, media partners,

and the CPhI Pharma Insights Reports. The Pharma Forum also

includes Exhibitor Innovation Galleries, and the Pharma Insight

Briefings, offering unbiased, in-depth sessions including regional

updates and specialist topics covering regulation, quality control,

traceability, sustainability, and health to name but a few.

Planning toolsPharmTech: How should visitors prepare to make the best use of

their time at CPhI?

Oudejans: Before arriving, we recommend reviewing our

Event Preview guide, which gives a thorough overview and

helps plan a good itinerary to ensure you make the most of

the event. At the show itself, arrive early after opening, and

not midway through the first or even second day. And while

it may sound obvious, make sure you are well rested, it’s

a long three days, with traveling at each end and it can be

tiring. Another key tip—often overlooked by attendees—is

to leave enough time to navigate between your meetings.

Finally, CPhI has created a whole host of services to

aid you in making the most of your visit. These services

range from onsite staff and information points that

provide assistance in navigation through to matchmaking

services, offering crucial help in pre-tailoring meetings to

fit your bespoke needs. This offering enables attendees

to make sure they meet the customers and new business

contacts they most desire to do business with. PT

Rutger Oudejans, CPhI Worldwide



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Pharma industry experts from around the world head to Madrid, Spain for exhibitions, conferences, networking, and

business meetings at CPhI Worldwide. These event highights will help you plan your time at the event.

CPhI Worldwide: Events and Highlights

The 26th annual CPhI Worldwide exhibition and co-located

events—ICSE, InnoPack, and P-Mec—bring together

pharmaceutical industry professionals from around the world

to view equipment and services exhibits, attend educational

conferences, network with industry peers, and conduct business.

Pre-Connect CongressThe Pre-Connect Congress offers educational sessions on

a range of technology and business topics. A Regulatory

Keynote and Senior Leadership Theater highlight the program.

See pages s55–s58 for session descriptions and details.

ExhibitionMore than 2100 companies representing the pharmaceutical

development and manufacturing marketplace exhibit APIs,

excipients, fine chemicals and intermediates, biologics, equipment,

packaging, supply chain, laboratory, analytical instruments,

drug delivery, clinical trial services, contract services, and more

at the show. See pages s59–s60 for exhibition highlights.

Pharma Insight BriefingsPharma Insight Briefings, hosted in the Pharma Forum,

offer CPhI visitors updates on key industry trends including

contract manufacturing, APIs and ingredients, packaging,

drug delivery, biotechnology, consumer and animal

health, natural extracts, and regional pharma activity. See

pages s61–s64 for session descriptions and details.

Pharma AwardsThe CPhI Pharma Awards honor innovation in eight categories:

outsourcing, process and formulation development,

packaging, APIs and excipients, manufacturing, supply

chain, biologics development and manufacturing, and

executive leadership. For details, see page s65.

Women’s Networking BreakfastBuilding on a successful inaugural event in 2014, the Women’s

Networking Breakfast provides an opportunity for female

executives from global pharmaceutical companies to meet,

develop new business contacts, and learn how to advance in the

pharma industry. The breakfast is scheduled for Wednesday, Oct.

14, 08:30-11:00, at the Novotel Campo de las Naciones, Madrid. For

details, visit: www.cphi.com/europe/agenda/womens-breakfast

CPhI Worldwide

Dates

Pre-Connect Congress: Oct. 12, 2015

Exhibition: Oct. 13–15, 2015

Venue

IFEMA, Feria de Madrid, Spain

Website

www.cphi.com

Visitors: 36,000+

Exhibits: 2500+

Countries represented: 150+

CPhI Worldwide Statistics*

*Based on CPhI Worldwide dataCourtesy of UBM



CPhI Worldwide Events (as of Aug. 24, 2015)

Monday, Oct. 12

Time Event Activity Location

08:30–09:30 Pre-Connect Congress Registration Novotel Campo de las Naciones, Madrid

09:30–11:15 Pre-Connect CongressDrug Delivery & Design Generics

Novotel Campo de las Naciones, Madrid

11:15–11:45 Pre-Connect Congress Coffee and refreshment break Novotel Campo de las Naciones, Madrid

11:45–13:30 Pre-Connect CongressBiologics, Biosimilars & BiobettersPharmaceuctical Packaging


13:30-14:30 Pre-Connect Congress Lunch and networking Novotel Campo de las Naciones, Madrid

14:30–16:15 Pre-Connect CongressAPI Sourcing & ManufactureMergers & Acquisitions


16:45–17:05 Pre-Connect Congress Regulatory Keynote Novotel Campo de las Naciones, Madrid

17:05–18:05 Pre-Connect Congress Senior Leadership Theatre Novotel Campo de las Naciones, Madrid

17:30 Reception Exhibitors’ Party Exhibit Halls North Entrance

18:15–19:15 Pre-Connect Congress Reception Novotel Campo de las Naciones, Madrid

Tuesday, Oct. 13


09:30 Exhibition Exhibition Opens Exhibit Halls

10:00–12:25 CPhI Pharma Awards CPhI Pharma Awards: Presentations by Finalists Exhibitors’ Showcase (CPhI, ICSE and InnoPack)

10:00–10:45 Pharma Insight Briefings Insight into LRC-TriCEPS Technology Pharma Forum

11:00–11:45 Pharma Insight Briefings Natural Extracts—Top 10 Global Trends Pharma Forum

