HIGH POTENCY PEER-REVIEWED LOGISTICStisztateritermekek.hu/wp-content/uploads/2015/09/... · 2015-09-02 · Peer-Reviewed 32 Black Specks in Tablet Stability Samples A study of root

AUGUST 2015 Volume 27 Number 8

HIGH POTENCY

Containment Performance

PEER-REVIEWED

Stability Testing

LOGISTICS

Shipping Services

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*2,400 samples of femtogram levels of alprazolam spiked

into protein-precipitated human plasma extracts over a

6 day period (over 400 samples were injected each day).

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Cover design and Art direction: Dan Ward

PTE magazine is audited

by the BPA

August 2015

Features

COVER STORY

16 Taking the Pulse of Manufacturing

Trends and Equipment Use

The 2015 equipment survey says satisfaction is high

and the use of continuous manufacturing and process

analytical technology is growing, but may be limited

by lack of knowledge and experience.

HIGH POTENCY

22 Environmental Containment Performance

Engineered containment performance testing is

a more robust method for validating containment

systems than worker-exposure measurement methods.

OPERATIONAL EXCELLENCE

37 Getting Comfortable with Lean

Companies are embracing lean manufacturing

not so much for inventory management, but to

improve supply chain visibility and control.

LOGISTICS

40 Understanding Risks in Pharmaceutical Shipping

Choosing the correct shipping solutions helps

mitigate the risks inherent in global logistics.

PharmTech.com

Columns and Regulars6 European Regulatory Watch

Regulation of Medical Devices and Companion Diagnostics

10 US Regulatory Watch

Campaign Against Fake Drugs Gains Momentum

12 Outsourcing Review

Outsourcing Becoming More Cost-Competitive

28 API Synthesis & Manufacturing

The Potential of Perfusion

44 Troubleshooting

Implementing Electronic Production Records

46 Product/Service Profiles

50 Ask the Expert

Defining Crucial CAPA Components

50 Ad Index

Peer-Reviewed32 Black Specks in Tablet Stability Samples

A study of root cause in stability samples

suggests the need for tighter control of the

sodium lauryl sulfate manufacturing processes.

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32 40

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Advancing Development & Manufacturing

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Pharmaceutical Technology Europe AugusT 2015 3

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PharmTech Europe

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6 Pharmaceutical Technology Europe AUGUST 2015 PharmTech.com

Sean Milmo

is a freelance writer based in Essex, UK,

[email protected].

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In Europe, the regulation of medical devices has traditionally

been completely separate from pharmaceuticals. But in

recent years, pressure has been mounting for a more integrated

approach to the control of medical devices, particularly in-vitro

diagnostic (IVD) tests, so that medicines regulators would be

much more involved in their approval. Medicines regulators

have tended to avoid participating in the assessment of devices,

even though at the national level, they work within agencies

that are ultimately responsible for authorization of the devices.

Nonetheless, health technology assessment (HTA) bodies, which

decide on which and often by how much pharmaceuticals

and healthcare products should be reimbursed, have started

investigating combinations of individual medicines and IVD tests

for detecting patients most responsive to them. These HTA

evaluations, however, are not comprehensive because they do

not cover the design, materials, and manufacturing process that

may affect the accuracy and reliability of the IVD equipment.

The impetus behind moves for the combined examination

of pharmaceuticals and devices, particularly companion

diagnostics specifically intended to select patients for targeted

therapy, has come from the trend towards personalized

medicines in Europe. Another driver has been the development

of electronic digitalized technologies enabling diagnostics and

health monitoring to be conducted outside laboratories at

points of care (POC) and, increasingly, by lay people with the

use of electronic wearable devices, during exercising and other

every-day activities.

As a result, the question of whether companion diagnostics

and other medical devices that help provide more effective

pharmaceutical treatments need to be regulated in ways

similar to that for medicines has become a key issue among

politicians, regulators, professionals, and healthcare sectors in

Europe. Should medicines licensing authorities control devices,

particularly with regard to design and manufacturing standards?

New legislation proposed

The European Union’s two legislative arms—the European

Parliament and the Council of Ministers representing the EU’s 28

member states—are currently in the later stages of approving

a new legislation that attempts to resolve some of these issues.

Two new proposed regulations (1, 2), one on medical devices and

other IVDs, have been drawn up by the European Commission,

the Brussels-based EU executive, to replace existing rules (3–5),

the first of which was introduced in 1990.

The objective of the regulations is primarily to achieve greater

harmonization and consistency in the way the assessment and

certification rules are applied. Initially, the commission aimed

to make only a series of incremental improvements. But then a

number of scandals took place, which forced the commission to

put forward more radical measures.

In the medical devices market, a French company was found

to have distributed breast implants made with industrial rather

than medical-grade silicone, while across Europe, there was a

widespread deterioration in the quality of metal-on-metal hip

implants (6). One of the most disturbing occurrences was with

IVDs, where an officially approved HIV test providing a high

level of false negative results was able to stay on the market

for several years (7).

The role of notified bodies

The main aim of the two new regulations is to raise standards

of assessment and monitoring along the regulatory chain. The

nationally designated organizations—called notified bodies—

responsible for evaluating and certifying medical and IVD devices

are being given powers to make unannounced audits of sites of

manufacturers and their subcontractors to check, in particular,

whether they are complying with quality management systems.

The notifying bodies, which mainly comprise certification services

companies or research institutes, will themselves be subject

to much stricter accreditation requirements, which a lot of the

existing ones may not be able to meet.

These notifying bodies will be scrutinized more closely by

the national agencies, many of them also medicine licensing

authorities, to which they are accountable. They will be subject

to joint assessments by teams from other member states.

Their workload will rise considerably. With IVD devices, the

vast majority of products will be switched from a classification

needing only self-certification by their manufacturers to one in

which they will have to be assessed by a notified body. Similar to

medical devices, submissions for approvals of IVD tests will have

to be supported by much more clinical evidence than before. In

addition, this clinical information will have to regularly updated

with data from post-marketing surveillance.

Assessment of diagnostic products

A central Medical Device Coordination Group (MDCG), consisting

of experts in medical and IVD devices, will be set up to help in

the assessment of high-risk and companion diagnostic products.

The evaluation of some high-risk devices is considered to be so

complex that it will be carried out at the national level by

specially designated notified bodies.

The MDCG will also be involved in drawing up quality

standards or common technical specifications (CTS) for

companion diagnostic devices. A network of high-calibre

laboratories, known as reference laboratories, will be allocated

the task of verifying that devices comply with CTS.

Regulation of Medical Devices and Companion DiagnosticsThe trend towards personalized medicines in Europe requires a more

integrated framework that regulates the approval of devices and diagnostics.


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When assessing companion diagnostic devices, notified

bodies will have to consult with national medicines authorities

or the European Medicines Agency (EMA) “regarding the

suitability of the device in relation to the medicinal product

concerned,” according to the Commission’s draft law (1). The

new IVD regulation, however, does not lay down to what

extent the notified body has to take account of the opinion of

EMA or national agency, except that it must be included in the

documentation for the product.

Industry concerns

This centralization of the evaluation process is worrying the

medical and IVD devices industry. “We don’t need a centralized

component in the assessment procedure,” said Oliver Sude,

legal counsel to the European Confederation of Pharmaceutical

Entrepreneurs (EUCOPE), an association representing SMEs

making pharmaceuticals and medical devices. “The present

decentralized system is on the whole working relatively well,”

he told Pharmaceutical Technology Europe in an interview.

Members of the European Parliament (MEPs) are, however,

opposed to EMA and/or the national medicines agencies being

consulted on the evaluation of the performance of companion

diagnostics on the grounds they have neither “the necessary

competence or mandate” (7). This is in line with the opposition

of the industry to medicines regulators being consulted

during the approval process of a companion diagnostic. The

European Diagnostic Manufacturers Association (EDMA) has

suggested a system in reverse, in which the medicines agencies

would consult the notified bodies when approving drugs with

companion diagnostic tests.

“At the time of approval of a medicinal product that relies on

a companion diagnostic, it is to be expected that the medicines

agency would want to have an assurance that the companion

diagnostic used performs as required,” EDMA says in a position

paper (8) on the new IVD regulation. EMA has been assisting

in the development of companion diagnostics by issuing draft

guidance on the detecting of genomic biomarkers in patients

for anticancer drug treatments, while also creating a system for

consultation with innovators in the areas. However, while the

agency has approved anticancer medicines with the licensed

indication based on the selection of patients with certain

pharmacogenetic biomarkers, none of the authorizations has

referred to the use of a specific companion diagnostic device.

Combined approach

A growing number of HTAs in Europe have been investigating

medicines, particularly anticancer ones, with companion

diagnostics in the hope that they would be able to

recommend the combination of a drug with a specific IVD test.

This approach is seen as a way of reducing treatment costs

at a time when healthcare funds are being squeezed. But few

have been able to make specific recommendations mainly due

to the scarcity of evidence showing that one IVD test works

better than another in combination with an individual drug.

The National Institute for Health and Clinical Evidence (NICE),

the UK’s main HTA, has published approximately 15 studies

of pharmaceuticals with companion diagnostics. The vast

majority of these publications, however, are appraisals rather

than guidance documents with specific recommendations.

In a paper (9) published in 2014 on the assessment of

companion diagnostics, a team of NICE researchers described

the difficulties they encountered when trying to evaluate tests

for epidermal growth factor receptor tyrosine kinase (EGFR-TK)

mutations prior to anticancer drug treatments. It cited one test

with 99% sensitivity and 69% specificity estimates while other

tests had sensitivity and specificity estimates ranging from

61% to 84%, respectively.

“A wide variety of different test methods and strategies were

being applied across the laboratories (in England) providing

EGFR-TK mutation tests services,” the researchers said in the

paper published in the Clinical Cancer Research Journal (9).

“During the assessment (of the tests), it became clear that for

several of the test strategies, there was very limited evidence on

which to determine clinical and cost effectiveness,” they added.

With pharmaceutical companies investing more in the

co-development of medicines and companion diagnostic

devices with their medicines, they will be hoping that

medicines authorities in Europe will be able to make “one

drug, one test” approvals, or even that HTAs will even be able

to make similar recommendations. “Part of the problem is

that regulations often lag behind technological progress,”

Benjamin Roussel, activity leader at Yole Developpement,

Lyons, France, a market research consultancy specializing in

the IVD sector, told Pharmaceutical Technology Europe. “With

IVD devices, the European regulations could take a long time

to catch up,” he added.

Regulating companion diagnostics within the same

legislative framework as pharmaceuticals could be a

strong platform for sustained market growth in IVD devices.

Nevertheless, the creation of such a regulatory structure

seems unlikely to happen in the near future.

References 1. EC proposed regulation 2012/0266, Medical Devices (Brussels,

September 2012). 2. EC proposed regulation 2012/0267, In Vitro Diagnostic Medi-

cal Devices (Brussels, September 2012). 3. EC Directive 1990/385/EEC, Active Implantable Medical De-

vices (Brussels, June 1990). 4. EC Directive 1993/42/EEC, Medical Devices (Brussels, June

1993). 5. EC Directive 1998/79/EC, In-Vitro Diagnostic Medical Devices

(Brussels, October 1998). 6. UK House of Commons, Science and Technology Committee,

“Regulation of medical implants in the EU and UK,” Fifth Re-port of Session 2012–13, 17 October 2012.

7. European Parliament, “Text tabled of amendments with explanatory statement on proposed regulation on in vitro diagnostic medical devices,” AT-0327/2013 (Brussels, October 2013).

8. European Diagnostic Manufacturers Association (EDMA), “A Need for Separate Legislation,” EDMA Analysis of Pro-posed Regulation on in vitro diagnostic medical devices www.edma-ivd.be/uploads/PositionPapers/EDMA_2013-22-03_PP_FINAL.pdf, accessed 15 July 2015.

9. S.K. Byron et al., Clin Cancer Res 20 (6) 1469-1476 (2014). PTE


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As concerns mount around the world regarding adulterated AAand counterfeit drugs and medical products, the United

States Food and Drug Administration is joining manufacturers and

other regulatory bodies to take more aggressive action against

“fake pharma” operators. There were more than 2000 incidents of

pharmaceutical crime in 2014, according to the Pharmaceutical

Security Institute (PSI); these involve diversion, theft, and

counterfeiting in more than 100 countries, primarily in Asia.

Illegal drug websites drive such activities, as seen in the latest

international crackdown on these operations: the June 2015

Operation Pangea VIII. Led by INTERPOL, the action netted more

than 1000 websites selling unapproved and illegal medicines and

medical devices worldwide and led to FDA warning letters to

approximately 400 websites. Similarly, reports of unauthorized

foreign versions of Allergan’s Botox in the US made headlines,

along with the arrest of members of a Miami crime ring for

allegedly distributing $200 million in illegally diverted drugs to

treat cancer, HIV, and psychological disorders. In April 2015, FDA

sent more than 300 letters alerting physicians against purchasing

unapproved drugs from Gallant Pharmaceutical International, the

target of a vast investigation of illicit sales.

Growing international concerns about a global pandemic

in substandard drugs are evident (1). The rise in poor quality

medicines and the related increase in resistance to critical

treatments for infectious diseases is examined in 17 research

papers supported by the National Institutes of Health’s Fogarty

International Centre and the Bill & Melinda Gates Foundation.

Studies sampled antimalarials, antibiotics, and TB treatments

for quality and found that up to 41% had either too much or

too little active ingredient and other formulation problems (2).

FDA framework

FDA is responding with a new strategic framework to fight illegal

medicines, under the auspices of the agency’s Counterfeit Drug

Council chaired by Howard Sklamberg, deputy commissioner

for global regulatory operations and policy. The programme is

mapped out in the Global Product Safety Net for SSFFC (sub-

standard, spurious, falsely labelled, falsified, and counterfeit)

Medical Products, reported Cynthia Schnedar, director of the

Office of Compliance (OC) in the Centre for Drug Evaluation and

Research (CDER), at a June 2015 conference on “Fighting Fakes”

sponsored by the Rx-360 consortium (3). The framework aims to

reduce public health risks caused by SSFFC medical products by

blocking their entry into the US market, by improving detection

of these products, and by developing more effective responses

when such products are identified.

Enforcement efforts to catch and shut down bogus product

distributors will be supported by the establishment of a more

effective US drug supply chain system able to track and identify

legitimate as well as illegal medical products, as required by the

Drug Quality and Security Act of 2013. CDER’s Office of Drug

Security, Integrity and Response (OSDIR) in the OC has been

implementing product serialization requirements, and product

tracking to the lot level is now in effect. By November 2017,

manufacturers must have unique product identifiers on all

prescription drug packages. This will support a system able to

identify and verify products at the package level by 2020; a fully

interoperable, electronic package level-tracing programme is

slated for 2023.

Achieving these goals involves establishing standards for

product verification and for exchange and documentation

of transactions. FDA is planning a pilot test of its ability to

respond to reports of fake or illegitimate products in the

supply chain. And agency scientists are examining new

analytical methods for detecting harmful adulterants in

pharmaceutical ingredients with an eye to creating a spectral

library with profiles for qualified ingredients and suppliers.

Global collaboration

The SSFFC framework also bolsters FDA collaborations with other

US and international agencies, such as the US Department of

State’s International Forum on SSFFC products and World Health

Organization (WHO) actions against illegal medical products,

explained OC deputy director Ilisa Bernstein at the Rx-360

conference. FDA is engaged in several US–European Union

mutual reliance initiatives to make the legitimate drug supply

chain safer and more secure, Bernstein noted. And FDA is

working closely with the Pharmaceutical Inspection Cooperation

Scheme (PIC/S); the PIC/S Permanent Forum on International

Pharmaceutical Crime aims to provide more support for

legitimate international drug supply chain operations.

Michael Deats, WHO group lead for surveillance and monitoring,

described how WHO is expanding oversight of SSFFC products

while working to gain agreement on common definitions and

tracking technologies. WHO oversight in Africa has led to reports

on more than 700 suspect products and 11 drug alerts, Deats

reported, noting that the current surge in falsified artemisinin-

based antimalarials threatens to undermine effective treatment.

