pharmaceutical technology ebook quality throughout the supply chain
Quality Througout the Supply Chain 2016
CONTINUOUS IMPROVEMENT
EDITORIAL
Editorial Director Rita Peters rita.peters@ubm.com
Senior Editor Agnes Shanley agnes.shanley@ubm.com
Managing Editor Susan Haigney susan.haigney@ubm.com
Science Editor Adeline Siew, PhD adeline.siew@ubm.com
Manufacturing Editor Jennifer Markarian jennifer.markarian@ubm.com
Science Editor Randi Hernandez randi.hernandez@ubm.com
Community Manager Caroline Hroncich caroline.hroncich@ubm.com
Art Director Dan Ward
Contributing Editors Jill Wechsler jillwechsler7@gmail.com; Jim Miller
info@pharmsource.com; Hallie Forcinio editorhal@cs.com; Susan J. Schniepp
sue.schniepp@mac.com; Eric Langer info@bioplanassociates.com;
and Cynthia A. Challener, PhD challener@vtlink.net
Correspondent Sean Milmo (Europe, smilmo@btconnect.com)
4 Could Greater Transparency Improve
Pharmaceutical Quality and Compliance?
Agnes Shanley
EXCIPIENT QUALITY
9 Ensuring Quality in
Pharmaceutical Raw Materials
Agnes Shanley
BATCH RECORDKEEPING MANAGEMENT
14 Paperless Batch Records for the Masses
Agnes Shanley
Address
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Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com
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Publisher Mike Tracey mike.tracey@ubm.com
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tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255
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STERILIZATION
21 Too Much by Half: Misapplication
of the Half-Cycle Approach to Sterilization
James Agalloco
AGING FACILITIES
27 Is Global Regulatory
Gridlock Slowing Modernization?
Agnes Shanley
MICROBIAL TESTING
33 Microbiological Testing,
Time is of the Essence
Cynthia A. Challener
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38 Investigation Effectiveness
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Drives Human Performance Excellence
Clifford Berry
48 Extending QMS to Contract Partners
Agnes Shanley
51 Ad Index
Issue Editor: Agnes Shanley
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P h a r mTe c h . c o m
Continuous Improvement
Could Greater Transparency
Improve Pharmaceutical
Quality and Compliance?
Agnes Shanley
4
F
or years, leaders within the FDA, particularly Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), (1) have noted the need for FDA to break
with old “command-and-control” methods. A few years
ago, Woodcock proposed an incentive program that would reward
companies for strong compliance and product quality records, and
penalize those with lax practices. Results of a 2015 survey (2) of industry experts in California suggested that such a “scorecard” might
increase industry investment in quality.
Originally, mention of the scorecard brought immediate questions of whether FDA should supervise the effort. A number of
different ideas have been proposed, but a new approach was outlined at the Parenteral Drug Association (PDA) Annual Meeting
in September 2016 by Martin Van Trieste, former chief quality officer at Amgen, who retired in June 2016. Van Trieste had founded
Rx360, the industry supply-chain safety coalition that is working
to combat pharmaceutical counterfeiting, substandard drugs, and
illegal diversion.
He has been collaborating with veteran quality executive Richard
Love, founder of HarborView LLC, on software development and
new algorithms that are based on key pharmaceutical quality performance indicators. Their goal is a website, the first version of which
went live in November 2016, and a smartphone app that will help
consumers make informed buying decisions, and allow proactive
pharmaceutical manufacturers to use product quality as a sales and
marketing strategy. He discussed the concept with Pharmaceutical
Technology.
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
AMEREAGLE/SHUTTERSTOCK.COM
A new website and
methodology grades
manufacturers, and their
products, based on quality
and good business practices.
Founder Martin Van Trieste
explains the approach and
the thinking behind it.
A new approach
PharmTech: What inspired you to start working on
this project?
Van Trieste: The more I’ve thought about it, the
more I’ve seen that the industry needs a transformational approach to product quality and patient
safety. This is the age of the Internet. More power
must go to the pharma consumer, just as it has
to consumers in other sectors with sites such as
Angie’s List and Yelp. Transparency has a positive
impact on business, and the best performing companies tend to prosper.
PharmTech: Why isn’t the old approach working?
Van Trieste: In the old scenario, the head of quality defends what is needed to improve quality to
senior management, but the top manager generally
considers it an expense, or a cost of doing business,
rather than an investment in the future.