12:00–12:45 Pharma Insight Briefings Animal Health Pharma Forum

13:00–13:45 Pharma Insight Briefings Consumer Health Pharma Forum

14:00–14:45 Pharma Insight Briefings Patient-centric, child-resistant packaging Pharma Forum

15:00–15:45 Pharma Insight BriefingsCommercial Pharmaceutical Production of Complex APIs via Plant Cell Fermentation

Pharma Forum

16:00–16:45 Pharma Insight BriefingsApplications of Ethylene Vinyl Acetate Copolymers (EVA) in Drug Delivery Systems

Pharma Forum

16:45–17:30 Pharma Insight Briefings Reception hosted by Celanese Pharma Forum

17:30 Exhibition Exhibition Closes Exhibit Halls

Wednesday, Oct. 14


08:30–11:00 Special Event Women's Networking Breakfast Novotel Campo de las Naciones, Madrid


10:00–10:45 Pharma Insight BriefingsRealizing Process Innovation in Aseptic Manufacturing: An ‘Improved RABS concept’

Pharma Forum

11:00–11:45 Pharma Insight Briefings Innovations in Pharmaceutical Packaging Pharma Forum

12:00–12:45 Pharma Insight Briefings Contract Manufacturing & Outsourcing Update Pharma Forum

13:00–13:45 Pharma Insight Briefings API Outlook in India & China Pharma Forum

14:00–14:45 Pharma Insight BriefingsThe Global Outlook for Generics, Biosimilars and API Manufacturers

Pharma Forum

15:00–15:45 Pharma Insight BriefingsStrategies for Developing a Successful Global Clinical and Commercial API Supply Chain

Pharma Forum

16:45–17:30 Pharma Insight Briefings Reception hosted by WuxiAppTec Pharma Forum


Thursday, Oct. 15



10:15–11:00 Pharma Insight Briefings Quality by Design Pharma Forum

11:15–12:00 Pharma Insight Briefings Insight into the Mexican Market Pharma Forum

12:15–13:00 Pharma Insight Briefings Insight into the Spanish Market Pharma Forum

13:15–14:00 Pharma Insight Briefings Insight into the MENA Market Pharma Forum


Event times, speakers, and topics are subject to change. Visit www.cphi.com for the most current information.



Experts share insight on emerging trends, new technologies, and best practices in the Pre-Connect Congress.

The Education Connection

Now in its seventh year, the Pre-Connect Congress covers key

topic areas in the bio/pharma industry. Experts from bio/

pharma companies, contract service providers, equipment

suppliers, regulatory authorities, and research and consulting

organizations will present the latest trends and developments.

The Pre-Connect Congress will be held Monday Oct. 12, 2015, at

the Novotel Campo de las Naciones, Madrid. To register, visit

www.cphi.com/europe/agenda/pre-connect-congress.

Monday, Oct. 128:30–9:30

Registration, welcome coffee and networking

Track One, Module A

Drug Delivery & DesignUtilizing the latest drug delivery technologies to develop better

treatments

9:30–9:45

Welcome from the Chair

Sharon Johnson, senior vice-president, Quality, Product

Development & Regulatory Affairs, Catalent Pharma Solutions

9:45–10:05

A Structured Approach

to Accelerating Drug Development

Enabled by Innovative Delivery Technologies

New OptiForm program lead will present the latest technologies and

options, including parallel development.

Julien Meissonnier, R&D platform director,

Catalent Pharma Solutions

10:05–10:30

Development of New Excipients

for Better Drug Delivery Systems

• Development challenges around new ‘Novel’ excipients

• What benefits do these novel excipients offer in drug delivery

systems?

• How the regulatory framework for the approval of new excipients

creates a dilemma for the manufacturers and users

Felicitas Guth, senior research manager, BASF

10:30–10:50

Optimizing Molecules’ Physical Characteristics

for Better Drug Design

Using inhaled particles to deliver multiple APIs

TBC

10:50–11:15

Effective Transdermal Delivery Using Silicone Technology

• Technical aspects of existing BIO PSAs adhesives and pipeline

innovations

Xavier Thomas, European industry expert, Dow Corning

Track Two, Module D

GenericsGrowth opportunities, emerging markets, and evolving dynamics

9:30–9:35


Maarten Van Baelen, market access director, European Generics &

Biosimilars Association

9:35–10:00

Emerging Market Outlook

• The demand for generics in emerging markets based on afford-

ability and chronic disease profile

• Which markets offer the best growth potential?

Gurpreet Sandhu, managing director, Reva Pharma

10:00–10:25

Added-Value Generics to Suit Patient Needs

• Achieving a competitive advantage through adapting and

reformulating existing compounds to develop new products

Elena Klimova, senior consultant on generics, IMS Health

10:25–10:50

The FDA NDA 505(b)(2) Approval PathwaySM

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• Key regulatory updates and successful 505(b)(2) application

examples

Ken Phelps, president and CEO, Camargo Pharmaceutical Services

James Coward, senior director and global head market

development, Capsugel Dosage Form Solutions

10:50–11:15

The Changing Dynamics of the Generics Business Model

• How generics companies are filling the R&D gap by becoming

innovation generators.

• The emerging concept of hybridity: Is there such a thing as a pure

play generics company?

• Why consolidation is essential for future innovation and cost

effective therapies.