A particularly alarming situation, he noted, involved distribution of

an ineffective vaccine for meningococcal C, following an outbreak

of disease that dried up supplies of the legitimate product;

difficulty in detecting lack of efficacy in a vaccine makes such

fakes particularly dangerous and easily foisted on unsuspecting

patients and health authorities. To build support for stronger

action against such illegal actors, WHO has launched a project to

calculate the harm caused by divergence and how it threatens

local manufacturers, local economies, and public health.

Similarly, an Asia-Pacific Economic Cooperation (APEC) high-

level steering committee has determined that poor quality

medicines threaten the economies and public health of member

Campaign Against Fake Drugs Gains MomentumUSFDA and the pharmaceutical industry are taking more aggressive measures to secure the supply chain.

Jill Wechsler is Pharmaceutical Technology

Europe’s Washington editor, tel. +1.301.656.4634,

[email protected].


nations. This determination has built

support for a “major initiative” to establish

a Roadmap to Promote Global Medical

Product Quality and Supply Chain Security

under its Life Sciences Innovation Forum

(LSIF). The Roadmap will be discussed

further at an APEC work stream meeting

in August 2015 in Korea, reported OSDIR

counsel Mark Paxton. Sessions will cover

a range of strategies for protecting trade

in legitimate products, including good

distribution practices, GMP audits, quality

management systems, import and export

practices, Internet dispensing practices,

detection technologies, and single

point-of-contact systems within each

APEC economy.

The APEC August meeting follows an

LSIF training programme on medical

product integrity and supply chain

security, which took place in the

Philippines in January 2015. The group

anticipates that a track-and-trace pilot

may further acceptance of GS1 standards

for product identification, which could

achieve greater efficiency in cross-border

shipping, while enhancing supply chain

security.

While biopharma manufacturers

generally support these and other

efforts to combat SSFFC medicines,

the campaign could be undermined

by the reluctance of some companies

to acknowledge the appearance of

illegal products in the supply chain

for fear that will trigger recalls and

discourage product use. Another

problem is the limited involvement of

generic drugmakers in international

anticounterfeiting efforts. And most

troubling is the emergence of different

national drug tracing systems that use a

range of product serialization and data

exchange models and requirements.

These developments point to the

importance of manufacturers and

regulatory authorities seeking agreement

on policies for transaction data

management, ownership, and access

that will lead to harmonized, international

drug tracking and identification systems

around the world. Experts also urge

brand and generic-drug firms, along with

wholesalers and distributors, to develop

a single voice on these issues to gain

more credibility and attention from both

domestic and international policymakers.

References

1. American Journal of Tropical Medicine

and Hygiene, Supplement (June 2015),

www.ajtmh.org/content/92/6_Suppl,

accessed 8 July 2015.

2. NIH, “Global Pandemic of Fake

Medicines Poses Urgent Risk, Sci-

entists Say,” Press Release, 20 April

2015, www.nih.gov/news/health/

apr2015/fic-20.htm, accessed 14 July

2015.

3. C. Schnedar, Fighting Fakes, presenta-

tion, June 2015, www.fda.gov/down-

loads/AboutFDA/CentersOffices/

OfficeofMedicalProductsandTobacco/

CDER/UCM453109.pdf. PTE

The Smart Excipient

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OUTSOURCING REVIEW

(Sp

otl

igh

t im

ag

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Sto

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/Ge

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es

Biopharmaceutical manufacturers are beginning

to consider outsourcing as a viable option for

cutting their organization’s costs, especially as

industry service suppliers offer a broader array of

potential activities. Biopharma companies report

they are contracting out more and different jobs and

manufacturing operations in an effort to reduce costs,

according to BioPlan Associates’ 12th Annual Report

and Survey of Biopharmaceutical Manufacturing

Capacity and Production (1).

The 2015 study measured a broad set of cost-

cutting activities that companies have undertaken

during the past 12 months. BioPlan specifically

evaluated whether cost cutting was being increased

in various areas of outsourcing. As a cost-cutting

action, outsourcing sits near the bottom rung

compared to more common cost-cutting measures.

The use of outsourcing as a cost-cutting approach,

however, is on the rise.

Specifically, approximately 15% of respondents

to the 2015 survey had outsourced manufacturing

to domestic service providers in the past year

specifically to reduce costs, up from 9% in 2014

and the highest mark this decade. Likewise, the

percentage of respondents offshoring work in an

effort to cut costs has been on a gradual rise, from

5.7% in 2011 to a new high point of 14.3% in 2015.

While those are fairly small percentages, the

increase indicates a recognition that outsourcing,

when done for strategic reasons, can also effectively

reduce costs and increase productivity. Many

respondents have been outsourcing for years; any

cost-savings realized would have been accrued in prior

years and, as such, these respondents would be less

apt to account for them when thinking about the most

recent 12 months. Outsourcing is also increasingly

being viewed in a wider lens than just costs, with

the decision calculus including benefits such as

flexibility, lower capital investment, and even access

to novel technologies. Nevertheless, the increases in

outsourcing due to cost cutting over the past few years

may also suggest that outsourcing service providers

are now becoming a more cost-competitive option.

Figure 1 shows the growth in outsourcing of

various manufacturing options from 2011–2015, as

related to a desire to reduce costs.

Other trends evaluated in the study also support

an increasing cost-competitiveness among service

providers. For example, when clients were asked

to evaluate the importance of various contract

manufacturing organization (CMO) attributes, there

was a large year-over-year increase in the proportion

who find it “very important” that CMOs demonstrate

the cost effectiveness of their services. The 34.3% of

respondents considering this a very important priority

is the second-highest level this decade. And yet,

again, this is in the bottom half of selection criteria,

indicating that cost-effectiveness, while important, is

only part of the picture.

Capacity trends put pressure on CMOs to optimize service delivery More biopharmaceutical products are tending

toward specialized, targeted therapies as opposed to

blockbusters. As such, some biopharma companies

with excess bioprocessing capacity may begin

offering manufacturing services themselves. Such a

move would have the effect of adding capacity and

competition to the CMO market. These new entrants

could be driven by motivations to sell their excess

capacity more for cost recovery (in terms of staffing

and other fixed costs). This sale of excess capacity

could result in more aggressive industry pricing, which

in turn could impact small- and mid-sized CMOs.

Outsourcing of process development jobs on the riseOne of the biggest jumps noted in cost-containment

this year relates to process development jobs. Indeed,

more than 17% of respondents report having reduced

costs in the past year by having outsourced process

development jobs from approximately 12% in the four

prior years.

This outsourcing of process development

projects is interesting in light of difficulties the

industry is having in filling those positions at their

facilities. Separately in the report, qualified industry

respondents were asked to identify the job positions

they are currently having trouble filling at their

facilities. The top positions, by a sizable margin, are

upstream (38.5%) and downstream (37.2%) process

development staff, well ahead of other challenging

positions to fill, such as quality assurance (24.4%) and

process engineers (23.1%) (see Figure 2).

Difficulties in hiring process development staff

are probably due to the expertise and experience

Outsourcing Becoming More Cost CompetitiveBiopharma companies are outsourcing more jobs to cut costs.

OUTSOURCING REVIEW

Eric Langer is president

of BioPlan Associates,

tel. +1.301.921.5979, elanger

@bioplanassociates.com,

and a periodic contributor

to Outsourcing Review.

12 Pharmaceutical Technology Europe AuguSt 2015 PharmTech.com


Constant innovation

Enhancing and improving through research and design

Visit www.tablettingscience.comor telephone +44 (0) 115 972 6153


necessary (which could now be

in limited supply), and may also

be a reflection of those qualified

candidates seeking higher salaries.

With hiring difficulties in this area

persisting year after year, it may be

that more companies are now looking

to outsource to specialized providers

rather than to hire in-house. Or, the

growth in those biopharma companies

realizing cost-savings from outsourcing

these jobs may be a reflection simply

of these providers being more cost-

effective than hiring in-house. With

a dwindling supply of experienced

process development staff as many

reach retirement age, companies are

increasingly forced to hire experience

from other companies, with this in

turn likely having them offer higher

salaries and other associated costs.

Outsourcing spending still growingThere has been a modest increase in

the percentage of companies realizing

cost-savings from outsourcing jobs

and manufacturing, and in this

connection, outsourcing budgets

continue to be healthy, especially for

outsourced manufacturing and R&D.

Planned budget increases this year

for outsourced biopharmaceutical

manufacturing average 3.8% among

more than 230 qualified industry

respondents, holding steady after

expected growth of 3.9% in 2014.

This is the third consecutive year of

planned budget growth for outsourced

manufacturing after a period largely

of flat spending between 2009 and

2012 (ranging from -1.3% to +0.8% in

budget changes). While outsourced

manufacturing budget growth this

year is in the lower half of the 12 areas

surveyed, it is generally on par with

spending increases planned for aspects

like new facility construction and new

technologies for upstream production.

When the analysis was widened to

include outsourcing of manufacturing

or R&D, the survey showed that

a majority (53%) of respondents

plan to increase their spending this

year, including 17% planning an

increase greater than 25%. Based

on the distribution of responses,

it is estimated that spending on

outsourcing of R&D or manufacturing

will rise by 13% this year, similar to

2014’s estimate of 13.5%.

ConclusionSeveral trends point to an increasingly

competitive outsourcing market.

Data indicates that more clients are

looking for their CMO partners to

demonstrate the cost-effectiveness

of their services, and concurrently,

a greater share are reporting cost-

savings from outsourcing of jobs and

manufacturing. At the same time,

companies’ unused capacity could

turn into a competitive threat for

CMOs, driving down prices for some,

especially larger projects. All of this

is occurring in a climate of rising

spending on outsourcing, which in

turn spurs more competition among

service suppliers for those budgets.

Reference1. BioPlan Associates, 12th Annual Report

and Survey of Biopharmaceutical

Manufacturing Capacity and

Production (Rockville, MD, April 2015),

www.bioplanassociates.com/12th. PTE

Figure 1: Selected cost-cutting actions undertaken specific to outsourcing, 2011–2015.

Figure 2: Selected areas where hiring difficulties exist in biopharmaceutical operations.

Outsourced manufacturing todomestic service providers

14.9%

2015

2014

2013

2012

2011

14.3%13.1%

12.6%

9.0%

9.4%

9.4%5.7%

Source: 12th Annual Report and Survey of Biopharmaceutical Manufacuturing, April 2015,

www.bioplanassociates.com/12th

7.1%

14.0%

Outsourced manufacturing tonon-domestic service

providers (offshoring)

38.5%

37.2%

24.4%

Source: 12th Annual Report and Survey of Biopharmaceutical Manufacuturing, April 2015,

www.bioplanassociates.com/12th

Hiring diffculties: “Which job positions at your facility

are you currently fnding it diffcult to fll?”

Process development staff, upstream

Process development staff, downstream

Quality assurance

All

fig

ure

s a

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or.

14 Pharmaceutical Technology Europe AuguSt 2015 PharmTech.com


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Each year, Pharmaceutical Technology Europe

surveys readers who work in finished drug

manufacturing, both solid dosage and parenterals,

to learn how well today’s equipment meets their

needs. The survey also examines industry issues

and trends. In 2015, themes included continuous

manufacturing, process analytical technology (PAT),

quality by design (QbD), and quality metrics (1).

Results suggest that most professionals who

operate, supervise, or engineer pharmaceutical

manufacturing systems are satisfied with existing

equipment and innovation. Responses suggest that

more readers are using PAT, QbD, and continuous

manufacturing, but that lack of knowledge may be

limiting growth of these technologies. The following is

a summary of findings from the 2015 survey.

Solid-dosage equipmentRespondents who use solid-dosage equipment

indicated that they are, for the most part, satisfied

with the equipment they are currently using. Ratings

were similar to those given in 2014 (2). As shown

in Figure 1, in six categories (encapsulation, tablet

compression, coating, packaging, mixing/blending,

and granulation), nearly 90% or more said utility was

excellent, and that they were completely satisfied or

replied with “good, but see areas for improvement.”

Approximately 80% of respondents indicated

that powder transfer/materials handling and

feeding/dispensing equipment were excellent or

good. In-process testing/PAT and process control/

automation, however, were indicated by one-third

or more of respondents as “poor, needs significant

improvement” or “inadequate, many problems.”

Integration with manufacturing and business

systems, which was a new category for 2015, also

ranked relatively low. Innovation is generally keeping

pace with needs in these areas, respondents said,

although system integration stood out as a potential

area for improvement, with 23% of respondents stating

that solutions are not available for many issues.

Continuous solid-dosage manufacturing Just over half (53%) of the respondents who use

solid-dosage equipment indicated that they employ

continuous processing either overall or in select unit

Taking the Pulse of Manufacturing Trends and Equipment UseOur 2015 survey shows satisfaction is high and the use of continuous manufacturing and process

analytical technology is growing, but may be limited by lack of knowledge and experience.

Jennifer Markarian



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Equipment Survey

operations, which is an increase

from the 40% who responded this

way in 2014. The expectation for

technological advances in continuous

manufacturing is high. Approximately

27% believe that in the next five years,

technology will evolve to permit end-

to-end continuous manufacturing

from raw materials to finished drug

product without a break between API

and drug product. In addition, 29%

believe that technology will evolve to

permit fully continuous manufacturing

of solid-dosage drug products, with

the conventional break between API

and drug-product manufacturing,

and industry will begin to use these

processes. Approximately 30% believe

technology will evolve to permit

fully continuous manufacturing, but

industry adoption will lag or use it in

select unit operations.

More than half of respondents

said that capital costs and

insufficient expertise were barriers

to implementing continuous

manufacturing at their facilities. In

addition, 41% complained that the PAT

solutions available in the market were

not sufficient to enable continuous

processing, citing that as a barrier,

while 37% said that concerns about

regulatory acceptance were impeding

use of continuous manufacturing.

Less than 30% of respondents thought

there was a lack of equipment

available in the market.

Parenteral equipment Satisfaction with equipment used in

parenteral manufacturing was high

(see Figure 2), and the percentages of

respondents rating this equipment as

“excellent” or “good” were generally

similar to or higher than those in 2014 (2).

Nearly all areas had satisfaction

rates of approximately 80% or

more. One exception was that more

than a quarter of respondents noted

significant problems in integrating

systems for existing equipment; 15%

Respondent’s prof les

Pharmaceutical Technology Europe’s

Equipment and Manufacturing Survey

targeted individuals in production and

engineering. The survey was conducted by

email in May and June 2015. Approximately

34% of respondents were from innovator

pharmaceutical companies, 29% were

from generic-drug companies, and 22%

were from contract manufacturers. The

remaining respondents (less than 6% each)

included consumer healthcare companies

making over-the-counter products,

equipment or machinery vendors, excipient

and raw material suppliers, and consultants.

Respondents were split nearly evenly

between solid-dosage and parenteral drug

manufacturing. Companies represented by

the survey manufacture products in diverse

geographies. Respondents could choose

more than one region, and they indicated

production in: the United States (61%),

Canada (21%), Mexico/Central/South

America (21%), Europe (51%), Asia (41%),

and other regions (13%), which included

Africa, Australia, India, Israel, and Russia.

Figure 2: Utility of parenteral equipment.

Figure 1: Utility of existing solid-dosage equipment.

18%

20%

23%

15%

16%

28%

29%

35%

36%

29%

26%

45%

44%

44%

65%

65%

60%

61%

56%

55%

62%

70%

27%

29%

28%

20%

18%

12%

9%

8%

9%

9%

3%

11%

7%

5%

0%

2%

0%

1%

2%

0%

0%

0% 20% 40% 60% 80% 100%

In-process testing/PAT

Integration with manufacturing and business systems

Process control and automation

Feeding/dispensing

Powder transfer/materials handling

Granulation

Mixing/blending

Packaging

Coating

Tablet compression

Encapsulation

Excellent Good Poor Inadequate

Percentages may not equal 100% due to rounding.

15%

17%

22%

32%

31%

23%

28%

27%

58%

62%

65%

56%

57%

66%

66%

73%

24%

16%

14%

13%

12%

9%

6%

0%

4%

5%

0%

0%

0%

2%

0%

0%

0% 20% 40% 60% 80% 100%

Integration with manufacturing and business systems

Process control and automation

Disposables

Sterilization

Fill-Finish (pre lled syringes)

Fill–Finish (vials, cartridges)

Barrier isolation

Lyophilization

Excellent Good Poor Inadequate


Figure 3: Single most challenging area

for high containment/high-potency manufacturing.