If the consumer of your products changes buying
habits based on product quality and the robustness of your supply chain, then product quality becomes a business issue. Sales and marketing teams
will see benefit, and invest more in product quality.
This would result in a real change in dynamics that
could be revolutionary.
We live in a very litigious society. Some consumer lawsuits have already been seen based on
product problems that involve purchasing agents,
pharmacy benefit managers, and buyer groups.
The basic questions behind some of these suits are
simple: ‘Why was I given a grade-D generic pharmaceutical product, which resulted in this adverse
reaction, rather than a grade-A generic? Was this
done just to save money?’ In today’s environment,
large companies will lose suits like this.
If market dynamics are introduced, it could spur
a logarithmic change in the industry’s approach
to quality and compliance. I’m a realist and recognize that this approach could take many years
to catch on, but I figured we could start with a ‘JD
Edwards’-type scorecard. Currently there is a lot
of motivation for improvement.
PharmTech: Today, the consumer at the typical retail pharmacy is not informed of the source of the
medication that is being used to fill his or her prescription. Shouldn’t that information be provided?
Van Trieste: We don’t have that level of transparency now, but I believe that the country of origin
for both actives and finished drugs should be revealed to the consumer. At the PDA conference, I
asked the audience a hypothetical question: ‘If you
could choose between three products, one made in
western Europe, one in India, and one in China,
which one would you choose?’
No hands went up for India or China. Whatever
else that says, it proves that consumers want sourcing information and something that tells you more
about how a drug was made.
PharmTech: So you are taking a ‘report card’ approach?
Van Trieste: Richard Love at HarborView and I are
developing software and an app that would allow
the consumer to take a photograph of a prescription bottle at the pharmacy. The system will be
set up so that it would check that photo against a
database, providing information on the company
that makes the drug and the factory where it was
made, to let people know whether it was manufactured at a well- or poorly-managed facility.
PharmTech: Is this a realistic idea, given how secretive pharmaceutical companies are?
Van Trieste: Pharma is lagging behind other industries in its use of information, and ‘big data’ for
the consumer. Think of Uber or Tesla. You don’t
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
5
Continuous Improvement
buy a Tesla from a dealership, and you can rate
your Uber experience instantly. Technology will
enable better quality.
PharmTech: Why do you think it is that country
and manufacturer of origin are not disclosed to
the consumer today?
Van Trieste: I’ve asked FDA, and they said that
such information could be considered a trade secret, and the agency cannot disclose trade secrets.
Back in the day when current good manufacturing practices (cGMPs) took effect, or even earlier,
in the 1930s when the Food Drug and Cosmetic
Safety Act was established, most drugs and APIs
were made in the United States, so our laws and
practices are based on the fact that most drugs
were produced in the US. But times have changed
and, today, consumers have a right to know.
PharmTech: What data can consumers realistically
be expected to check?
Van Trieste: Well, some data is already publicly
available. The tools that exist today for analyzing Big Data were not there, even three years ago.
They allow users to go through 483s, warning letters, and drug shortages documentation in a very
short amount of time.
So, we are developing a scorecard based mainly
on information that is publicly available, adding
on information from PDA’s quality-culture metrics.
We’ve developed proprietary computer algorithms
to use that information.
PharmTech: What other data are you using for the
algorithms?
Van Trieste: We also incorporate manufacturing
data on process capability, and ask whether or not
the company has redundant sourcing for raw materials. Additional questions focus on inventory
levels. From these data, we issue a quality grade
6
that also indicates the probability of the given
manufacturer to have a drug shortage.
New tools for transparency
PharmTech: Tell us about the website.
Van Trieste: It is called medicine-i.com, and will
allow users to sift through compliance data as well
as data on the probability of shortages. I believe
that companies with good quality programs will
want to be in the system. For others, the program
will start some difficult internal conversations.
PharmTech: Will APIs and their suppliers be included in the grading process?
Van Trieste: APIs will be part of the calculation but
their manufacturers will not be graded. However,
if a finished drug manufacturer buys API from a
supplier, that supplier’s records will have been analyzed too (e.g., whether or not the company and
the facility were cited by FDA). The API manufacturer’s customer will receive a higher grade if their
API comes from a reputable company with a good
compliance history.
A website like this will improve transparency
and give consumers more power. Over time, retail
outlets will only want to stock products that have
been made by good suppliers.
PharmTech: How do you think the industry will
react to this program?