Moderator: Maarten Van Baelen, market access director, European

Generic & Biosimilars Association

Nicola Travierso, general manager, NTC Pharma

Marlene Llopiz, CEO, Investigaci—n Farmacol—gica y

BiogfarmacŽutica, S.A.P.I. de C.V. (IFaB)

Track One, Module B

Biologics, Biosimilars & BiobettersMaintaining competiveness and value in an increasingly crowded

marketplace

11:45–11:50


Richard Dicicco, chairman, Harvest Moon Pharmaceuticals

11:50–12:15

Monoclonal Antibodies—Policy & Commercial Considerations

• The case for biosimilar monoclonal antibodies.

• How will business evolve from a commercial perspective?

• Stakeholder education as a critical success factor.

• Policy framework for optimal uptake of biosimilars.

Peter Stenico, head of commercial operations Western Europe,

biopharmaceuticals and oncology injectables, Sandoz

12:15–12:40

Case Study: Bringing Biosimilars to Market Faster with

Innovative Technologies, Development Models, and Successful

Collaborations

• New technology platforms to facilitate bringing better biosimilars

to clinic faster.

• An overview of new business models, innovative technologies,

and case studies.

• Biocad will present the path for getting the first biosimilar

monoclonal antibody approved in Russia.

Christelle Dagoneau, director, Business Development, Catalent

Pharma Solutions

Roman Ivanov, vice-president, Research & Development, Biocad,

Russia

12:40–13:05

Biologics: Switching, Substitution, and Interchangeability

• Exploring the factors governing switching, substitution and

interchangeability

• Lessons from Norway, the government funded switching study,

and possible industry response to US legislation

Steinar Madsen, medical director, Norwegian Medicines Agency

13:05–13:30

Panel Discussion: The Evolving Biosimilar Landscape

• The impact of the FDA’s landmark approval of Sandoz’s Zarxio:

What is the basis of approval for US biosimilar products?

• Which is more profitable for US biosimilars: Patient switching or

interchangeability?

• Will these products generate the system savings that policy-

makers are hoping for across US and European markets?

• A look at new players entering the market.

Moderator: Michel Mikhail, expert in Biosimilar Development &

formerly chief regulatory officer & executive vice president, Global

Regulatory, Fresenius Kabi

Paul Greenland, vice-president biologics, Hospira

Laurent Rebier, director business developmentÐbiosimilars, Merck

Serono SA

Track Two, Module E

Pharmaceutical PackagingImproving patient outcomes through

innovative packaging

11:45–11:50


Michael Nieuwesteeg, managing director, NVC Netherlands

Packaging Centre

11:50–12:15

Better Health Through Packaging—The ΦΠΙ Project

• The importance of innovation in pharmaceutical packaging

• Accessible design and safety of use

• Therapy compliance enhancement

• Safeguarding the integrity of the medicine and its supply chain

Ger Standhardt, managerÐknowledge development and projects,

NVC Netherlands Packaging Centre

12:15–12:40

The Proven ROI of Adherence Packaging

• The global challenge of medication non-adherence

• Data about how patient-centric adherence packaging can help

change patient behaviour and create an adherence habit

• Research data proving effectiveness and ROI

Tom Grinnan, senior commercial

director for EMEAA Healthcare,

WestRock



12:40–13:05

The Countdown to Serialization: Managing the Transformation

• The level of industry engagement in light of looming deadlines

• Assessing the impact on the contract manufacturer network

• Key challenges for deployment and cost effective implementation

Wim De Bruyn, lecturer ICT-management University College Ghent

(Belgium), president Agoria Industrial Software SG, ISA, ISPE, MESA

Track One, Module C

API Sourcing & ManufactureImproving efficiency, assessing new opportunities and managing risk

14:30–14:35


Gurpreet Sandhu, managing director, Reva Pharma

14:35–15:00

API Sourcing Update: What Will Determine Where APIs are

Manufactured Over the Coming Decade?

• With continued issues of quality and increasing prices, can India

and China maintain their status as key API manufacturing hubs?

• Which countries have the potential to emerge as new

manufacturing hubs?

Kate Kuhrt, senior director, Generics & Biotech, Thomson Reuters

15:00–15:25

Towards Continuous Manufacturing

• The benefits of a platform approach to continuous

manufacturing

• Approaches to achieving the desired crystalline form: How does

this work from a development perspective?

• The regulators view: the move to adopt continuous

manufacturing from a quality perspective.

Clive Badman, OBE, executive director Business engagement group

and industrial chairman CMAC, formerly head PTS Pre-Competitive

Activities, GlaxoSmithKline

15:25–15:50

The Rise and Rise of Contract API Manufacturing

• Outsourcing trends in small-molecule API manufacture.

• How CMOs are addressing the specialized production needs of

highly potent APIs.

• What are the manufacturing, containment and requirements of

this new breed of APIs?

Akshay Kant Chaturvedi, Head-Corporate IPM & Legal Affairs, Shilpa

Medicare

15:50–16:15

Data Integrity: The US Food and Drug Administration (FDA) and

European Union Perspective

• Ensuring quality through compliance: The value of data integrity.

• A look at warning letters and certificates of non compliance.

• What are the expectations of the regulators and how can these

be achieved?