System set up/changeover

Getting materials into/out of the contained system during production

Ergonomics/ease of operator interaction with the restricted system during production

Air ow or air- ow changes

Environmental issues

Containment

Personnel protection

25%

17%

8% 15%

15%

13%

8%


All

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ure

s a

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uth

ors

.



Capsule filling:Manufacturing efficiency and the

added value of technical service

EVENT OVERVIEW:

As challenging new formulations are developed, how

prepared is your team to optimize the formulation

performance in encapsulation? This webinar will provide

insight into improving productivity in the use of capsules for

pharmaceutical products for both the formulator and supply

chain. Capsule flling technologies, dosing options, excipients,

capsule selection, and other factors will be discussed. An

example from the feld will illustrate encapsulation practices.

Key Learning Objectives:

n Understand the diferent capsule flling technologies and

dosing options

n Examine the role of excipients and their relation to flling

technology.

n Determine correct capsule selection

n Recognize that success is depending on correct

formulation from the beginning of the project

Who Should Attend:

n Formulator

n Operator

n Production

n M&E—flling

machine maintenance

ON-DEMAND WEBCAST originally aired June 30, 2015

For questions, contact Sara Barschdorf at [email protected]

Presenters

PATRICK SIENAERTManager Quality Assurance Capsugel

TOM WALRAEVENS Technical Service HeadCapsugel

Moderator

RITA PETERSEditorial DirectorPharmaceutical Technology

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

Presented by Sponsored by


Equipment Survey

noted a need for more innovation in

this area. A little more than 10% of

respondents noted a lack of innovation

in process control and automation;

in all other areas, more than 90% of

respondents were satisfied with the

level of innovation.

High-potency containmentOf respondents in both solid-dosage

and parenteral manufacturing who

use containment for high-potency

drug production, just over half

indicated that their company’s

level of activity (either in-house or

outsourced) had increased in the

past year. When asked to choose the

one most challenging area for high-

containment/high-potency, responses

were diverse, as shown in Figure 3.

Equipment metricsKeeping track of equipment

problems and analyzing trends

to improve operations are not

new concepts in manufacturing.

A pharmaceutical industry-wide

metrics initiative, however, will soon

be launched. Regulators, industry

associations, and manufacturers

have been collaborating to identify

appropriate quality metrics, and

FDA is working on draft guidance.

The Quality Metrics Project Team

of the International Society for

Pharmaceutical Engineering (ISPE)

concluded its initial pilot programme

(Wave 1) in April 2015, and in June, it

announced a second pilot programme

(Wave 2). These metrics will be used

by regulators for risk-based plant

inspections, but pharmaceutical

manufacturers can also use them

for continuous improvement. Nearly

90% of respondents to this year’s

survey believe that metrics and

trend analysis enhances the ability to

improve equipment operation. Nearly

three-quarters of respondents use

trend analysis to evaluate equipment

performance, and 65% have metrics in

place to measure equipment failure.

A little more than half of survey

respondents, in both solid-dosage

and parenteral equipment areas,

were aware of equipment failures

that had led to significant downtime

or quality problems in the past

year. These failures were attributed

somewhat evenly to the following

broad categories of root causes:

contamination or cleaning (29%),

utilities (28%), process validation

(20%), and nonconformance (19%);

other causes (4%) were mechanical

issues with the equipment itself.

QbDIn the four equipment areas surveyed

(see Figure 4), at least half of

respondents apply QbD to some

extent, and 20–30% fully use QbD (in

process development/optimization).

Some (16% in solid dosage, 22% in

lyophilization, and 27% in sterile/

aseptic processing) still do not

use QbD.

Barriers to implementing or using

QbD principles (multiple answers

allowed) included lack of knowledge

or training (53%), regulatory guidance

clarity (50%), management buy-in

(34%), and availability of necessary

equipment/software tools (30%).

Another barrier noted was the cost

and time required. Approximately

10% say no barriers exist.

PATPAT can include many types of tests

to measure in-process materials.

Availability of PAT has increased,

although a lack of standard solutions

and experience still hinders use

(3). Figure 5 shows the breakdown

of PAT use by survey respondents

in five manufacturing areas. In all

areas, 25–33% of respondents use

PAT, and another 26–44% plan to

implement PAT use in the coming

year. Respondents indicated that the

benefits and drivers for using PAT

(multiple answers allowed) include

better process understanding (44%),

increased efficiency (40%), shorter

process times (34%), and reduced

costs (31%).

Innovation outlook When asked to identify the most

important areas for innovation in

pharmaceutical manufacturing,

respondents noted a wide range

of issues, including continuous

manufacturing, single-use

technologies, PAT, process control,

and QbD. Others noted cost as an

important issue, including making

single-use and other new technologies

more affordable, as well as lowering

costs by reducing downtime and

running processes more efficiently.

References1. 2015 Pharmaceutical Technology

Europe’s Equipment and Manufacturing

Survey.

2. J. Markarian, Pharm. Technol. 38 (7)

28-31 (2014).

3. A. Siew, Pharm. Technol. 39 (6) (2015).

PTE

Figure 4: Use of quality-by-design (QbD) principles in process design.

Figure 5: Current and planned use of process analytical technology.

27%

29%

23%

23%

57%

54%

55%

51%

17%

16%

22%

27%

0% 20% 40% 60% 80% 100%

Solid Dosage (Tablets)

Solid Dosage (Capsules)

Lyophilization

Sterile/Aseptic Processing

Fully use

Apply to some extent

Do not use QbD in this area


28%

31%

33%

32%

25%

44%

40%

31%

31%

26%

28%

29%

35%

37%

49%

0% 20% 40% 60% 80% 100%

Tablets

Capsules

Lyophilization

Sterile/Aseptic Processing

Utilities

Use

Plan to implement this year

Do not plan to use




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Ima

ge

is

co

urt

esy

of

Po

wd

er

Syst

em

s Li

mit

ed

.

With the advent of potent drugs, the pharmaceutical

industry needed contained work practices for operator and

environmental protection; manufacturers had to implement and

validate containment solutions. To accomplish these operations,

the pharmaceutical industry looked at containment designs used in

nuclear energy plants. In addition to using advanced containment

technologies, health physicists in the nuclear industry conducted

intense surveillance monitoring for workers and their equipment and

used engineered performance testing. The same test method can be

used for validating pharmaceutical containment solutions.

Engineered containment performance testing (ECPT)To monitor containment performance, the nuclear community

developed a statistically robust method, based on a model of repeat

sampling of a data set of five samples. When the data is compliant,

a statistical strength of >95% coefficient of variability (CVt) is

achieved. Engineering performance of hardware is established, and

testing encompasses operation of tasks by an operator based on

repeatability. This methodology provided a more complete and robust

method of testing a containment system, based on actual equipment

performance, prior to testing the operator exposure during operation.

When the need to qualify pharmaceutical containment performance

began in earnest in 1993, this design model was adopted with great

success. Repeatability of the method was proven feasible. Baseline

data developed during installation qualification (IQ) allowed glovebox

integrity to be tracked through operational qualification (OQ),

performance qualification (PQ), process performance qualification

Michelle Frisch, MBA,

is senior manager, Global

Technical Systems, Powder

Systems Limited, and

a member of the AGS

Standards Committee;

michelle.frisch@powder

systems.com; and

Brian G. Ward, PhD,

CChem, FRSC, is the

owner of Barrier Concepts

and a member of the AGS

Standards Committee;

[email protected].

Environmental Containment Performance—Is There Accountability?Engineered containment performance testing is a more robust method for

validating containment systems than worker-exposure measurement methods.

(PPQ), and maintenance throughout

the working life and final disposal of

the equipment. This method provided

robust statistical data and was later

adopted for monitoring of equipment,

manufacturing suites, entire facilities,

and in one case, shared warehousing

and dispensing to satisfy a regulatory

request.

Standardized measurement of particulate airborne concentration (SMEPAC)

In the late 1990s, occupational health

professionals focused on worker

exposure measurement as the

primary target to qualify containment

equipment through workplace

outcomes, regardless of the source.

The method was formalized as

SMEPAC, later adopted and revised

by the International Society for

Pharmaceutical Engineering (ISPE).

The random nature of this guidance

on sampling methods and distribution

does not lend to a specific measure

of containment equipment or device.

The data has no statistical validity.

More importantly, the method does

not provide a baseline dataset for

future integrity testing.

Comparing sampling methodologyOne has to first decide what the

data is to be used for. It is legitimate

to use the Good Practice Guide for

Assessing Containment Performance

(formally SMEPAC)/ISPE method for

worker outcomes due to all sources

of emissions within a single test

environment. The ECPT statistical

methodology targets the engineering

capability of the containment device

while accounting for artifacts due to

all extraneous sources, regardless

of the placement of the device. In

both cases, it helps if the dustiness

index of the source/test agent is

known for comparison purposes. The

two approaches differ in both major

sampling design and sampling details.

The SMEPAC method and approach

addresses the outcome of the

operational procedure within a room

enclosure. Samples are deployed in

a specific manner to measure the

worker, room air, and containment

enclosure breach-point environments

using single samples per trial run. The

22 Pharmaceutical Technology Europe August 2015 PharmTech.com



total number of sample locations is

usually restricted to less than eight.

The ECPT statistical (artifact

corrected) method uses a randomized

grouping of five samples placed

within the air space surrounding the

containment enclosure, plus samples

located at potential breach points,

the worker, the test enclosure, and

the air inside and outside the test

environment. Sample randomization

is achieved by:

• dividing the internal volume of

the containment equipment into

equal volumes (eight or more)

• extending these volumes outside

the enclosure (eight internal

spaces leads to 56 external)

• sequential numbering of the

resulting spaces around the skin

of the equipment

• using a random number

approach to locate five sample

locations within these spaces

• excluding breach point locations

for this sample set.

These differences in sampling

clearly show that the ECPT method

will provide more relevant results. The

following case study demonstrates an

example of ECPT set-up and results.

Case study In this case study, the ECPT

methodology was used. Engineered

containment performance was

completed on a filter dryer with a heel

removal glovebox. The glovebox (see

Figure 1) is used for taking samples

during the process and off-loading of

the final compound.

The filter dryer and the glovebox

were tested as separate entities,

not just in the room environment

such as in the SMEPAC method. The

strategy was to conduct three unit-

operation studies in a controlled

and unventilated space, which is

the worst-case scenario. This plan

targeted sample locations inside the

spatial array for a total of three hours.

Performance of operator tasks was

done during the equipment operation,

including statistically random

sampling around the equipment.

The scope of work included

measurement of the operational

fugitive releases using milled

lactose as the placebo compound,

environmental impact during the

operation of the equipment, and the

operator exposure potential. The

testing included background samples

prior to equipment operation, during

operation of the equipment, and after

cleaning. Cleaning is an important

part of the testing, which is not

considered in some testing protocols.

To test the equipment, an

environment enclosure was erected

around the equipment. A sampling

manifold was constructed around

the equipment to locate the samples

at key selected sample points. The

equipment was placed in a non-

ventilated testing enclosure.

The sequence of pre- and post-

study operations involved the

following:

• The filter dryer manway was

opened.

• A pre-dispensed package of

milled lactose was inserted.

• The manway was closed.



• The hardware exterior was

cleaned with wet wipes.

• The filter dryer was rolled into

the testing enclosure.

• The walls were rolled down.

• After the procedure, the walls

were rolled up.

• The filter dryer with glovebox

was rolled out of the test space.

• The filter dryer, along with

glovebox contents, was cleaned

out to prepare for the next

operational simulation.

Containment sampling set up of the filter dryer with heel removal gloveboxThe agitator shaft on the filter dryer

was treated as a singular fugitive

release measurement. The filter

dryer and the associated glovebox

were treated as two separate test

cases. Equal volume spatial arrays

were established around the two

study cases. Two arrays were

numbered. Two separate sequences

of consecutive random numbers were

created. A random number sequence

was superimposed over each array.

Sampling matricesSampling matrices that used three

internal volumes are shown in

Figure 2.

A validation sample was required to

ensure the integrity of the sampling

and analysis procedure. The actual

sample number is typically 12,

including the spiked cassette for

validation. The setup procedure takes

longer for ECPT than SMEPAC/ISPE;

however, compared with the total

cost of a SMEPAC/ISPE study, the cost

increment is 5–10% for a baseline

data-set having lifetime value.

Sample and manifold methodology All particulate sampling methods

are a compromise. Considerations

are upper and lower particle-size

cut point, sample flow rate, sample

cassette and sample pump selection,

and matching airflow velocities (i.e.,

isokinetic sampling). While general

room airflow is approximately

90–100 ft/min, the airflow around

containment equipment approaches

stagnation. The effect of sampling

rate in liters/min (lpm) versus

entrance flow rate in linear feet/

minute (lin. ft/min) for the common

cassettes is shown in Table I.

Obviously, changing the flow rate

effectively changes the sampling

characteristics by changing the

upper cut-point. Increasing flow rate

introduces both particle bounce

losses, and vortexing beneath the

inlet orifice, both of which reduce the

sample mass collected on the filter.

Increased flow rate also reduces the

sojourn time of sample air within the

filter membrane, which increases

sample loss of small particles due to

penetration, effectively increasing

the lower particle-size cut-off

point—which affects particles of

<0.25 micron median diameter.

Higher sampling rates also produce

artificially lower data by vacuuming

adjacent areas.

Smaller particles represent low

weight per particle, but a review of

milled particle-size profiles shows

that the particle-size count increases

almost exponentially to the lowest

Table I: Effect of sampling rate in liters/min versus entrance flow rate in linear feet/minute (lin. ft/min) for the common cassettes.

Size and configuration of cassette opening (mm) Sampling rate

2 liters/min 4 liters/min

2

45o downward facing closed face cassette (a Luer #2 taper inlet) >500 lin. ft/min >1000 lin. ft/min

9

45o downward facing IOM sampler (9-mm inlet configuration) 95 lin. ft/min 190 lin. ft/min

25

Upward vertical facing open face 25-mm extended cowl 10 lin. ft/min 20 lin. ft/min

Figure 1: 0.125 m2 filter dryer and glovebox.

All

fig

ure

s a

re c

ou

rte

sy o

f th

e a

uth

ors

.




observable diameter (0.2 micron)

using a particle counter. The lowest

observed mass is due to the particles

being smaller than the wavelength

of light.

Containment leaks have a large

predominance of smoke-size (<0.2

micron) particles that remain airborne

for a long time; therefore, filter

bypass is significant. Lower sampling

rates and inlet velocities approach

a truer leakage characteristic of

containment. Samples taken in the air

volume surrounding the containment

are also subject to less artifact errors

than any taken at a distance or on a

moving operator.

Pump selection is also a major

consideration. All pumps have a

cyclic flow rate due to their design.

Performance over time typically

results in a failure rate of >10%, which

results in loss of sample-set integrity.

Conventional battery-operated pumps

exhibit flow pulsations multiple times

per second over a dynamic range

of 0–4 lpm for every pump cycle at

2 lpm average flow rate. The back

pressure due to the filter membrane

and back-up pads serves to dampen

this effect but is different for every

filter and back-up pad combination.

The use of a carbon-vane vacuum

pump having a capacity of 3.5

cu. ft/min at ambient pressure

will allow up to 14 simultaneous

samples to be collected. These

Figure 2: Filter dryer and glovebox spatial array locations.

Filter dryer spatial array & sample Glovebox spatial array & sample

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pumps have a long working life with

early warning of failure. Addition

of an adjustable vacuum break

at the head of the pump creates

constant and reproducible sampling

conditions. A typical vacuum

setting is -19 inches mercury gauge

pressure to allow delivery to 14 or

fewer sample devices operating at

2 lpm. Pressure fluctuations are

present but reduced to less than 1%

of total flow. Vacuum is distributed

using a manifold to deliver suction

airflow to the sampling matrix.

Retaining the manifold design

allows for repeat testing throughout

the usable life of the containment

system.

The case study results are shown

in Table II. The actual hardware

emission during the operational tests

is based on the following:

• An enclosure size of 8 ft x 12 in/

ft x 2.54 cm/in3 = 14.5 m3 internal

volume

• Mass of lactose released is 0.21

µg/m3 x 14.5 m3 = approximately

3 µg, assuming there is no other

source of lactose.