Octavi Colomina, technical director at TDV SL and president,

Asociación Fórum Auditorias

Track Two, Module F

Mergers & AcquisitionsChanging trends: driving growth through strategic partnerships

14:30–14:35


Kevin Bottomley, managing director, Results Healthcare at Results

International LLP

14:35–15:00

An Overview of M&A in the Pharmaceutical Industry

Trends, drivers, restrictors, and the outlook for 2015

Christoph Bieri, chair, Healthcare Industry Group, IMAP

15:00–16:15

M&A Toolkit: Panel Discussion and Audience Q&A

Using M&A to Reconfigure Pharmaceutical Manufacturing

Networks

• Removing non-core pharma manufacturing assets and optimizing

network performance

• Building a better CMO

Best Practice Workshop: Preparing and Executing a Successful

M&A Deal Sell-Side

• Preparing to go to market, marketing the asset, running a

successful process, due diligence, closing the deal

Best Practice Workshop: Being a Successful Acquirer

• How to identify acquisition opportunities

• Running a successful buy-side campaign

Post-Acquisition Insight

• Transitioning ownership

• New owners, new culture

• Ensuring a successful growing ongoing business

Moderator: Kevin Bottomley, Managing Director, Results Healthcare

at Results International LLP

Tim Tyson, chairman and CEO, Avara Pharmaceutical Services

Gerard Bellettre, Industrials Affairs, Emerging Markets division,

Strategic Planning, Investments and Business Development, Sanofi

Jaime Gil Gregorio, head of Global Solid Projects, Sandoz

Lubo Soltys, partner, Wood & Co

16:45–17:05

Regulatory KeynoteHow to Prepare for a FDA Inspection

Robert Fish, senior consultant, EAS Consulting and former director

at FDA



Driven by competitive pressures and using models pioneered in

other industries, pharmaceutical companies are extending

collaboration efforts well beyond their walls. Like other industries,

pharma is moving to more of an “open innovation” model.

Pharma outsourcing has opened up the traditionally closed

world of pharma innovation. Previously, pharmaceutical

companies would typically outsource specific projects on a

transactional basis; today, more are creating strategic

partnerships with their contract research, development and

manufacturing organization (CRO and CDMO/CMO) partners,

sharing sensitive data, and even financial risks and rewards.

A study by Deloitte Consulting suggested that open innovation

in biopharma could strengthen new drug pipelines (1) and that

drugs sourced via open innovation could have a three-fold higher

likelihood of success than those generated traditionally.

Deloitte’s study shows an evolution in the open innovation

model, from the traditional approach of outsourcing with a

university, research institute, or CRO, to licensing. Newer

models include the innovation hubs, as well as leading edge

partnerships as the transSMART Foundation, the Structural

Genomic Consortium, and Asia Cancer Research Group.

In 2014, Deloitte researchers found, of the 12 largest

biopharma companies, 54% sourced new drugs via open

innovation, 83% of that figure via outsourcing or licensing.

Forty-six percent sourced drugs the traditional way (1).

Matthew Hudes, managing principal at Deloitte’s biotech

consulting division, shared perspectives on the pharmaceutical

industry’s new open innovation model with Pharmaceutical

Technology (2).

A new innovation mindsetPharmTech: Why is pharma changing its models and mindset

for innovation?

Hudes: We’ve seen this coming for some time, with the patent

cliff and some recent high-profile failures in pharma’s development

pipeline. About six years ago, we saw an increased outreach to

external sources of innovation. What is remarkable about this is

not that it is going on, or even the extent to which it is going on, but

the diversity of ways in which this outreach is taking place.

It’s a big experiment, and we don’t know which model will

prevail in the future, but it is rare to see such a diversity of

business models. Science is diverse, but not, typically, the

business models behind it.

PharmTech: Can you give examples of these models?

Hudes: I think about it as having two main dimensions:

control and source (external vs. internal). If you put those two

factors together, you get a broad spectrum of what is going on.

In one type of model, large companies are lifting out assets and

people from an academic setting and moving them to a place

where they can focus on a specific project, and giving them

everything they need and access to all their resources, on an

exclusive basis. The project is treated like a major product

extension, and companies that are taking this approach are having

terrific results. They have been picking up intellectual property (IP)

that has been, if not languishing in, then bumping up against the

limits of what can be achieved in an academic setting.

Another model takes a ‘hands-off’ approach, in which large

pharma invests in an innovation center, in a place where there

are many resources and where they are interested in launching

companies. They don’t own or contribute to the IP, and don’t

even have first right of refusal. Through proximity, they get an

early, inside look at what these innovations are, but use a

community approach. This way, they can invite competitors into

that space for collaboration as well.

There’s another set of approaches that I would call pure open

innovation, which involves the sponsorship and identification of

a problem posed to a community. Anyone can respond to it.

There are variations on that theme. For instance, who gets to

own the discovery that eventually comes out of the effort: Is it

the company who sponsors the effort, or is the prize shared

among those who solve the problem?

We’re seeing the industry collaborate on some major

infrastructure challenges, such as how to get drugs to market

more quickly, and dealing with questions such as enrolling

investigators, or developing technical standards to get clinical

trials to happen more efficiently.

References1. R. Marcello et al., Executing an Open Model for Biotech Innovation,

Executive Summary, May 2015.

2. A. Shanley, “Opening Up Pharma Innovation,” Pharmaceutical

Technology Outsourcing Resources Supplement 39 (17) 2015. PT

Market Insight: Partnerships and Collaborations

17:05–18:05

Senior Leadership TheatreFrom Pipeline to Patient: Leadership Perspectives on

Market Development and Commercialization

• New models for innovation

• Partnering with patients for pipeline success

• Streamlining the supply chain

• Promoting better outcomes

Moderator: William Looney, editor-in-chief, Pharmaceutical Executive

Prof Trevor Jones, CBE, former director general, Association of the

British Pharmaceutical Industry

Sharon Johnson, senior vice president, Quality, Product

Development & Regulatory Affairs, Catalent Pharma Solutions

18:15–19:15: Reception



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CPhI Worldwide and co-located events ICSE, InnoPak, P-MEC, and LABWorld 2015 bring technologies, processes, and

services from all phases of the drug development and manufacturing spectrum to one location.

Exhibits Display Emerging Technologies

Fine chemicals, APIs, excipients, manufacturing equipment,

laboratory instruments, packaging systems, and contract

manufacturing services are on display in the 11 exhibit halls

of CPhI Worldwide and co-located events ICSE, InnoPak,

P-MEC, and LABWorld 2015. The facility floor plan on page 60

provides an overview of all exhibit hall locations. For detailed

floor plans of each exhibit hall, see www.cphi.com.

CPhI WorldwideCPhI Worldwide exhibits are arranged in product category zones:

• APIs: Halls 6, 8, 12, and 14

• Biopharmaceuticals: Hall 8

• Custom Manufacturing: Hall 5

• Excipients: Hall 7

• Fine Chemicals & Intermediates: Hall 5

• Finished Formulation: Halls 8 and 10

• General Floor: Halls 7 and 9

• Natural Extracts: Hall 8

• North American Pavilion: Hall 7

ICSE: Contract ServicesOutsourcing solution providers that offer clinical trials, contract

research, contract manufacturing, biotech, IT, analytical services,

packaging, and logistics services are showcased in the ICSE

exhibition in Exhibit Halls 1 and 3. Zones are defined for:

• Bio Services

• Logistics & Cold Chain

• Analytical & Lab Services

• CRO & (Pre) Clinical Trials

• North America

• New Exhibitors

InnoPack 2015: Packaging and Drug DeliveryInnoPack, located in Hall 4, features products and

services for primary, secondary, and tertiary packaging

industries, as well as drug-delivery system suppliers.

P-MEC and LABWorld 2015Located in Hall 4, P-MEC features pharmaceutical machinery

and equipment. LABWorld provides access to laboratory,

analytical, and biotechnology instrumentation.

Exhibition Activities

Exhibitor ShowcasesKey exhibitors will present their technologies, services,

and commentary on industry trends in Exhibitor Showcase

presentations. These 25-minute sessions will provide

insight on innovations and emerging industry practices.

Innovation GalleryThe Innovation Gallery provides a platform for exhibitors

to display innovations and new product introductions.

Innovation ToursInnovation Tours bring visitors to new technologies and

trends on display in the exhibit halls. The planned, 60-minute

tours cover the scope of pharmaceutical development and

manufacturing in the CPhI, ICSE, and InnoPack exhibits.

Connect with Business Contacts At a large event such as CPhI Worldwide, scheduling

meetings with exhibitors, visitors, speakers, investors, and

other participants presents challenges. CPhI Worldwide

offers a “matchmaking” program to facilitate the scheduling

of meetings during the event between exhibitors and

visitors. The service allows exhibitors and visitors to find

new business contacts and reach people who are difficult

to locate. Details will be posted on www.cphi.com.

Exhibition Hours

Tuesday, Oct. 13, 2015: 09:30–17:30

Wednesday, Oct. 14, 2015: 09:30–17:30

Thursday, Oct. 15, 2015: 09:30–16:00



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APIs, contract services, biotechnology, packaging, drug delivery, and regional business trends

are among the free educational topics covered in the Pharma Insight Briefing sessions at CPhI Worldwide.

Technical and Business Insights

By attending the Pharma Insight Briefings, CPhI Worldwide

participants can learn about key industry trends and new

technologies through free, 45-minute presentations. These

presentations will cover contract manufacturing, APIs and

ingredients, packaging, drug delivery, biotechnology, consumer and

animal health, natural extracts, and regional pharma activity.

All presentations are located in the Pharma Forum between

exhibit halls 5 and 6. The programme below lists sessions

and speaker information as of Aug. 24, 2015.

Tuesday, Oct. 13

10:00–10:45

BiotechnologyInsight into LRC-TriCEPS Technology

• Target and off-target identification on the living cells

• Elucidating the mode of action of biologics

• Support of candidate selection based on data from living cells

Paul Helbling, CEO, Dualsystems Biotech AG

11:00–11:45

Natural ExtractsNatural Extracts—Top 10 Global Trends

• Market Trends: Capitalizing on high demand by providing

customer centric extracts, developing customer specific

solutions

• Customization: Application profiling and product differentiation:

penetrating new application sectors of food fortification

and dietary supplements

• Paradigm shifts: Examining the substitution from synthetic

alternatives, how natural medicine can compliment APIs

• Innovation: Enhancing properties of extracts through

combination formulae and microencapsulation

• Partnerships: Evolving roles and how best to capitalize and profit

from licensing, CMO, CRO and other partnerships

Rajiv Khatau, managing director, LODAAT LLC

12:00–12:45

Animal Health• Latest trends in animal health delivery

• New perspectives and new treatments

• Using advanced human technologies to deliver breakthrough

improvements in product delivery

Dan Peizer, global director, sales & marketing, animal health,

Catalent

13:00–13:45

Consumer Health• Hot trends: Vitamins & Omega 3 oils

• Innovation in dose formats for better consumer health products

• Latest in Rx to OTC switches

Claudia Valla, product development adviser, Catalent

14:00–14:45

Pharma PackagingPatient-Centric, Child-Resistant Packaging

• The impact of child-resistant medication packaging on

reductions in child poisonings

• Geographic and industry trends in child-resistant packaging

• Incorporating research and insights to design consumer-

preferred child-resistant packaging

• Research about how consumers’ interaction with packaging

impacts sales

Tom Grinnan, senior commercial director EMEAA healthcare,

WestRock

15:00–15:45

BiotechnologyCommercial Pharmaceutical Production of Complex APIs via

Plant Cell Fermentation (PCF) Technology

• Overview of plant cell fermentation & history of PCF in the

pharmaceutical industry

• The PCF process & future opportunities in the pharma industry

• The paclitaxel and docetaxel experience: first commercial APIs

via PCF



• Why PCF is an ideal choice for many plant-derived drugs

• Processing PCF broth into complex finished APIs

Gilbert Gorr, PhD, chief scientific officer, and Roland Franke, PhD, VP

business development and chief technology officer, Phyton Biotech LLC

16:00-16:45

Drug DeliveryApplications of Ethylene Vinyl

Acetate Copolymers (EVA)

in Drug Delivery Systems

• Why EVA in drug development and controlled release?

• Current application areas & uses

• Next-generation innovations

• Celanese’s support of conventional and novel uses

Donald Loveday, strategic marketing manager, and

Christian Schneider, research & development scientist, Celanese

16:45-17:30

Reception hosted by Celanese

Wednesday, Oct. 14

10:00–10:45

Contract ManufacturingRealizing Process Innovation

in Aseptic Manufacturing:

An Improved RABS Concept

• The challenge of reliable aseptic manufacturing processes and

realizing cost effective production methods

• Assessing aseptic filling technologies: isolators and restricted

access barrier systems (RABS)

• Evolving the RABS concept to better meet future industry trends

in quality and safety

Hermann Piana, Vetter Pharma International GmbH

11:00–11:45

Pharma PackagingInnovations in Pharmaceutical Packaging

Ger Standhart, manager knowledge development & projects,

NVC Netherlands Packaging Centre

12:00–12:45

Contract Manufacturing Contract Manufacturing & Outsourcing Update

• CMO industry size, growth, and share of marketed products

• Key offerings and capabilities of the CMOs

• Major participants in the industry

• Key trends shaping the CMO industry

• Major challenges and opportunities facing CMOs

Jim Miller, president, PharmSource

In association with Pharmaceutical Technology

13:00–13:45

APIs and IngredientsPanel Discussion: API Outlook in India & China

• The rising strength of Chinese and Indian API markets

• Contract manufacturing trends

• APIs: Price competitiveness

• APIs: IP and regulatory focus

• How do regulatory bodies look at China & India today?

Moderator: Gurpreet Sandhu, managing director, Reva Pharma

Panelists: Prasanth Nandigala, director, Virchow Pharmaceuticals;

Cora Kwok, managing director, I&C Hong Kong Ltd; Arito Mori, sales

manager, Asahi Kasei Finechem Ltd; Seshachalam, vice-president

Regulatory & QA, Shilpa Medicare Ltd

14:00–14:45

APIs and IngredientsThe Global Outlook for Generics, Biosimilars, and API

Manufacturers: Trends, Opportunities, and Challenges

• A review of the latest regulations and their impact

• Overview of the current state of R&D pipelines

• Today’s landscape of API manufacturing

• How are manufacturers responding to these challenges and

creating future opportunities?

Mike Chace-Ortiz, CEng, senior director, Generics, Thomson Reuters

15:00–16:45

Contract ManufacturingStrategies for Developing a Successful Global Clinical and

Commercial API Supply Chain

• Developing and Maintaining a Global API Supply Chain

Michael Semo, advisor, Small Molecule API Sourcing, Eli Lilly

• Effective Management of Development Phase Outsourcing

David Wightman, sourcing team manager, Pharmaceutical

Development, AstraZeneca

• Strategies for Successfully Defending Regulatory Starting

Materials Worldwide

Valdas Jurkauskas, executive director, Technical Operations,

STA, a company of WuXi AppTec

• A Successful CRO Collaboration for Early Chemical Development

Jos Brands, executive director, Merck Research Lab

16:45–17:30

Reception hosted by WuxiAppTec

Thursday, Oct. 15

10:15–11:00

RegulatoryQuality by Design

• Explore the concept of regulatory flexibility associated with QbD

and how can this be maximized

• Discuss the current guidelines ICH Q8, Q9, Q10, and Q11


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SPECIAL SESSION

CPhI Pharma Insights Briefing

The Outlook for the Bio/Pharmaceutical Contract Manufacturing Industry

Presented by Jim Miller, President, PharmSource

Wednesday, October 12 from 12:00 – 12:45 PM

While contract manufacturing organizations (CMOs) consolidate their positions in traditional markets and

technologies, they are not addressing some of the most important trends in pharmaceutical manufacturing.

Learn about these trends, as well as the status of the CMO industry, opportunities it offers to clients, and the

challenges it must face to remain relevant in the future.

Located in The Pharma Forum, outside of Halls 5 & 6.