Containment factor (mass based)

was calculated as follows:

Mass of material handled =

1 kg or 1000 g

Mass of material released =

3 µg = 3 x 10-6g

Containment factor

(based on a 1 kg charge)

= 1000/3 x 10-6

= 3 x 108 (±1.5 x 108)

Confidence factor > 98% CVt

Conclusion

During sampling and packaging, the

filter/dryer/split butterfly valve/sample

pack-out system functioned with a 3

x 108 ± 1.5 x 108 (at 1σ) containment

factor. Analysis of variance (ANOVA)

excludes cycle 1 area data due to

inhomogeneity. Confidence factor

(CVt) after three test cycles with

pooling of data is >98% (32 samples,

after cycle 1 area samples were

excluded statistically). Thus, the

containment factor for the hardware

(3 x 108) exceeds the measurable

control of any administrative

approach, such as personal protective

equipment (maximum containment

factor of 1500).

A work-culture contribution of

apparent releases was evident from

the work practices of an informed

operator. The operator “released”

lactose from clothing, which biased

personal data during cycles 1 and

3, and cycle 1 area data. Cycle

3 area data was not statistically

eliminated. Measurements of

hardware performance and

personal exposure differed by ~103

during cycle 1 due to operator-

assignable cause.

Extreme control and

documentation of events must

be practiced when engineering

performance of hardware is being

performed at the ppq levels.

Measurement levels in these tests

approached within 103 of those

achieved in the nuclear industry

using energy meters. By comparison,

advanced environmental data

achieved during extreme studies (e.g.,

dioxin contamination) only achieved

part-per-billion measurement levels

using state-of-the-art equipment.

In summary, both methods are

viable; however, the SMEPAC/

ISPE method is adequate for a

one-condition measure of worker

exposure but an extremely poor

characterization of containment

performance of equipment based on

the operational conditions and tasks.

The ECPT method is a statistically

designed study focused around the

containment air space, equipment

performance, and operator tasks.

The ECPT method, therefore,

provides a better measurement of

engineering capability, along with

worker exposure information. Which

one would you use for accountability

and proof of equipment and operator

protection? PTE

Table II: Case study test results. The sample locations relate to the array numbers in Figure 2.

Equipment array data

Airborne concentration in µg/m³

Sample

location

Study 1 Study 2 Study 3

Background Cycle 1 Background Cycle 2 Background Cycle 2

Filter dryer agitator 0.030 2.32 0.032 0.291 0.062 0.226

Filter dryer 3

Filter dryer 4

Filter dryer 16

Filter dryer 17

Filter dryer 19

0.046

0.031

0.071

0.136

0.016

2.32

3.66

1.94

1.85

2.91

0.047

0.019

0.027

0.019

0.050

0.422

0.403

0.407

0.047

0.318

0.127

0.033

0.063

0.035

0.030

0.204

0.216

0.179

0.170

0.197

Glovebox 1

Glovebox 7

Glovebox 15

Glovebox 21

Glovebox 22

0.058

0.013

0.036

0.020

0.037

3.10

3.47

3.20

2.53

2.39

0.045

0.019

0.015

0.023

0.033

0.355

0.301

0.297

0.327

0.313

0.046

0.041

0.077

0.047

0.042

0.093

0.241

0.184

0.218

0.176

Mean

1σ

0.045

0.035

2.70

0.61

0.030

0.013

0.316

0.028

0.055

0.101

0.191

0.040




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API SyntheSIS & MAnufActurIng

Mic

ha

el B

an

ks/

Ge

ttyIm

ag

es

Perfusion technology was first introduced

in the late 1980s to boost the low product

concentrations obtained from the early cell lines

used for biopharmaceutical manufacturing. Dramatic

increases in titers for batch and fed-batch cell-

culture processes over the next two decades largely

eliminated the need for perfusion and interest

waned. A key driver today is the production of

unstable proteins that require low residence times

in the bioreactor. Recently, however, rising cost

pressures have been driving the need to achieve

greater efficiency and productivity and reduce costs.

Continuous bioprocessing is seen as a possible

solution and, consequently, perfusion is once again

attracting significant attention.

In perfusion mode, high cell numbers are sustained

for much longer periods by constantly feeding fresh

media and removing spent media while the cells

remain in culture. With this approach, optimum

conditions for growth and production are maintained

by supplying the appropriate nutrients and removing

toxic waste products. Because the product is also

regularly removed and separated from the waste

products that can cause degradation, perfusion is

highly beneficial for biologic APIs that are unstable

under production conditions.

Different methods are used to remove the spent

cells, including centrifugation, in which the cells

are separated and then returned to the reactor;

alternating tangential-flow (ATF) filtration, in which

the cells remain in the reactor and the spent media

and product are collected in the filtrate; and the

use of adherent cells that bind to capillary fibers or

membranes in the bioreactor, which allows easy

separation from the spent media.

Introduction of the ATF technology (by Refine

Technology; now owned by Repligen) was quite

significant for perfusion processes, according to

Parrish Galliher, CTO of Xcellerex, which is part

of GE Healthcare’s Life Sciences business. “ATF

and other filtration perfusion processes allow for

complete clarification of the product, whereas with

centrifugation, approximately 90% of the cells are

recycled back to the bioreactor, and an additional

filtration step is required to remove the remaining

10% of the cells from the product.” He also notes that

advances in single-use technologies for perfusion have

greatly simplified the process because sterilization

and cleaning systems are no longer required, which in

turn has made it much easier to set up and evaluate

perfusion as a viable option for cell culture.

Perfusion in practiceAs indicated above, perfusion cell culture has been

used in the industry to produce biologics clinically

and commercially for more than 25 years. Currently, a

handful of companies manufacture biopharmaceutical

drug substances using perfusion technology, largely

because these products are not stable in the

bioreactor and must be removed quickly to minimize

degradation/modification, according to Galliher.

Many more companies are looking at perfusion at

the process development and clinical scales, however.

This interest goes beyond the desire to improve the

product quality of sensitive biologics; perfusion has

the potential to reduce the scale at which reactions

can be performed and increase productivity through

better equipment utilization. “With the recent

growing interest in continuous bioprocessing, there

is renewed interest from manufacturers, equipment

vendors, and academics in evaluating and pursuing

perfusion technology,” says Chris Hwang, senior

director of late-stage process development at

Genzyme.

Many potential benefitsProperly designed perfusion processes can

significantly increase volumetric productivities

(grams/L of bioreactor working volume per day) such

that the bioreactor scale can be significantly reduced,

which facilitates adoption of disposable technologies.

The result is an increase in operational and capacity

flexibility, reduced capital and operational costs, and

Potential for improved product quality and cost/time

savings is reviving interest in perfusion technology.

The Potential of Perfusion

cynthia A. challener,

PhD, is a contributing

editor to Pharmaceutical

Technology Europe.

continuous bioprocessing is seen as a possible solution and, consequently, perfusion is once again attracting significant attention.

28 Pharmaceutical Technology Europe AugusT 2015 Pharmtech.com


API Synthesis & Manufacturing

increased speed (facility readiness

and manufacturing operation),

according to Hwang.

In addition, due to the measurable

decrease in production scale, it is

possible to develop and scale up

processes to production scale in

development labs using the same

control/automation systems and

eliminate process scale-up in

manufacturing, which significantly

decreases technology-transfer risks.

Site-to-site transfer risks can also be

reduced because perfusion processes

can be used to produce any protein

(stable or non-stable), which

facilitates standardization.

Product quality is also important.

In addition to minimizing the risks

associated with product degradation/

modification due to the reduced

product residence time in the

bioreactor compared with what occurs

in a fed-batch system, perfusion

processes can achieve steady

state product quality and simplify

downstream operations, which all

result in decreased heterogeneity and

greater product consistency.

The jury is still out, however, on

whether perfusion and continuous

biomanufacturing can truly increase

development speeds and decrease

costs for products that do not

have stability/degradation issues,

according to Galliher. “Perfusion

is very easy to achieve on the lab

scale, but there are many reports

of additional challenges to its use

on the commercial scale. Opinions

vary widely among those who have

been involved in implementing

larger commercial perfusion

processes, with some eager to use

the technology again and others

who are not,” Galliher says. The

potential advantages are sufficiently

significant, though, and many

people are evaluating perfusion to

determine its applicability for their

biopharmaceutical processes.

Integration with downstream continuous processesIntegration of a perfusion bioreactor

process with continuous downstream

processes (integrated continuous

biomanufacturing, or ICB) increases

the advantages of perfusion,

according to Hwang. “If all of the unit

operations between the bioreactor

and downstream purification are

performed continuously, one can

minimize hold times and eliminate

many unit operations, and all of

the downstream equipment can

also be miniaturized and single-use

technologies can be utilized.

The application of appropriate

process analytical technology (PAT)

enables automation of the entire

production process without operator

intervention, except to ensure

uninterrupted medium and buffer

supply,” he explains.

Genzyme/Sanofi has successfully

demonstrated at production scale

the integration of a perfusion

bioreactor with continuous capture

for model enzymes and monoclonal

antibodies with the products

Cerezyme (imiglucerase for injection),

Fabrazyme (agalsidase beta), and

Myozyme (alglucosidase alfa). In

addition, proof-of-concept of a fully

continuous process (end-to-end) has

also been demonstrated at the lab

scale, according to Hwang.

numerous considerations remainDespite changing perceptions of

perfusion and continuous processing,

significant challenges do remain.

Some are very practical issues. A

lack of adequate sensor technology

for the on-line direct evaluation of

product quality parameters—protein

folding, aggregation, glycosylation,

oxidation, contamination, etc.—

is a risk, according to Galliher.

“Product quality at present can

only be monitored indirectly on-line

through determination of solution

temperature, pH, conductivity, etc.,

and the product quality cannot be

determined until it is sampled and

analyzed. As a result, more business

risk is accumulating the longer

a process is run, and that risk is

compounded even further if perfusion

is directly integrated with multiple

continuous downstream processes

that occur without product sampling

and analysis,” he explains. Robust

in-line product quality sensors will

reduce this operational risk.

Process quality by design (QbD)

and design-space studies can also

be more complex, because the

ability to maintain product quality

over an extended period of time

must be verified for a full production

run, which can go on for weeks or

months. These longer run times can

extend development times, according

to Parrish, because QbD screening

and optimization experiments take

longer. It is possible to reduce the

number of process parameters

that are investigated to keep the

development time similar to that of

a batch/batch-fed process, but that

may lead to the development of a

less robust process. The positive view

that the United States Food and Drug

Administration has of continuous

manufacturing presents an

opportunity to evolve the guidelines

for QbD studies when applied to

continuous processing.

Unexpected costs can also reduce

the positive impacts of perfusion. As

an example, Galliher notes the benefit

that a perfusion bioreactor can be

scaled down by as much as 10-fold

compared to a conventional bioreactor,

enabling adoption of single-use

technology with a smaller footprint

and lower costs. Because the process

is continuous, additional sterile-feed

and sterile-harvest collection vessels

are required to keep the process

operating. “These additional vessels

take up room and carry additional

costs that must be considered when

determining the overall benefits of

continuous biomanufacturing,” Galliher

observes. Concentrates of cell-growth

media and buffers coupled with in-line

dilution can reduce these additional

costs. Hwang also notes that in an ICB

process, many of these tanks would be

eliminated.

Other challenges have more to

do with perceptions and company

culture. “For companies that have

historically relied on batch upstream

and downstream processes for

protein production, moving to

perfusion/continuous processes

can be difficult due to management

concern about implementing what are

considered to be new technologies

for the company, particularly with

respect to the potential for increased

risk and development times,” Hwang

explains. There is also often a desire

to fully utilize existing production

capacity, and it can be very

challenging to overcome the deeply

entrenched batch technology mindset

throughout an organization. For



API Synthesis & Manufacturing

existing products, there are additional

concerns about implementing

continuous processes as part of

lifecycle-management strategies with

respect to product comparability.

To overcome these challenges,

Hwang recommends that, to gain

experience, companies invest

resources and capital for the testing

of continuous platforms that is

de-coupled from product development.

That way, risks can be minimized

because a new platform won’t be

considered ready for manufacturing

until the expected process benefits

can indeed be achieved.

future improvementsGiven the heightened interest

in perfusion and continuous

bioprocessing, it is not surprising that

equipment and device manufacturers

are working to develop improved

solutions for perfusion processes.

“Key goals are to make perfusion

more robust, scalable, and easier

to operate,” says Galliher. GE is

looking at all aspects of the system,

such as in-line dilution systems

and improvements of the filtration

process (prevention of clogging) to

increase flow rates for larger-scale,

single-use filtration systems.

Both Galliher and Hwang agree

that the development of novel, robust

PAT sensors for in-line monitoring of

process performance and product

attributes in real time will be crucial

for the more widespread adoption

of perfusion and other continuous

bioprocesses on a commercial scale.

For full integration into disposable

platforms for protein production, pre-

sterilized production-scale perfusion

systems must also be developed,

according to Hwang.

“FDA has been encouraging the

industry to transition to continuous

manufacturing (CM) since 2011

because the agency sees CM as

a key enabler for modernizing

pharmaceutical manufacturing. I

anticipate that with the continued

improvement of bioreactor cell

densities and further increases in

volumetric productivities, there

will be growing interest in the use

of perfusion technology for protein

production,” says Hwang. “Coupled

with the potential significant

strategic advantages of ICB, I

suspect that industry adoption will

continue to increase and further fuel

advancement of the intensification

of perfusion and continuous

bioprocesses,” he concludes. Pte

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 programme has been expanded

to eight categories of small- and large-molecule

drug development and manufacturing technologies.

Pharmaceutical Technology Europe is a partner for the

Best Innovation in Manufacturing Award.

The CPhI Pharma Awards, which were developed

to raise the profile of unique innovations, are open to

companies operating across the pharmaceutical and

biotechnology sectors. Companies exhibiting at CPhI

Worldwide in 2015 can enter for free. For companies

that are not exhibiting, the entry fee is €95.

Award finalists will present their technologies and

the winners will be announced at CPhI, 13–15 Oct., in

Madrid, Spain. Three categories awarded in previous

years return for 2015:

•Best Innovation in Packaging: Includes innovative

delivery devices, materials, packing/filling

processes, tamper-proof packaging, easy-access

packaging, labelling, regulation, recycling, blistering,

track and trace, and serialization.

•Best Innovation in Process and formulation

Development: Includes innovation at lower costs,

sustainability, environment-friendly products,

improved quality, high process yield, continuous

processing, quality by design, scale-up, and

validation.

•excellence in Partnering & Outsourcing: Includes

excellence in strategic partnerships, contract

development and manufacturing, QA/QC, data

management, tech-transfer, delivery, reliability, and

risk-sharing.

New categories expand recognition in the following areas:

•Best Innovation in Biologic Drug Development

and Manufacturing: Includes innovation in single-

use and aseptic/sterile technologies, prefilled

syringes, vials, bioreactors, media supplements,

cell lines, separation and filtration, and process

chromatography.

•Innovation in Supply chain & Logistic

Management: Includes innovation in logistics, cold

chain, transport, temperature-controlled shipping,

trackers, barcoding, quality control, and analytic

testing.

•Best Innovation in Manufacturing technology:

Includes innovation in equipment, manufacturing

processes, tech-transfer, tableting, and filling.

•ceO of the year: Attributes to be considered include

global reach, leadership skills, management capability,

charity, regulatory review, sales turnover profits,

vision, marketing, acquisitions, strategy, and financing.

•Best Innovation in APIs and excipients: Includes

innovation in formulation, excipients, drug delivery,

pegylation, manufacturing processes, freeze-drying,

intermediates, purity, and lyophilization.

Submission, judging, and winner selectionThe submission deadline for awards applications is 7 Aug.

2015. A Jury Panel will evaluate and discuss submissions.

Finalists, who will be announced on 21 Sept., will present

their technologies to the Jury Panel and CPhI attendees

on 13 Oct. The Jury Panel will reevaluate and score the en-

tries to determine the winning entries, which will be

announced at an award ceremony on 13 Oct.