GEt tHE LAtESt

COVERAGE OF:• ProcessDevelopment

• ManufacturingTrends

• Formulation

• AnalyticalTechnology

• RegulatoryCompliance

• QualityAssurance

• APIsynthesis

• Packaging

• Outsourcing

• IndustryBestPractices

PHARMACEUtICAL

tECHNOLOGY EUROPEoffersprint&digital

subscriptions

FREE PRINt & DIGItAL

SUBSCRIPtIONS

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SPECIAL EDUCATIONAL PROGRAMMING

PHARMACEUTICAL TECHNOLOGY EUROPE IS tHE

LEADING PHARMACEUtICAL DEVELOPMENt &

MANUFACtURING PUBLICAtION IN EUROPE.

WE HAVE BEEN PROVIDING OBJECtIVE AND

RELIABLE EXPERt EDItORIAL COVERAGE IN tHE

BIO/PHARMACEUtICAL INDUStRY SINCE 1989!

Come See US at Booth 1a3

SIGN UP FOR YOUR FREE SUBSCRIPTION TODAY!

Organised by:

The Science & Business of Biopharmaceuticals

INTERNATIONAL

Come see

these UBM

publications

at Booth 1A3


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• Introduce continuous manufacturing as the new frontier for QbD

• Share ideas & experiences to help answer current QbD issues

Walkiria Schlindwein, Michael Goodman, and Mustafa Zaman,

De Montfort University

Regional Updates 11:15–12:00

Insight into the Mexican Market

Marlene Ll—piz, chief executive officer, Investigaci—n Farmacol—gica

y BiogfarmacŽutica, S.A.P.I. de C.V. (IFaB)

12:15–13:00

Insight into the Spanish Market

GBR Reports

13:15–14:00

Insight into the MENA Market

Salim Labban, managing director, BroadMed

Contract manufacturing of drug product for developed markets grew

6% annually in 2013 and 2014 to $16.5 billion (1), reports Jim Miller,

president of PharmSource, but behind these robust growth numbers

are some indications that CMOs may want to proceed cautiously.

Miller provided insight on contract services trends in Pharmaceutical

Technology (2), and will explore the topic in more detail during a

Pharma Insight Briefing at CPhI Worldwide.

Inorganic growth through the acquisition of manufacturing facili-

ties from bio/pharmaceutical companies plays a lesser role in CMO

industry growth than it did previously, but it is still an important

factor in Europe—where there are many bio/pharmaceutical manu-

facturing sites—and Japan, where the contract manufacturing sector

is in early stages of development, Miller notes.

Consolidation has been the big story in the CMO market over the

past three years, and while there are hundreds of companies offering

contract manufacturing, only 30 account for more than half of

industry revenues, and a small number of CMOs increasingly domi-

nate the industry, according to Miller.

Global bio/pharma companies outsource approximately one-third of

drug product manufacture (1), but more are investing in captive capacity,

or in-house manufacturing operations. Spending on plant and equip-

ment by the 25 largest bio/pharma companies grew 13% in 2013, and

11% more in 2014 to $19 billion, Miller reports. However, evidence indi-

cates that the traditional best customers of CMOs—mid-size and small

commercial companies—are also investing more in in-house facilities

thanks to low capital costs and commercial success (see Figure 1).

The drug-development pipeline may offer more opportunities in

coming years, he says, but many emerging products are orphan drugs;

smaller patient populations generate small manufacturing volumes. In

addition, payer pushback on drug prices may also impact CMO rev-

enue growth.

CMOs will have to capture more value per product or find new

markets to grow at acceptable rates, Miller warns. Integrated services,

generic drug manufacturing, and emerging markets are opportunities

CMOs may want to consider.

Attend this Pharma Insight BriefingMiller will present a Pharma Insight Briefing, Contract Manufacturing

& Outsourcing Update on Wednesday, Oct. 14, 2015 from 12:00–

12:45 in the Pharma Forum at CPhI Worldwide. Topics include CMO

industry size, growth and share of marketed products; key offerings

and capabilities of the CMOs; major participants in the industry; key

trends shaping the CMO industry; and major challenges and opportuni-

ties facing CMOs. The presentation is sponsored by Pharmaceutical

Technology.

References1. PharmSource, Contract Dose Manufacturing Industry

by the Numbers, 2015 Edition, July 2015.2. J. Miller, “What’s Next for the CMO Industry?,” Pharmaceutical

Technology Outsourcing Resources Supplement 39 (17) 2015.

Optimism, opportunity, and caution ahead for CMOs

Figure 1: Capital expenditures by mid-size bio/pharma companies.

$0

$100

$200

$300

$400

$500

$600

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New technology categories for the CPhI Pharma Awards expand

recognition of innovative pharma and biopharma technologies and services.

Honoring Innovation

For more than 10 years, the CPhI Pharma Awards have

recognized top innovator companies from the global bio/

pharma community during the CPhI Worldwide event. In 2015,

the awards program has been expanded to eight categories.

The CPhI Pharma Awards are designed to help raise the

profile of unique innovations with key pharma professionals, the

global trade press, and industry professionals before, during,

and after the event via live, online, and print recognition.

The CPhI Pharma Awards 2015 are open to all companies

operating across the pharmaceutical and biotechnology sectors.

The judging processShortlisting Candidates—Finalists. After the deadline, all

entries are collated per category and sent to the independent

CPhI Pharma Awards Jury Panel. The Jury Panel members

will individually evaluate and score each entry before

discussing their decisions during a meeting in a neutral

location. Finalists are announced on Sept. 21, 2015.

Selecting a winner On Oct. 13, 2015, each finalist will deliver a presentation at

a dedicated feature area on the show floor for the judges

and industry peers, for a closer inspection and questioning

of the merits of the entries. The Jury Panel will reevaluate

and score the entries, then adjourn for a private deliberation

before announcing the winners at an award ceremony later

that day at the Exhibitor’s Party in the North Entrance area.

CPhI Pharma Awards 2015 CategoriesBest Innovation in Biologic Drug

Development and Manufacturing

(New for 2015): Includes, but is not

limited to, innovation in biologic APIs,

single-use, aseptic/sterile, pre-filled

syringes, vials, bioreactors, media supplements, cell lines,

separation and filtration, process chromatography, and more.

Innovation in Supply Chain &

Logistic Management (New for 2015):

Includes, but is not limited to, innovation in logistics, cold

chain, transport, temperate control shipping, trackers,

barcoding, quality control, and analytic testing.

Best Innovation in Manufacturing Technology (New

for 2015)—in partnership with Pharmaceutical Technology

magazine: Includes, but is not limited to, innovation in equipment,

manufacturing processes, bioavailability, micronization,

tech-transfer, tableting, drug delivery, and filling.

CEO of the Year (New for 2015), in partnership with

PharmaBoardRoom: Attributes to be considered, but not

limited to: global reach, leadership skills, management

capability, charity, regulatory review, sales turnover profits,

vision, marketing, acquisitions, strategy, and financing.

Best Innovation in APIs and Excipients (New for 2015):

Includes, but is not limited to, innovation in classical

formulation, classical excipients, drug delivery, novel

excipients, functional excipients, nanoparticles, pegylation,

manufacturing processes, freeze-drying, intermediates,

solid dose, liquid dose, inhalation, purity, lyophilization.

Best Innovation in Packaging: Includes, but is not limited

to, innovative delivery devices, innovative materials,

packing/filling processes, compliance issues, tamper-proof

packaging, easy-access packaging, labeling, regulation,

recycling, blistering, track and trace, and serialization.

Best Innovation in Process and Formulation Development:

Includes, but is not limited to, innovation in lower costs,

sustainability, environment friendly, low number of steps,

better quality, high process yield, continuous processing, QbD,

question-based review (QbR), CMC, and scale-up validation.

Excellence in Partnering & Outsourcing, in-cooperation

with Pharmaceutical Outsourcing magazine:

Includes, but is not limited to, excellence in strategic

partnerships, contract manufacture, QA/QC, data

management, CDMO, CRO, CMO, tech-transfer, delivery,

reliability, risk-sharing, and preferred provider.



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Madrid, Spain is the destination for CPhI Worldwide, the pharmaceutical industry’s annual exhibition and

conference. The resources listed below can help you plan your visit to the show and Spain’s capital city.

CPhI 2015 Registration and Travel

LocationCPhI Worldwide and co-located events are

held at IFEMA–Feria de Madrid in Madrid,

Spain. The Pre-Connect Conference is held

at Novotel Campo de las Naciones, Madrid.

Exhibition admissionAs CPhI Worldwide is a trade event,

no one under 18 years of age will be

allowed to enter the exhibition.

Visa informationExhibitors and visitors who require a

visa to enter Spain can obtain a formal

invitation letter from the organizer

until Sept. 7, 2015. Procedures to apply

for an invitation letter vary depending

on the country of origin. Information

about application procedures can

be found on www.cphi.com/europe/

visit/travel-planner. Questions can be

submitted to [email protected].

Travel and accommodationsEvents in Focus is an official travel

company for CPhl in 2015 and offers

hotel booking, ground transportation,

and dinner reservation services. Hotel

booking information can be accessed

via CPhI travel information web page.

The b network, one of the official

accommodation agencies for CPhI

WorldWide 2015, can assist visitors with

accommodation bookings in Madrid. The

online booking center can be accessed via

the CPhI travel information web page.

Tourism optionsMadrid, the capital of Spain, is known for

its collections of European art, including

works by Goya, Velázquez, and other

Spanish masters. Attractions include

the Prado Museum and Royal Palace.

Neoturismo, a Madrid-based company,

has partnered with CPhI Worldwide and

its co-located events to assist attendees

to book transport and tourist cards,

tours, activities, shows, and more.

Information can be accessed on the

CPhI travel information web page.

Registration/ticket packagesCPhI Worldwide offers a variety of visitor

package options. Visitors who register

online before the event can receive a free

Expo Pass. Conference and upgraded

visitor packages are also offered.

VIP and VIP Exclusive packages offer

additional travel services, access to a

VIP lounge, invitation to the CPhI Pharma

Awards, and other benefits. Visitors can

purchase a pass for a single or multiple

modules at the Pre-Connect Congress.

Registration and pricing information

can be found at www.cphi.com/

europe/visit/registration-info

Travel, Lodging,

and Tourism

For additional travel and Visa

details, visit the CPhI Travel

information web page:

www.cphi.com/europe/

visit/travel-planner

Registration and pricing

information can be found

at www.cphi.com/europe/

visit/registration-info

Ad IndexCOMPANY PAGE COMPANY PAGE COMPANY PAGE

Angus ..............................................68

Capsugel, A Div Of Pfizer ................11

Coating Place Inc ............................19

Corden Pharma Intl GmbH ................3

CPhI .......................................... 40–43

Cytec I ndustries ................................7

Federal Equipment Co ....................67

Hermes Pharma GmbH .....................6

Jost Chemical Co ............................15

Sonneborn, L LC .................................2

Veltek Associates .............................5

ES667821_PTSUPP0915_066.pgs 09.02.2015 01:17 ADV blackyellowmagentacyan

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