Rules, submission information, application forms,

and other details can be found at www.cphi.com/

awards/home.

call for entries: 2015 cPhI Pharma Awards

30 Pharmaceutical Technology Europe AugusT 2015 Pharmtech.com

ES644242_PTE0815_030.pgs 07.24.2015 02:17 ADV blackyellowmagenta

Innovative Tools for the Development and Manufacturing of

Biotherapeutic Proteins

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

EVENT OVERVIEW:

The biopharmaceutical industry has seen ever increasing innovation

over the past fve years. Most notably, there has been an increased

adoption of high-throughput process development (HTPD) and sin-

gle-use technologies. The Patheon Cell Culture development group is

leveraging HTPD technologies to identify and characterize the efect of

critical process parameters early in the development cycle. The down-

stream team has been on the forefront of implementing innovative

disposable technologies that facilitate cost efective and streamlined

manufacturing processes.

This webinar will review Patheon’s use of the Ambr™ 15 system for HTPD

using design-of -experiment methodology, next-generation depth fl-

tration technology, pre-packed columns, and high-capacity membrane

chromatography.

Key Learning Objectives

n Efective strategies to match product quality attributes for a

biosimilar product

n Reducing process development time lines

n Driving innovation in biologics process development

For questions contact Kristen Moore at [email protected]

Sponsored by Presented by

ON-DEMAND WEBCAST Originally aired July 30, 2015

PRESENTERS

Matt Caple

Scientifc Director

Cell Culture Development

Patheon

Paul Jorjorian

Senior Scientifc Manager

Purifcation Development

Patheon

Moderator

Rita Peters

Editorial Director

Pharmaceutical Technology

Who Should Attend

n Biopharmaceutical Scientists

n Project Managers

n QA/QC Scientists

n Process Development Scientists

n Research and Development

Scientists

n Formulation Scientists

n Project Managers

n Supply Chain Specialists



PEER-REVIEWED

Black Specks in

Tablet Stability Samples

Visual appearance of pharmaceuticals is important in

determining how closely patients comply with their

dosage requirements. One problem that is often seen in

tablets is discolouration, or black specks, on the surface.

These specks can form because of contaminants in raw

materials or from the tablet manufacturing process, and

various interactions that may occur during storage. The

development of tablet discolouration during storage is often

complicated to investigate, because it could involve a variety

of interactions between active ingredients, excipients, and

packaging materials. This technical case study describes

how black specks in tablets were investigated during a

stability study.

Materials and methods

Materials. The pharmaceutical tablets used in this study

were film-coated, controlled-release tablets manufactured

at Patheon. All excipients used to manufacture the tablets

were commercially available and met the united states

Pharmacopeia (usP)/European Pharmacopoeia (EP)/Japanese

Pharmacopoeia (JP) standards. Non-active ingredients

included:

• Lactose monohydrate

• Hydroxypropylmethylcellulose

• Starch 1500 (pregelatinized starch)

• Sodium lauryl sulfate (SLS)

• Colloidal silicon dioxide

• Magnesium stearate.

The content of API was low, at either 0.1 or 0.4 mg per

tablet.

Methods. The microbial limit test was performed using

usP <61> and <62>. Visual inspection was performed on the

core, coated tablets, and excipient/active binary mixtures

after storage at 40 °C/75% relative humidity (RH) and 60 °C/

ambient humidity for 4–6 weeks. Backscattered electron

microscopic imaging and elemental composition analysis for

the tablets with discolouration were performed using a JEOL

JSM 6400 Scanning Electron Microscope (SEM) coupled with

Energy Dispersive X-ray Spectroscopy (iXRF EDS/XRF). Mass

spectra of SLS were obtained by direct infusion of aqueous

solutions of SLS samples into an AB Sciex 3200 LC/MS/MS

system with electrospray ionization in both positive and

negative modes. Other SLS tests were performed as per the

usP/EP/JP monographs for SLS.

Geoff Carr, PhD, is director of analytical development, Canada,

for Patheon, in Mississauga, Ontario. [email protected].

Submitted: 5 January 2015. Accepted: 26 January 2015.

Geoff Carr

A study of root cause in stability samples suggests

the need for tighter control of the sodium lauryl

sulfate manufacturing processes.

MA

RT

IN B

AR

RA

UD

/OJO

IM

AG

ES

/GE

TT

Y I

MA

GE

S

CITATION: When referring to this article, please cite it as G. Carr, “Black

Specks in Stability Samples,” Pharmaceutical technology, 39 (8) 2015.


Stability Testing

Results and discussion

Tablet samples were subjected to a stability study under

real time (25 ˚C/60% RH) and accelerated (40˚C/75% RH)

conditions. After three months, the samples held under

accelerated conditions started to exhibit black specks as

demonstrated in Figure 1.

Because no observations of black specks were reported

when these tablets were initially tested for release, after one

month at 40 ˚ C/75% RH, or following storage at 25 ˚C/60%

RH, it could be concluded that the specks did not result

directly from contamination of tablet ingredients and were not

introduced during the manufacturing processes. Instead, they

were more likely due to some changes that occurred within

the product during the three months when the product was

exposed to accelerated storage conditions. An investigation

was started to identify a root cause for these observations.

Microbial limit test. Microbial contamination was

investigated as a potential cause of tablet discolouration,

because the warm, moist conditions within a 40 °C/75%

RH stability chamber presented a good environment for

accelerating growth of microbes.

Microbial limit tests (MLT) were performed on those tablets

whose surfaces showed significant discolouration. Results

met all acceptance criteria for total aerobic microbial count,

yeasts, molds, and indicator organisms, which ruled out

microbial contamination as a root cause of the black specks.

Excipient interactions. Because this phenomenon was

clearly due to product changes over time, and not some initial

contamination, some form of interaction between tablet

ingredients was strongly suspected. To study this further, the

authors decided to simplify the system by working with binary

mixtures. Thus, excipient compatibility tests were performed

by compressing binary mixtures (excipient/excipient,

excipient/active) of each component of the tablet formulation

into tablets and stressing the tablets under 60 °C and 40 °C

for up to six weeks. Three different lots of each excipient were

tested to evaluate batch-to-batch variability. The core and AL

L F

IGU

RE

S A

RE

SU

PP

LIE

D B

Y A

UT

HO

R.

Figure 1: Example of black specks on tablets.

Save the date!

23 to 24 September 2015 · Barcelona, Spain

Course No. 3144

MAKING SCIENCE WORK

APV/IPEC Europe Excipient Conference 2015

– An update on regulatory and application developments

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– An update on regulatory and application developments

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including 3 parallel workshop sessions

• Change Management of Excipients

according to IPEC Significant Change Guide

• Risk Assessment for Excipient GMP

• How to Establish a Quality Agreement

for Excipients



Stability Testing

coated drug product tablets were also stressed to evaluate

the compatibility of the coating material with the formulation

core. Binary mixture stress results showed that discolouration

developed mainly in those samples that contained

material from one specific lot of SLS. Further, the extent of

discolouration increased with increasing temperature.

In addition, discolouration shown on both core and coated

tablets indicated that it was not caused by incompatibility

between the formulation core and any coating material

ingredients.

Imaging and elemental analysis by SEM/EDS. Back-

scattered electron imaging and elemental composition analysis

on the areas of discolouration of the tablets were performed

by SEM/EDS. Results are shown in Figure 2; the image is in

negative mode so that the white area is actually the black

speck.As shown in the figure, discoloured areas on the

tablets are enriched with the elements sulfur (S) and sodium

(Na). The only excipient in the formulation that contained

S and Na was the SLS, which further supported a strong

relationship between SLS and tablet discolouration.

3.0K

2.0K

1.0K

Cnts

2.0K

1.0K

CntsC

C

OO

Na NaSiS

S

5 10 5 10

09-012-13877-39384-2 09-012-13877-39384-3

EDS Spectra

White phase Black spot

Figure 2: SEM/EDS analysis of black specks on tablets.

Table I: Physical appearance of stressed samples of Sodium Lauryl Sulfate (SLS).

SampleStress

condition

Time points (weeks)

Initial 1 2 3 4

Lot A60 °C White powder

White powder

with yellow

to brownish

specks

White powder

with yellow

to brownish

specks

White powder

with yellow

to brownish

specks

White powder

with yellow

to brownish

specks

Ambient White powder White powder White powder White powder White powder

Lot B60 °C White powder White powder White powder White powder White powder

White powder White powder White powder White powder White powder


Stability Testing

Stress study on SLS. Four samples of two lots of SLS

were used in this study. Lot A was the same lot used to

manufacture tablets that showed discolouration after

holding for three months under accelerated conditions.

Lot B was a fresh sample from a different supplier. Both

lots were held at two different conditions: ambient (as a

control) and 60 °C for four weeks. The physical appearance

results are summarized in Table I.

Results indicated that discolouration appeared in

stressed samples of SLS from Lot A and did not show up

in stressed samples from Lot B or the control samples

of either lot. A new batch of tablets was manufactured

using the SLS from Lot B and then stressed at 60° C/

ambient RH for four weeks. No tablet discolouration was

reported over this period. Because both lots of SLS were of

a pharmaceutical grade that met the requirements of usP/

EP/JP, some further investigation was then conducted to

try to establish why the different lots performed differently

in tablets.

Analysis by mass spectroscopy (MS). Mass spectra of

SLS from Lot A and Lot B were obtained by direct infusion

of aqueous solutions of each lot into an AB Sciex 3200 MS/

MS system. Both positive and negative turbo ion-spray

modes were used to collect the MS data.

Figure 3 displays the mass spectra of negative mode.

Peaks at m/z at 60.0 and 212.0 are from blank, and the

peak at m/z 265 corresponds to SLS (C12

H25

SO4). Apart from

these peaks, there were two major peaks (m/z 293 and m/z

97) observed only in the SLS sample from Lot A. These two

peaks correspond to the C14 tetradecyl sulfate homologue

(C14

H29

SO4) and residual sulfuric acid (HSO

4), respectively.

The mass spectra of SLS collected from positive mode

were crowded with peaks, which made it dif f icult to

interpret. But, overall, the number of peaks from Lot A was

much greater than the number of peaks from Lot B.

The combined negative and positive mode results

indicated that SLS from Lot B has a higher degree of purity

than SLS from Lot A, but, more specifically, Lot A showed

a significant m/z peak that corresponded to sulfuric acid,

which was much less intense in the spectrum of material

from Lot B.

Compendial test results. Table II summarizes the

quality control (QC) release test results of the two lots of

SLS used in this study. Results showed that, although both

lots satisfied the specification requirements of usP/EP/JP,

Lot A had a higher level of unreacted alcohols and a lower

assay value than Lot B. In addition, the alkalinity and pH

value of Lot A are lower than those from Lot B, which again

supports the view that this particular lot does contain an

excess of sulfuric acid.

Discussion. The investigation data demonstrated that

the discolouration of the tablets is closely related to the

impurities of the SLS used in the tablet formulation.

SLS is commercially manufactured by sulfation of lauryl

alcohol, followed by neutralization with sodium carbonate.

The three most common industrial synthetic processes are:

Table II: Comparison of compendial test results of sodium lauryl sulfate (SLS). USP is united states Pharmacopeia,

EP is European Pharmacopoeia, JP is Japanese Pharmacopoeia, NMT is not more than, NLT is not less than.

Tests Method LimitResults

Lot A Lot B

Alkalinity USP/EP/JP NMT 0.60 mL required

for neutralization

0.04 mL 0.10

Unsulfated alcohol USP/EP/JP NMT 4.0% 0.7% 0.0%

NaCl and Na2SO

4EP NMT 8.0% 1.3% 2.0%

SLS assay USP NLT 85.0% 92.0% 96.0%

pH in aqueous solution USP/EP/JP N/A 6.7 9.6



Stability Testing

SO3 /air process

Step 1 C12H

25OH + SO

3 → C

12H

25SO

4H

Step 2 C12H

25SO

4H + Na

2CO

3 → C

12H

25SO

4Na + CO

2 + H

2O

Oleum (H2 SO

4 /SO

3 ) process

Step 1 C12H

25OH + H

2SO

4/SO

3 → C

12H

25SO

4H + H

2O

Step 2 C12H

25SO

4H + Na

2CO

3 → C

12H

25SO

4Na + CO

2 + H

2O

Chlorosulfonic acid process

Step 1 C12H

25OH + ClSO

3H → C

12H

25SO

4H + HCl

Step 2 C12H

25SO

4H + Na

2CO

3 → C

12H

25SO

4Na + CO

2 + H

2O

For the starting material, lauryl alcohol is usually made

from natural products (e.g., coconut or palm kernel oil)

followed by a series of hydrolysis and reduction reactions.

Due to the natural origin, the lauryl alcohol used for the

starting material often contains a minor quantity of C-10,

C-14, and C-16 homologues, and they can be further

transferred into the final product. Because of the similar

chemical/physical property of those homologues, they are

not considered to be impurities of SLS.

From the synthetic routes, the most common synthetic

impurities of SLS are the unreacted residual alcohols, residual

sulfuric acid (resulting from incomplete neutralization and/

or inefficient purification), salts (NaCl and/or Na2SO

4), and

the remaining Na2CO

3 after the final neutralization reaction.

This is probably why compendial monographs of SLS include

specification requirements for alkalinity, sodium chloride,

sodium sulfate, and unsulfated alcohols content.

The impurity profile and levels in the SLS final product depend

on the actual sulfation process used for SLS manufacturing

and how well the process is controlled. For example, the

oleum process is an equilibrium process, which usually

leaves large quantities of sulfuric acid in the final reaction

mixture, and the unreacted sulfuric acid must be separated

from the reaction matrix before the final neutralization step

takes place. Therefore, SLS manufactured from this process

usually contains a relatively high level of sulfate. On the other

hand, for the SO3/air or the chlorosulfonic acid process, the

reaction is stoichiometric and fast. When reaction conditions

are tightly controlled, there is much less sulfuric acid or

sulfate formed, resulting in a product of higher quality.

It is possible that during the manufacturing of SLS (Lot A),

the neutralization step had not been completed, resulting

in the presence of residual sulfuric acid in the final product.

This could explain the low alkalinity and pH value reported

in Lot A from the QC release test results (Table II). Upon

storage at higher temperature, the residual sulfuric acid

undergoes dehydration reactions with the carbohydrate

excipients (e.g., lactose) in the tablet formulation, resulting

in the formation of black specks.

Conclusion

The most likely mechanism of tablet discolouration was

related to the dehydration reaction between the residual

sulfuric acid (due to incomplete neutralization during SLS

manufacture) and the carbohydrate excipients present in

the formulation, upon storage at higher temperatures.

Tablet discolouration is closely related to the quality of SLS

used in tablet formulation, and the quality of SLS depends

on the synthetic route and degree of process control used

by the SLS during manufacture.

Current specifications of SLS in compendial monographs

are not sufficient to control the quality of SLS, because

they do not discriminate between dif ferent SLS lots,

including those that may cause this type of drug product

failures. Therefore, it is recommended to develop a testing

requirement in the usP/EP/JP monograph that more tightly

controls the formation of residual sulfuric acid and other

impurities during SLS manufacturing. PTE

Figure 3: Mass spectra of Sodium Lauryl Sulfate (SLS) from negative mode

2.2e8

2.0e8

1.8e8

1.6e8

1.4e8

1.2e8

1.0e8

8.0e7

6.0e7

4.0e7

2.0e7

1.30e8

1.20e8

1.10e8

1.00e8

9.00e7

8.00e7

7.00e7

6.00e7

5.00e7

4.00e7

3.00e7

2.00e7

1.00e7

40 60

60.079.9

97.0

99.2 140.8

212.1

237.2 279.0295.3

293.4

60.0

45.161.0

89.0 97.0 148.0 156.0 195.0

212.0

265.3

213.2263.3

279.3295.2 321.2 365.2 377.1

265.0

307.3

80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400m/z, amu

40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400m/z, amu

Lot A Lot B

-Q1: 64 mCA scans from Sample 17 (NEG Stepan fresh) of SLS investigation.wiff (Turbo Spray) -Q1: 50 mCA scans from Sample 11 (NEG Cognis Fresh) of SLS investigation.wiff (Turbo Spray)Max. 2.2e8 cps. Max. 1.3e8 cps.

Inte

nsi

ty, cp

s

Inte

nsi

ty, cp

s


In the past two decades, drug manufacturing

companies launched the industry’s first corporate

lean manufacturing (Lean) and operational excellence

(OpEx) programmes. Using modern industrial

engineering concepts advanced by thinkers such as

Deming, Juran, Shewhart, and principles from the

Toyota Production System (TPS), companies began

to apply models from other industries to change

the way they approached operations and inventory

management at key facilities. At Johnson & Johnson,

Bristol Myers Squibb, Novartis, and Wyeth, the rise of

teams led by empowered operators and a focus on

inventory management and metrics such as overall

equipment effectiveness (OEE) were seen.

As Japanese terms and phrases such as Kanban,

Kaizen, and gemba (see Sidebar) entered pharma’s

lexicon, observers challenged the industry to get

better at inventory management, offering Dell

Computer and Amazon as role models (1). If Apple can

get its inventory turns to 74 (1), and Dell to 36, they

reasoned, why should pharma’s continue to hover

around 2.3 (2)?

Now, there is little media coverage of Lean

pharma programmes. Drug companies have reduced

headcount—between 2009 and 2014, 156,000 jobs

were lost in the United States alone, according to the

executive recruiter, Challenger Grey Christmas (3).

Pharmaceutical manufacturers have also shut down

major research and manufacturing facilities.

Mergers have complicated the picture—not only

recent inversions, but prior consolidations, which have

challenged companies to connect different legacy

systems and cultures. The Lean and OpEx showcase

plants of the past have been closed or sold. Wyeth is

now part of Pfizer, and its showcase Lean Pearl River

plant is no longer manufacturing. Novartis’ Diovan has

come off patent, and its Lean plant in Suffern has been

shut down. J&J, the first drug company to launch a

formal corporate OpEx programme, has faced some

serious compliance and quality problems at its facilities.

Does this mean that pharma has suspended its

efforts in Lean and OpEx? Observers see pharma

as entering a new, more difficult phase in its Lean

evolution, since manufacturing has become so much

more complex at pharma facilities. A dedicated

pharmaceutical manufacturing plant that might have

made one or two products in the past may now be

manufacturing 20 or 30 for different global markets.

“The biggest challenge for today’s pharma OpEx

programmes is that plants have much higher mix now

than they did in the past,” says Tom Knight, CEO of

Invistics, a Georgia-based company that offers cloud-

based software to monitor and improve control of

Lean metrics. “Employees are being asked to do more

production at the same facility,” he says.

“The easily achievable cost saving projects of

the past were completed with much fanfare. Now,

the more complex projects will take more effort,

resources, buy-in, management commitment, and

time,” notes Prabir Basu, consultant and former

head of the National Institute for Pharmaceutical

Technology and Education (NIPTE).

Adding complexity is the fact that OpEx requires

open communications, and pharma still tends to be

Agnes Shanley

Jett

a P

rod

uc

tio

ns/

Ble

nd

Im

ag

es/

Ge

tty

Ima

ge

s

Getting Comfortable With LeanContract research, development, and manufacturing organizations are

embracing lean manufacturing, while Big Pharma is applying it, not so

much for inventory management, but to improve supply chain visibility and control.

Pharmaceutical Technology Europe August 2015 37


Operational Excellence

siloed. “Over the past decade, I’ve

come to the conclusion that pharma’s

compliance and quality issues are

largely due to communications. You

need to communicate before you can

coordinate, and to coordinate before

you can collaborate,” says William

Botha, a lean consultant based in

California who has held senior positions

at large biopharma companies.

“There is often a miscommunication

of standards and vision, and lack of

feedback to teams on where they are

in terms of performance and what is

required,” he says. “Lean and OpEx

tools, from standard work to kaizen, are

all about communication,” he says.

Some see this silence about Lean as

a sign that OpEx adopters have made

it part of their cultures. After all, after

movies like Gung Ho in the 1980s, one

never hears about automotive’s Lean

projects anymore, notes Greg Anthos,

senior managing consultant for life

sciences with Tunnell Consulting (King

of Prussia, PA). “Early pharma adopters

have moved from major upskilling to

more of a maintenance of skills and

more targeted activities in focused

target areas,” Anthos says. “At some

companies, Lean and OpEx have

become the way they do business, as

they have at GE and Ford.”

There are still a lot of OpEx projects

going on, notes Lean expert Thomas

Friedli, professor at the University

of St. Gallen, Switzerland. “Today,

generics companies are working to

systematize their global approaches to

continuous improvement, and contract

manufacturers are also following this

path,” he says. He also sees much more

engagement to OpEx coming from

quality departments.

Perhaps today’s Lean goals have

become more limited but also, more

realistic. Drug shortages, aging

facilities, a drier pipeline of new

products, and manufacturing problems

have made it less important to manage

inventories as well as Apple, than to

guarantee a stable supply of quality

product.

As a result, observers may not be

seeing that much improvement in

pharma’s inventory turns, but they note

a real improvement in metrics such

as reduction in cycle time and cost of

goods sold (COGS). These efforts are

occurring as Big Pharma outsources

more functions. In turn, contract

companies are developing their own

flavors of OpEx and Lean.

CMOs: pharma’s latest convertsWhere, in the past, Big Pharma

companies would transfer their own

OpEx programmes to contract partners

and suppliers, today, contract research,

development and manufacturing

organizations (CMOs, CDMOs, and

CROs) have their own programmes

in place. Patheon is an example, but

smaller companies such as Rottendorf

are also doing this.

Some pharma companies and their

contract partners share data to gain

one view of their combined supply

chain. Shire Pharmaceuticals and its

contract partner Patheon, for instance,

linked data to build a dashboard that

provides visibility at all points along

the supply chain, from API plant to

finished drug product to packaging and

finally, logistics, and distribution. The

companies used Invistics’ technology

to build this feature, and other pharma-

contract duos are building common

dashboards to increase transparency.

“Often, separate companies have very

little visibility into their supply chain.

This can lead to firefighting, a lot of

excess inventory and wasted effort,”

says Knight. The project reduced Shire’s

cycle times by 40%.

In another project, Mylan

Pharmaceuticals is using a

platform developed by Invistics and

BuzzeoPDMA, based on Lean and Six

Sigma principles, to offer real-time

dashboards and insight into controlled

substance supply chains and sample

activity.

From plant floor to development labA growing number of Big Pharma’s

current OpEx projects are moving

well beyond the plant floor, into areas

such as development, from late- stage

research to commercialization. “That’s

where you can have the greatest

impact on the patient on the outcome

and the cost structure of the product,”

says Anthos. “Adopters are applying

Lean and OpEx concepts earlier in

process development, not only to get a

more robust product, but also a more

effective and efficient process from the

start,” he notes. This isn’t always easy,

he adds, because they’re also trying to

speed time to market, and the goals are

sometimes in conflict.

A growing number of quality

professionals are advocating for OpEx

and Lean, notes Botha. This will be

important, because the recent past has

seen so many compliance failures in the

industry. However, there is a need to

build quality into the OpEx programme,

notes Basu, or the company will

eventually compromise on quality.

“When I was involved in Six

Sigma type operational excellence

programmes at Pharmacia, quality

and regulatory groups were part of

the team, and they were integral to

the cost savings programmes,” he

says. Short-sighted managers do not

realize that integrated programmes

not only improve quality but save

money. In addition, they often fail to

understand that most of the cost of

poor quality and noncompliance results

from inefficient operations, Basu says.

“Cost and effort go into failed batches,

incident investigations and deviation

explanations,” he says, noting that

long-term management commitment

is needed for synergistic programmes

to succed.

Guilt by association?The very term “Lean” may have a

negative connotation to many who

don’t know what it is, Basu notes.

Some companies have used the term

as a euphemism for downsizing and

cutting corners.

Applying Lean and efficiency

programs to a dysfunctional system

only leads to failure. Anthos suggests

that managers ask some deep

questions, and fix any problems that

they find, before embarking on any

efficiency programs. “How robust

are your processes? Can you make

a product on time and get it to the

patient, at the right quality and

efficacy? It’s a waste of time to talk

about efficiencies when you’re not

good at what you’re doing.”

Critics have also complained that

Lean and OpEx are being misapplied

to drug discovery and R&D, and

stifling innovation. Outreach and

training are needed to counter

these problems, experts agree.

The serendipity of inspiration and

innovation, those “aha” moments,

cannot be subjected to Lean and

OpEx analysis, but the processes and



Operational Excellence

labs supporting that innovation and

connecting it to other vital operations

can, and should, says Anthos.

The key to success in Lean and

OpEx remains top-down management

support, consultants agree. In today’s

business environment, some pharma

CEOs are too distracted by major

top-line business challenges, such as

which companies to acquire, which

therapeutic areas to focus on, and

how to improve their business models,

Anthos says. Thus, the image of the

Toyota-style CEO rolling up his or her

sleeves and going to visit company labs

and manufacturing facilities has not yet

taken root in pharma.

Some managers had an awakening

as part of consent decrees, which

required that they spend more time in

the gemba. But Botha sees a change

taking place in younger pharma

managers.“Younger leaders like to get

on the floor more, maybe because

they haven’t spent 20–30 years being

rewarded for being in meetings,” he

says. “They are more social, more savvy

about building relationships, and they

seem to understand that it’s all about

people, and that what got them to their

current position won’t guarantee the

next promotion.”

To paraphrase Mark Twain, rumours

of Lean’s death in pharma have been

highly exaggerated. If you don’t hear

anything about OpEx at the pharma

plant near you, or even your own lab

or facility, that doesn’t mean it isn’t

happening. Pharma Lean and OpEx

programmes are alive and well, but

moving into new spaces.

References1. Apple Turns Over Entire Inventory Every

Five Days, appleinsider.com, http://

appleinsider.com/articles/12/05/31/

apple_turns_over_entire_inventory_

every_five_days, accessed 23 July 2015.

2. R. Spector, How Lean is Pharma?

Pharmamanufacturing.com, 2010,

www.pharmamanufacturing.com/arti-

cles/2010/109/, accessed 23 July 2015.

3. Pharma Mergers Mean Layoffs, wsj.com,

www.wsj.com/articles/SB1000142405

2702304393704579532141039817448,

accessed 23 July 2015. PTE

The Toyota Production system

(TPS) introduced many to new

terms routinely used in Japan,

that are crucial to success in

eliminating waste and improving

agility.

Kanban—Used in Just in Time

or “pull” operations, in which

manufacturing is dictated by

market demand, are communica-

tions tools that show delivery of a

given quality.

Kaizen—Small, incremental

improvements in some process,

typically solicited from people on

the plant floor or lab.

Gemba—The place where truth

will be found, or where work is

done. TPS requires top managers

to visit the gemba to understand

employee and customer needs.

A full glossary can be found at

http://us.kaizen.com/know.

Lean Lexicon

Continuous monitoring system checklist Yes No

• Will it keep me compliant with all major

regulatory regimes?

• Does the system o�er wireless monitoring?

• Does it automate reporting to save time?

• Is the system quick and easy to install

and validate?

• Is there dedicated support?

• Does the system have a proven track record?

√

√

√√

√

√

www.vaisala.com/cms

Prevent the UnexpectedProtecting Your Critical Assets

24/7 – the Vaisala viewLinc

Monitoring System


Shipping of pharmaceutical drug products —which

may involve long, complex routes and require

temperature-controlled environments—can be

challenging. “Temperature excursions, customs

delays, packaging breakdowns, incorrect shipping,

and packing choice are all risks inherent in today’s

global logistics market,” notes Sue Lee, global

technical portfolio manager for World Courier. The

shipping process is crucial; indeed, “Lives may depend

on a drug making it safely from origin to destination,

within temperature range, and on-time,” notes Carl

Asmus, vice-president of supply chain solutions and

market development at FedEx.

Pharmaceutical Technology Europe spoke with

Lee; Asmus; Brian Kohr, president and CEO of CSafe,

a cold-chain solutions provider; and Wanis Kabbaj,

marketing director, UPS healthcare strategy, about

these risks and the shipping solutions available to

mitigate them.

ChallengesPTE: What type of bio/pharmaceutical

products are the most challenging to ship,

and what solutions can be used?

Lee (World Courier): As the industry

moves from “blockbuster” products to personalized

medicine, especially customized treatments for

patients with rare diseases, expensive medications

with low volume and high value will become the

shipping norm. These shipments present extreme

challenges in their intrinsic value. At the same time,

we’ve seen a significant jump in the number of clinical

trials conducted in emerging markets, where transport

and storage of investigational medical products

and patient samples can present a host of daily and

diverse obstacles.

Solutions for these shipments can be as unique as

the shipments themselves. The expertise and control

offered by a knowledgeable shipping partner—in

everything from choosing the best system for the route

and correct preconditioning of phase-change materials,

to correctly configuring and positioning temperature

monitors—are invaluable. The right packaging, following

the right route, and the right expertise in each local

market is crucial to providing a successful, unbroken

supply chain for these potentially life-saving therapies.

The recent partnership of World Courier with

Medical Research Network (MRN) seeks to address

many of the challenges of global clinical trials by

creating a solution that combines product transport,

storage, and nursing services in a secure, transparent

solution. As emphasis shifts to patient-centric

medicine, the question is not just getting a product

from point A to point B, it’s also what happens to the

product once it gets to point B.

Lastly, new therapies are bringing a broad range of

temperature needs to the supply chain. For example,

there are now therapies that require storage at body

temperature, and by necessity, they will require

a different approach compared to the traditional

cold chain. Humidity, light, and even movement-

sensitivity (i.e., products that cannot be jarred during

shipment) might be factored into shipping concerns.

All combined, it’s safe to say that as products

themselves grow more complex, more diverse, and

more specialized, supply-chain technologies and

processes must become more advanced to support

individual shipper needs.

Jennifer Markarian

Understanding Risks in Pharmaceutical ShippingChoosing the correct shipping solutions,

including packaging, transportation mode,

and monitoring, helps mitigate the risks

inherent in global logistics.

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Successful Binding of Peroxide Sensitive APIs

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

EVENT OVERVIEW:

The formulation of peroxide sensitive active ingredients (API) is a grow-

ing topic. Not only novel APIs are often subject to peroxide-induced

deterioration, also reformulation or repacking of existing APIs for

increased patient compliance often faces the issue of potential perox-

ide interaction caused by the binder used. In this webinar, we will show

n that Kollicoat IR forms no peroxides at all

n that it’s binding capability is at least as good as the one of PVP,

often even better

n and that it can be used in standard granulation equipment.

Key Learning Objectives

n Why Kollicoat IR is a powerful binder and that it practically does not

form peroxides.

n In which commonly used production processes it can be applied.

n How easy it is to be processed.

Who Should Attend

This webinar targets all formulators looking for a solution to fnally

combine excellent binding properties with no peroxide exposure—

not only until packaging, or until the bottle or blister is opened, but

throughout the whole lifecycle of the drug – from production to patient

administration.

For questions contact

Sara Barschdorf at

[email protected]

Sponsored by Presented by

ON-DEMAND WEBCAST Originally aired July 7, 2015

PRESENTERS

Bernhard Fussnegger

Global Development & Technical

Marketing

BASF SE

Jan Bebber

Platform Marketing Pharma

Ingredients

BASF SE

Moderator

Rita Peters

Editorial Director

Pharmaceutical Technology


Shipping Services

Kabbaj (UPS): New, large-molecule,

biologic treatments are increasing.

These drugs are typically less stable

than small-molecule drugs, making

them more challenging to ship and

requiring a highly customized solution.

A high-end cold-chain solution using

active containers and an extensive

visibility control-tower solution is key.

In addition, high-value drugs that

are shipped in a small-package

network require acute attention to

detail. These shipments travel as one

package among others, but because of

their value, we need to make sure they

are shipped to the right person and on

time. In this case, properly engineered

passive packaging is key. Appropriate

packaging combined with proactive

monitoring and intervention adds

layers of protection.

Controlled substances like

oxycodone present potential security

risks and become challenging to ship.

To mitigate these risks, we use real-

time monitoring devices that track

shipments constantly by using geo-

fencing. Geo-fencing allows UPS to

predetermine a safe route and define

an acceptable digression distance for

the drug to mitigate diversion and theft.

Any biomaterial that requires

cryogenic temperatures (-150 °C), such

as clinical trials or biologic materials

(e.g., blood, tissue, reproductive

material), presents challenges within

the supply chain. UPS works with a

cryogenic container that is designed for

our network and holds the temperature

at -150 °C for at least 10 days. Visibility

solutions help customers keep an eye

on these shipments in real-time.

Asmus (FedEx): Complex

pharmaceutical trials offer many

challenges, from security to

temperature control. For example,

FedEx recently worked with Clinical

Supplies Management on a trial

involving medication that was prepared

in a laboratory, shipped overnight

throughout the United States to be

used within 48 hours, and maintained

at 2–8 °C. Tracking and monitoring

devices enabled verification of location

and temperature control.

Temperature controlPTE: What are the most

concerning aspects of

temperature control for

the shipping service

provider? For the customer?

Kohr (CSafe): Challenges are

similar for both a service provider and

their customers: finding a solution

that performs; meets regulatory

obligations; meets any other

objectives, such as sustainability; and

has an acceptable cost.

Kabbaj (UPS): For the shipping

service providers, there are three

concerning aspects of temperature

control: hand-offs, customs,

and unexpected events. When a

product is transported from origin

to destination, the chain of custody

can become complicated and long

as the product passes among the

shipper, the airline, the forwarder,

and eventually to the end customer.

All of these changes in custody are

potential areas of concern because

the risk for temperature deviation

increases. As supply chains become

longer and cross multiple borders,

customs is a key area of concern for

providers. Some countries outside of

North America and Europe have much

slower customs processes where

goods may be held up in transit longer

than expected. Finally, unexpected

events, including mechanical issues

as well as low probability, high-

risk events, such as labour strikes,

extreme weather, volcano eruptions,

and earthquakes, can have strong

consequences on the integrity of

temperature-sensitive shipments.

Providers must have a firm hold on

the amount of risk they are willing

to accept and contingency plans in

place to react or mitigate any risk

associated with unplanned events.

For the customer, there are two

main temperature-control concerns:

cost and quality. Customers must

find the right tradeoff between cost

and the quality of their temperature

integrity. At a high cost, you can

mitigate most risk, but is that

something you want or need? How

do you get to a point where the cost

is competitive, but quality and risk

mitigation are high? Contracting

the right quality agreement with

providers and ensuring it is respected

throughout the entire supply chain

is important. If the provider is using

third-party vendors, how do you make

sure that the service level you were

sold is being taken into consideration

at every step of the supply chain?

Outline the level of monitoring,

auditing, and visibility that is

expected and formalize an agreement

to make sure it gets done.

PTE: How do you

address shipping

requests to areas that

do not have facilities for

temperature control?

Asmus (FedEx): Packaging and

transportation solutions that can

maintain temperature integrity and

also eliminate unnecessary costs are

key. For example, thermal blankets

for pallets are available to offer

protection against sunlight, humidity,

and tarmac heat.

Lee (World Courier): Controlling

the external temperature will always

remain the best possible option,

whether using temperature-control

offerings from the airlines, certified

airports, or over-packing the whole

consignment with an active unit.

However, these methods are not

always a viable option due to lack

of infrastructure at the destination.

Manufacturers need to invest in

packaging that is independent of the

physical facilities available over the

duration of the shipment, allowing

the shipment temperature to remain

stable even when storage conditions

differ from expectation.

It is important to have a

knowledgeable team on the ground at

every step. A reliable partner that can

be present during pickup and delivery

will allow for greater control over the

product’s shipping life. All challenges

Changes in custody are potential areas of concern because the risk for temperature deviation increases. —Wanis Kabbaj, uPs

Lives may depend on a drug making it safely from origin to destination, within temperature range, and on-time. —Carl Asmus, FedEx



Shipping Services

and risks should be clearly identified

in advance of the product being

shipped, so that the shipping partner

can work to alleviate issues early

and often. This approach is also hard

wired into regulatory requirements,

including the European Union’s good

distribution practice guidelines.

Kabbaj (UPS): Most of the global

areas where UPS operates do not

have temperature controls. A key way

to address requests in these areas

is through packaging and monitoring

services. Cold-chain packaging

will protect the product from

temperature variations throughout

the trip. Active, passive, and semi-

active packaging solutions can be

considered in conjunction with the

known temperature conditions of

the journey. Once proper packaging

is defined, the compatible mode of

transportation can be determined.

Passive packaging may be protective

for a certain amount of hours, so you

must ensure a timely delivery before

the pack-out expires. For active

packaging, you need to make sure

that the temperature is maintained

throughout the supply chain, which

can be done by implementing

processes and training employees on

how to handle those active-packaging

solutions when they need to handle

or intervene. Risk-management

solutions must be in place for handling

temperature-sensitive freight. A

solution that proactively determines

when a shipment is likely to be

distressed or in jeopardy, an improved

track-and-trace solution for real-time

risk management, and capabilities

to act on the data to expedite or

reroute the shipment are all important

components of a risk-management

solution.

It is important to note that the idea

of temperature-controlled facilities

providing full coverage throughout

the supply chain is misleading. No

full chain is completely temperature-

controlled without appropriate

packaging. When product in passive

packaging leaves the controlled

premise of a facility, truck, or airplane

during handoff, it is in danger of

temperature excursion if not delivered

by the time the packaging expires.

Kohr (CSafe): When we designed

our active packaging unit, we created

a solution that did not require

refrigerated trucking, refrigerated

warehousing, re-icing, or any other

human intervention other than

moving the product from A to Z. If

there are no temperature-control

facilities at Z and the container was

going to sit for a period of time, the

container is designed to simply plug

into a wall outlet.

Transportation modePTE: Identifying and

mitigating risk is crucial.

Do some risks depend

upon the mode of

transportation, and what factors go

into choosing transportation mode?

Kabbaj (UPS): Risk, particularly

for temperature control, absolutely

depends on the mode of

transportation. Typically, the faster

and more integrated the mode, the

lower the risk. For example, if you

ship a small package by air with an

integrator like UPS, you are only

dealing with one vendor that controls

all the assets and the network that

your product is transiting through,

and you are transporting the

product quickly. In this instance, the

handoffs and exposure to the outside

environment are limited, so there is

lower risk.

On the other hand, a ground

transportation shipment over a

long distance and through multiple

transportation providers and modes

(i.e., truck and rail) is subject to more

risk. The mode is much slower than

air and the exposure to external

temperature variations increases

during handoffs.

Cost, temperature, and timing

are all important in selecting the

appropriate mode of transportation

for a temperature-sensitive shipment.

It is important for shippers to leverage

extensive logistics portfolios with global

air, ocean, and freight services. These

should give customers the flexibility

to meet specific cargo size and timing

needs while maximizing routing, transit

times, and cost management.

Kohr (CSafe): Each mode of

transportation (air, ocean, and ground)

provides different benefits and risks.

The risks include cost, likelihood of

quality issues, liability, and level of

capital deployed due to inventory in

transit. Not every product or routing

is suited for the same supply-chain

solution or for every season. Companies

that exercise and deploy various options

are leading the way. Everyone wants

simplicity, but simplicity may bring

increased costs and increased risk. An

active temperature-control container,

for example, all but eliminates the

human and environmental elements,

but may not be the right supply-chain

option from a cost perspective. There

is always that crucial balance of cost

versus risk.

Asmus (FedEx): Transportation

mode is only one element of the

decision; it is important to determine

the ideal transportation mode for their

shipments based on many factors,

such as service level and price point.

Lee (World Courier): As shipping

and packing technology advances,

the goal is to reduce the inherent

risks associated with the mode of

transportation. Experts agree the

shipper should consider choosing

packaging that is independent of

the supply chain itself, which can

keep shipments on-temperature.

The question is less about mode of

transport, and more about choosing

the right packaging for your product

and its journey. For example, semi-

active packaging solutions usually

bode well for shipments that are only

going a short distance. However, for

longer distances, customers should

be looking at passive packaging

solutions like phase-change material.

Passive packaging allows for more

precision and temperature control

and maintains product stability over

long distances and through extreme

climates. PTE

The goal is to reduce the inherent risks associated with the mode of transportation. —sue Lee, World Courier

Everyone wants simplicity, but simplicity may bring increased costs and increased risk. —Brian Kohr, Csafe



Jennifer Markarian

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TROUBLESHOOTING

Paperless operations improve efficiency

and increase assurance of product quality.

Implementing Electronic Production Records

Replacing stacks of paper records with easily

searched and shared electronic records has

clear benefits for both the near and long term,

but making the switch requires careful planning

and risk management. Pharmaceutical Technology

Europe spoke with Ken Kovacs, quality business

systems manager at Fujirebio Diagnostics, about the

advantages of using electronic production records

and the keys to successfully implementing a system.

Electronic-record conceptPTE: What are electronic production

records (EPRs), and how do they relate to

electronic batch records (EBRs)?

Kovacs: Production record requirements

are identified in various United States Food and Drug

Administration regulations, such as 21 Code of Federal

Regulations (CFR) Part 211 for Finished Pharmaceuticals

(1) and 21 CFR Part 820 for Medical Devices (2).

Production records can be considered a collection

of all the records required to manufacture an FDA-

regulated product as well as all the records produced

during the manufacturing of those products to meet

specific regulatory requirements. EPRs provide an

electronic equivalent to paper production records as

required by agency regulations.

The concept of EPRs has not been used as extensively

in industry as EBRs. An International Society for

Pharmaceutical Engineering (ISPE) special interest group

(SIG), the Good Automated Manufacturing Practice

(GAMP) Manufacturing Execution Systems (MES)

SIG, used EPR as a more universal term to include all

associated production records for both pharmaceutical

and medical device industries, which is important

because of the increasing overlap in these industries

(e.g., combination drug-device products). Both batch

records and device history records can be considered

subsets or components of production records. ISPE’s

GAMP 5 (3) and the GAMP Manufacturing Execution

System Good Practice Guide (4) provide appendices

describing EPR systems and associated functionalities,

such as ‘review by exception’ and electronic signatures.

Implementing EPRs creates the ability to generate

and distribute electronic records within the enterprise

in a timely manner, dynamically control processes

to decrease product variability, and assure product

quality during production. CGMP-compliance issue

investigations and their associated paper-based

records may also be simplified through information

derived from EPRs. Over time, EPR systems can evolve

to provide real-time product disposition and provide a

database of scientific knowledge needed for process

understanding and future product development.

AdvantagesPTE: What have you found to be the

biggest advantages of EPRs?

Kovacs: Fujirebio Diagnostics’ current

EPR system has saved several thousand

hours of people’s time when compared to the previous,

manual data-logging process and review of associated

paper-based GMP reports. Paper-based logs and reports

have been eliminated. Parameter data are automatically

logged, analyzed in real time, and retained in a database

by the computerized system. Authorized personnel are

immediately notified via email in the event an adverse

warning or excursion occurs with any monitored

parameter, and system functionality allows us to

capture personnel comments and electronic signatures

by department for each event.

Monthly departmental summary reports (SRs) are

generated for ‘review by exception’ and routed via

workflow software to each department for review and

electronic signature approval. The SRs are then routed

to quality assurance (QA) for final review and approval.

Once approved by QA, the system generates a monthly

electronic SR for each department and appropriately

files it for retention and future use. All data and

electronic records are routinely backed up through

information-technology processes and procedures.

With this system, we now have the ability to more

easily analyze equipment and process operations for

a better understanding of critical process parameters

and product quality attributes.

ImplementationPTE: How did Fujirebio Diagnostics go

about implementing EPR?

Kovacs: Our executive management

team had already identified an



Troubleshooting

electronic initiative as a concept for

implementing electronic records.

The EPR project team then identified

a strong business need for this

specific EPR system. A project

justification and return-on-investment

calculation based on implementing

an infrastructure conducive to

installing future applied solutions

was developed for management

review. Based on this strong need

and justification, the project was

quickly approved. Before developing

an infrastructure and architecture,

the project team agreed on using

International Society of Automation

(ISA) ISA95 (5–6) and ISA88 (7)

standards and models as guidance for

system design.

Personnel from the entire company

were engaged to obtain their feedback

and expectations for this new system.

Twenty seven individuals from all

departments participated in the

development of the user requirements

specification (URS). This project was

truly company-driven by users and

management working together.

PTE: What were the keys

to successful

implementation?

Kovacs: Direction from

executive management provided the

support for launching this project and

was crucial to getting this system

approved. Project implementation

was guided by our formal system

development life cycle (SDLC) and

a step-wise project management

methodology that includes a risk-based

approach to design and validation. The

use of global standards and models

greatly reduced the time needed

to define a site-wide architecture

and system functionality. Once the

URS was completed, a request for

proposal package was developed, and

leading system integrators (SI) were

identified and invited to participate in

our selection process. A SI providing

what we identified as the best

applied solution to address our user

requirements was then selected.

Deliverables required for each phase

of our SDLC were completed as the

project progressed.

Before going live with this system,

a comprehensive documentation

package was completed, robust

qualification testing was executed for

validation, and more than 60 users

were trained. Completion of system

validation allowed us to move one

step closer to system turnover. After

formalizing a system support team

and process, the system was then

operated in parallel with existing,

manual standard operating procedures

(SOPs) for three months. Because

this was the first implementation of a

record system of this type, we wanted

to ensure that everyone was properly

trained and that everyone understood

the process of generating and

approving the e-records. In addition

to system-level training, we included

training on our e-signature and

e-record SOP, which is based on 21 CFR

Part 11 requirements. The comparison

of e-records to paper was integrated

in our approach to system qualification

for validation. At the end of three

months, our user community was

comfortable with the new system and

was also eager to make the transition

to e-records, after seeing how much

easier it is to use compared to the time

previously spent in manually logging

data and reviewing stacks of paper

records. Migration to the electronic

record system was then made official,

with manual activities relegated to a

back-up role. Existing SOPs previously

used for generating manual logs and

paper records will now be used only if

there is an operational interruption to

the automated system.

During the entire project, timely

meetings were conducted with the SI

and contractors, team contributors

were acknowledged and thanked,

and project update bulletins were

frequently posted to keep all company

personnel apprised of progress being

made. This communication was

important because the new system

was a significant change that affected

people in 18 different departments.

Next stepsPTE: How does the new

infrastructure provide a

basis for further

improvements to

manufacturing equipment systems?

Kovacs: During initial discussions on

what an electronic initiative meant to

Fujirebio Diagnostics, a ‘future state’ of

paperless operations was envisioned

and various strategies identified to

make it all happen. The infrastructure

implemented with our first project was

designed to provide an architecture

that addresses equipment integration,

data acquisition, and information

management from the shop floor

through manufacturing operations and

up to our business systems. System

hardware and software products from

global suppliers were chosen to provide

for easy expansion and compatibility

with future applied solutions.

Since this system was originally

installed, we have doubled the

number of GMP-related equipment

that is being monitored, added more

electronic record capabilities, and used

system information to support other

operations and quality processes. We

are now scoping out a new project to

further expand data acquisition into

other areas in manufacturing with

added functionality for manufacturing

operations management. By

implementing an infrastructure up

front with capabilities to meet future

needs for data management and

EPRs, we now have an established

step-wise strategic approach to rolling

out applications that support our

electronic initiative path forward.

References1. Code of Federal Regulations, Title 21,

Food and Drugs (Government Printing

Office, Washington, DC) Part 211,

Subpart J—Records and Reports (2014).

2. Code of Federal Regulations, Title 21,

Food and Drugs (Government Printing

Office, Washington, DC) Part 820,

Subpart M—Records (2014).

3. ISPE, GAMP 5: A Risk-Based Approach to

Compliant GxP Computerized Systems

(February 2008).

4. ISPE, GAMP Good Practice Guide:

Manufacturing Execution Systems—A

Strategic and Program Management

Approach (February 2010).

5. ISA, ANSI/ISA-95.00.01-2010 (IEC

62264-1 Mod) Enterprise-Control

System Integration—Part 1: Models and

Terminology (Research Triangle Park,

NC, 2010).

6. ISA, ANSI/ISA-95.00.03-2013 Enterprise-

Control System Integration—Part

3: Activity Models of Manufacturing

Operations Management (Research

Triangle Park, NC, 2013).

7. ISA, ANSI/ISA-88.00.01-2010

Batch Control Part 1: Models and

Terminology (Research Triangle Park,

NC, 2010). PTE

Pharmaceutical Technology Europe AUGUST 2015 45


Product/Service ProfileS

fermentation, drug Product,

Potent, Hot Melt extrusion,

Prefilled Syringes,

Biologics and Bulk Active

Pharmaceutical ingredients

(APis)

AbbVie is a global, research-based

biopharmaceutical company formed in 2013

following separation from Abbott

Laboratories. The company’s mission is to

employ its vast expertise, dedicated people

and unique approach to innovation to

develop and market solutions to some of the

world’s most advanced technical issues.

Through its rich heritage from its

predecessor, AbbVie has been in the

business of developing and producing

products for more than 130 years.

AbbVie’s Contract Manufacturing

business has been serving our partners for

over 35 years. Our contract/toll

development and manufacturing capabilities

span Fermentation, Drug Product, Potent,

Hot Melt Extrusion, Preflled Syringes,

Biologics, and Bulk Active Pharmaceutical

Ingredients (APIs) across ten production

facilities in North America and Europe.

Abbvie

www.abbviecontractmfg.com

[email protected]

catalent Pharma Solutions

Catalent Pharma Solutions has invested in

its Somerset, NJ, facility to create a Center

of Excellence for potent handling across the

company’s portfolio of oral solid dose forms.

The investment included an expansion

of facility and engineering controls for

high potency tableting to supplement

existing capabilities, giving additional

capabilities to handle potent compounds

for large scale blending, fuid bed

processing, and high shear granulation.

Catalent’s acquisition of Micron

Technologies allows the company to

undertake particle size engineering of potent

compounds, complementing handling and

manufacturing facilities at Somerset.

Further investment was announced in

2014 at Catalent’s Kansas City, MO, facility

to increase highly potent and cytotoxic

clinical drug packaging capabilities.

Catalent offers end-to-end solutions

for development, analysis, and clinical and

commercial manufacturing for oral solid

manufacturing of potent compounds.

catalent Pharma Solutions

www.catalent.com

[email protected]

complex Sterile contract

Manufacturing

Parenteral manufacturing is a complicated

process. Cytotoxics, antibody-drug

conjugates (ADCs), highly potent

compounds, biologics, and lyophilized

products present many challenges and

require specialized understanding and

expertise. Baxter’s BioPharma Solutions

business brings more than sixty (60)

years of experience in handling complex

sterile manufacturing cytotoxics for global

markets. In 2013, Baxter announced a

third expansion of its fll/fnish cytotoxic

contract manufacturing facility in Halle

(Westfalen), Germany (following previous

expansions in 2007 and 2011) to meet

clients’ growing needs for cytotoxic

manufacturing. The expansion includes

the installation of a new commercial flling

line with two freeze dryers, and a clinical

flling line with an additional freeze dryer.

Both the new commercial and clinical

lines will be equipped with an automated

loading/unloading, capping and inspection

infrastructure. This expansion is expected

to be complete in late 2015, and has

been designed to support international

manufacturing and regulatory requirements

serving the needs of clients globally.

Baxter BioPharma Solutions

www.baxterbiopharmasolutions.com

[email protected]

46 Pharmaceutical Technology Europe August 2015 Pharmtech.com



cGS compact Granulation

System

The CGS Compact Granulation System

incorporates the most important

processing steps mixing, granulating,

drying, and bin blending to transform

pharmaceutical powder mixtures into high

quality tablet granules. The system shows

a compact design comprising of a Mixer-

Granulator, Fluid Bed Batch Processor,

and an integrated Bin Blender. Process

and product safety as well as operational

effciency are the key benefts of the CGS.

It also provides very good accessibility of

all components due to a GMP-compliant

platform conception. The granulation suite

offers ideal conditions for a completely

contained handling of the product from

feeding of raw materials into the mixer

granulator to the last step of fnal blending.

Once the main processing operations

granulation and drying are completed the

product is automatically transferred into

the fnal bin. After fnalising the production,

only minimum effort is required for

cleaning preparation. All product contacted

areas are WIP or even CIP cleaned.

dioSNA dierks & Söhne GmbH

www.diosna.com

[email protected]

Bio/Pharmaceutical GMP

Product testing

Eurofns BioPharma Product Testing offers

the most complete range of testing

services, harmonized quality systems, and

LIMS to more than 800 virtual and large

pharmaceutical, biopharmaceutical, and

medical device companies worldwide.

We offer complete CMC Testing

Services for the Bio/Pharmaceutical

industry, including all starting material,

process intermediates, drug substance,

drug product and manufacturing support,

as well as broad technical expertise in

Biochemistry, Molecular & Cell Biology,

Virology, Chemistry, and Microbiology.

With a global capacity of more than

50,000 square meters and 14 facilities

located in Belgium, Denmark, France,

Germany, Ireland, Italy, Spain, Sweden, and

the US, our network of GMP laboratories

and vast experience allow us to support

projects of any size from conception

to market. Further, we have teams of

scientists placed at more than 40 client

facilities throughout Europe and the U.S.

through our award-winning Professional

Scientifc Services (PSS) insourcing program.

eurofns BioPharma Product testing

www.eurofns.com/Biopharma

[email protected]

etQ compliance

Management Software

EtQ is the leading FDA Compliance, Quality,

EHS, and Operational Risk Management

software provider for identifying, mitigating,

and preventing high-risk events through

integration, automation, and collaboration.

Founded in 1992, EtQ has always had a

unique knowledge of FDA Compliance,

Quality, EHS, and Operational Risk

processes, and strives to make overall

compliance operations and management

systems better for businesses. EtQ is

headquartered in Farmingdale, NY, with

main offces located in the US and Europe.

EtQ has been providing software solutions

to a variety of markets for more than 20

years. For more information, please visit

www.etq.com or contact us at 800.354.4476.

etQ

www.etq.com

[email protected]




Puretol™ White Mineral oils

Petro-Canada Lubricants Inc. manufactures

PURETOL™ White Mineral Oils from start

to fnish—from integrated feedstock

processing to certifed white mineral oils.

PURETOL White Mineral Oils are highly

refned, colourless, and odourless. With

their unique properties, PURETOL oils

may be used in many pharmaceutical

applications: capsule lubricants, pelletizing

aids, and ointment bases. They also provide

effective bases for personal care and

cosmetic products where they are used

to lubricate, soften, smooth, moisturize,

and add emolliency. Uses range from

baby oil, skin lotions and sunscreen

to hair care products. PURETOL oils

meet the requirements of the European

Pharmacopoeia (EP). PURETOL usP and

NF grades meet FDA 21 CFR 172.878 and

FDA 21 CFR 178.3620(a) requirements for

direct and indirect food contact. Select

PURETOL grades are NSF 3H and/or HX-1

registered and are available for use as

components in various food applications.

All PURETOL grades are Kosher Pareve

and Halal certifed. Petro-Canada

Lubricants delivers directly to customers

through their dedicated infrastructure

and effcient distribution system. For

more information, visit PURETOL.eu.

Petro-canada lubricants inc.

www.Puretol.eu

[email protected]

Xdf (eXtended dwell flat)

XDF (eXtended Dwell Flat) is a unique

patented elliptical head form which

has been designed to increase dwell

time on existing presses without the

need for expensive modifcations.

Launched at ACHEMA 2015, XDF

can run on standard cams, giving users

higher press speeds with challenging

products and formulations. It also

enhances tablet compaction/cohesion

and can increase dwell time by up to 50%

over a standard punch head. It allows

more dwell than a D-type punch on a

B-type tool. This increase helps to solve

compression problems without upsizing

punches or investing in a new press.

Benefts include:

• Improved productivity

•Designed to run on standard cams

•Solve dwell time problems

without upsizing punches

•More than D-type dwell

on B-type punch

•Allows faster press operation

•Enhanced tablet compaction

i Holland ltd

www.tablettingscience.com

[email protected]

excipients and raw Materials

for Pharmaceutical and

Biopharmaceutical Production

Since the beginning, PanReac AppliChem

has played an important role in the

pharmaceutical and biopharmaceutical

industries, producing and supplying

the best raw materials to be used in

manufacturing process or as excipients

in the fnal formulation.

PanReac AppliChem has an integrated

management system implemented in all

activities relevant to the following standards:

IPEC/PQG GMP Guide, ISO 9001:2008,

ISO 14001:2004, and OHSAS 18001:2007.

Our Quality Control Laboratories,

ftted with the latest technologies,

analyse and guarantee all products

comply with the specifcations of

Pharmacopeia. From raw materials to

fnal products, we ensure our products

are safe across the entire value chain.

Pharma grade product range meets

the specifcations defned in the latest

version of usP and Ph. Eur., among

other pharmacopeias. BioChemica and

Cell Culture grade guarantee stable

and consistent biopharmaceutical

production process (upstream).

For further information, meet us at CPhI

Worldwide 2015, Madrid 13–15 October,

Hall 7 stand 5K16.

Panreac Applichem

www.panreac.com, www.applichem.com

[email protected]

48 Pharmaceutical Technology Europe August 2015 Pharmtech.com


Nexera UC unified

chromatography System

Shimadzu’s new Nexera uC unif ed

chromatography system is the world’s f rst-

ever unif ed and fully automated instrument

combining supercritical f uid extraction (SFE)

with supercritical f uid chromatography

(SFC). The SFE/SFC/MS platform merges

quick and easy online sample preparation

with advanced chromatographic analysis

and high sensitivity detection.

The Nexera uC serves a wide range of

applications, e.g. food control, research in

biopharmaceuticals, and environmental

analysis. It enables highly reproducible

extraction and stable analysis even of

unstable samples prone to oxidation or

dissociation if exposed to light or air.

Shimadzu europa GmbH

www.shimadzu.eu

[email protected]

vaisala continuous

Monitoring System

Whether you have freezers, refrigerators,

warehouses, or incubators, the Vaisala

Continuous Monitoring System keeps you

fully compliant, helps to streamline your

operations, and protects your products and

the health of the people who use them.

The Vaisala Continuous Monitoring

System is independent of all other

control and monitoring systems, making

the validation quick and easy.

It provides you with a variety of alarm

notif cation options and reports, fully

conf gurable to meet your needs and keep

your company compliant. Information

is logged continuously and is available

for review at any time, any place.

The Vaisala Continuous Monitoring

System scales from 1 to 1000s of locations

globally and includes software, data

loggers and instruments, and services.

vaisala oyj

www.vaisala.com/cms

[email protected]


Sterile Garments

VAI’s sterile disposable garments have been

redesigned for user comfort while meeting

the specif c needs of an aseptic operation.

Our sterile garments consist of two

different fabric types that are constructed

identically but are cited for use in two

different facets. Our 1600 garment line

is composed of a high quality, and non-

woven SMS fabric. Our 1700 garment

line is composed of a heavy weight,

non-woven, high quality, MicroPorous

coated material. Both lines, contain elastic

thumb loops, tunnelized elastic wrists

and ankles to reduce shifting, athletic

and active styling for all body types, and

a 5-year closed bag sterility assurance.

VAI’s sterile garments are folded in our

patented Easy2Gown® fold system. The

Easy2Gown design is a fold that makes a

proper aseptic gowning procedure an easy

process instead of a routine challenge. By

presenting the inside of the gown the sterile

outside is protected from the transfer of

contamination during the gowning process.

veltek Associates, inc.

www.sterile.com

[email protected]




ASK THE EXPERT

Susan Schniepp, Distinguished Fellow, and Andrew Harrison, Chief Regulatory Affairs

Officer and General Counsel, both of Regulatory Compliance Associates, discuss the

requirements for a successful corrective action and preventive action (CAPA) system.

Q.I work for a contact manufacturing organization, and

I am responsible for hosting audits and preparing the

responses to the observations. I have received multiple

comments on my CAPA system from many groups, many with

different perspectives. What are the real requirements for a

successful CAPA system?

A.You can take comfort in the fact that you are not alone

in this predicament. We consider investigations to be the

cornerstone of any CAPA system and based on the data in the

United States Food and Drug Administration database, in fiscal

year (FY) 2014, 25% of the FDA 483 citations issued were for A

inadequate, incomplete, and undocumented investigations (1).

For some reason or another, the industry tends to focus on the

immediate correction to the non-conformance, resulting in a

failure to investigate and execute the corrective and preventive

actions of the CAPA system in an effective and timely manner.

Basically, we need to view CAPAs as improvements we make to

our processes and procedures to eliminate non-conformances

in our products. These improvements are based on the results

of the investigations into the non-conformance for root cause.

Once the root cause is determined, then a corrective action is

identified and implemented into the process. The change is then

monitored during a period of time to determine if the proper

root cause was identified and if the corrective action was effec-

tive (i.e., effectiveness check). In some cases, the root-cause

analysis may reveal a potential for an objectionable situation to

occur resulting in compromised product. The solutions chosen

to avert predicted non-conformance are preventive actions.

The key to any CAPA system is the initial investigation into

the non-conformance to determine the root cause. However,

not all investigations are the result of a non-conformance and

not all investigations will result in a CAPA. It is important that

the investigation be thorough and complete before the CAPA

is initiated and implemented.

The investigation process should make use of root-cause

analysis tools designed to examine the impact of various

process inputs and their effect on the non-conformance. These

tools examine the impact of the equipment, process, people,

materials, environment, and management on the identified non-

conformance. In some cases, depending on the nature of the non-

conformance, some areas can be eliminated as having no impact.

The rationale for elimination, however, should be documented. As

the elimination process progresses, the investigation will naturally

and logically hone in on the root cause(s) of the non-conformance.

Once this is completed, the actual CAPA can begin.

If we look at the CAPA system as an expressway, the

immediate correction and the investigation are the on ramps,

the corrective and preventive actions are the lanes, and

the effectiveness checks are the off ramps. The immediate

correction and investigation into that occurrence should

determine if the non-conformance is a one-time occurrence

or if it has happened before. If the non-conformance has

happened before, the investigation needs to be conducted to

determine the underlying root cause of the non-conformance.

Once the root cause has been determined, the corrective and

preventive actions can be implemented and monitored. If the

non-conformance does not recur in a specified time frame, the

corrective action/preventive action is considered effective and

the CAPA can be closed.

The bottom line is there are many perspectives on what

constitutes a good CAPA system, but the reality is the quality

and thoroughness of the investigations ultimately drive the

effectiveness of the CAPA. When conducting the investigation,

it is important not to jump to conclusions on what caused the

non-conformance. The investigation should use root-cause

analysis tools and should address why potential areas are either

eliminated as the root cause or are a potential cause of the

non-conformance. If you can conduct a complete investigation,

you will ultimately have a robust CAPA programme.

Reference 1. FDA, Inspection Observations, FDA.gov, www.fda.gov/ICECI/

Inspections/ucm250720.htm PTE

Ad IndexCOMPANY PAGE COMPANY PAGE

AbbVie .........................................9

Airbridge Cargo Airlines ..........35

Aptar France Sas ......................25

APV Gmbh .................................33

BASF ..........................................41

Baxter Healthcare Corp ...........17

Beneo Gmbh .............................11

Capsugel Bornem.....................19

Catalent Pharma Solutions .....52

CPhI Korea .................................27

CPhI Worldwide ........................21

Diosna Dierks & Sohne Gmbh ..23

EtQ Inc .........................................5

I Holland Limited .......................13

Lonza Biologics Inc ...................15

Patheon Pharmaceuticals .......31

Petro Canada ............................51

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

Vaisala Oyj .................................39

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

Defining Crucial CAPA Components


On the surface

all white mineral oils appear

to be the same.

With PURETOLTM white mineral oils, your money goes further because it’s buying much more than

just another ingredient. You’re buying supply (we’re the world’s largest producer of white mineral oils).

You’re buying choice (name your preferred packaging and delivery modes). You’re buying quality (every PURETOL product is produced by us from start to fnish and meets the requirements of

USP/NF/DAB, the European Pharmacopoeia (EP) and German Pharmacopoeia (DAB 10)).

You’re buying support (world-class R&D and a dedicated team that knows its business – and yours).

Want to go deeper?

call: +44 (0) 121-781-7264 | e-mail: [email protected] | visit: lubricants.petro-canada.ca/puretol

Petro-Canada is a Suncor Energy business ™Trademark of Suncor Energy Inc. Used under licence.

Purity You Can Count On


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Documents

HIGH POTENCY PEER-REVIEWED LOGISTICStisztateritermekek.hu/wp-content/uploads/2015/09/... · 2015-09-02 · Peer-Reviewed 32 Black Specks in Tablet Stability Samples A study of root