Van Trieste: I predict that one third of the industry
will want to be involved, one third will be against
the whole idea, and the other third will take their
usual ‘let’s wait and see what the others do’ approach to gage other companies’ response.
I do predict that pharma, as an industry, will resist
the idea, which is rather controversial for this segment.
But transparency is inevitable, and it has already happened in other industries. Resistance is futile!
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
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Continuous Improvement
PharmTech: How are you organizing the management of this program?
Van Trieste: I may not be the one to carry out the
idea, ultimately, but I want to bring it to a certain
level of development. Our algorithms will remain
our trade secret and the structure of the enterprise,
but the information within them will be made
public (e.g., number of shortages, which products,
length of time since last shortage, how the company is handling inventories, and whether they
have the drug on hand if need be).
Companies will also be penalized for failing to
build redundancy into their supplier networks.So,
for example, if Company X has had a drug shortage
in the past, if they are not measuring process capability, and if they rely on one supplier, the probability of their having a shortage is higher than it
is for the company with supply redundancy, 120
days of inventory, and process capability analysis.
Drug counterfeiting will not be part of the analysis.
A focus on quality
Amgen), but they still have a way to go. But at
least they’ve realized that, if you measure something, you can improve it.
PharmTech: What is the pharmaceutical industry’s
Sigma level today? Ten years ago, people were putting it at 3 or 3.5.
Van Trieste: I’d say the industry is probably still at
3.5 Sigma level as a whole, and roughly 80% of the
medicines sold today in the US are generic drugs.
In discussions about quality management, the Generic Pharmaceuticals Association has been most
vocal about the thousands of products that their
members manufacture, and how difficult it would
be to measure CpK (process capability) for each
product. Why is it that other industries have figured out how to do this for even the least expensive
products or components?
In the end, numbers tell the story. If a company is performing at Three Sigma, the cost of
poor quality accounts for 25% of manufacturing
costs. For a company operating at the Six-Sigma
level, it is only 2% of manufacturing costs. For a
large company with cost of goods sold of roughly
$1 billion per year, that can mean the difference
between $20 million and $250 million per year.
Pressure within the healthcare sector in general
should drive greater interest in reducing the cost
of poor quality through investment and best
practices.
PharmTech: Does the industry’s top management
have a grasp of the cost of poor quality?
Van Trieste: In 33 years, I’ve worked for various
companies and interacted with people at many
different companies in different capacities. One
group of companies is highly progressive. Quality and manufacturing leaders at these companies figured out a long time ago how to communicate the importance of investing in quality to References
C-level executives. There are progressive phar- 1. T. Sullivan, “FDA Drug Shortages: Fundamental Problem is the
Inability for the Market to Observe and Reward Quality,” Polimaceutical companies out there. But there is still
cymed.com, April 12, 2013, www.policymed.com/2013/04/fdaa lot of work to do. Other companies are not
drug-shortages-fundamental-problem-is-the-inability-for-theprogressive about quality and the industry is
market-to-observe-and-reward-quality.html
not at Six Sigma quality levels. There are some 2. C. Medina and F. Richmond, Therapeutic Innovation and Regulatory Science, 49 (5), pp 730-738 (2015). PT
companies that are close (e.g., Lilly, BMS and
8
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
Excipient Quality
Ensuring Quality in
Pharmaceutical Raw Materials
Agnes Shanley
Gelatin is widely used for
encapsulation, and requires
close attention to “criticalto-quality” attributes. JeanPhilippe Talmon, chief
procurement officer at
Capsugel, discusses best
practices.
G
elatin is commonly used for drug encapsulation. JeanPhilippe Talmon, chief procurement officer at Capsugel spoke to Pharmaceutical Technology about the
critical quality attributes of gelatin as an excipient in
capsule production, as well as measures that can be taken to ensure
an uninterrupted supply of quality raw materials.
RAWPIXEL.COM/SHUTTERSTOCK.COM
Critical to quality
PharmTech: What are the most important ‘critical-to-quality’ attributes for gelatin, for encapsulation?
Talmon (Capsugel): In today’s increasingly interconnected and highly
regulated global pharmaceutical market, adherence to ‘critical-toquality’ attributes is required to deliver best-in-class products.
First, sourced gelatin must comply with the different pharmaceutical and food regulations in all the markets where the end product
is sold. In global pharmacopeias, there are mandatory attributes to
assure the quality, identity, and purity of the excipients used in the
drug product. There are also non-mandatory attributes that provide information on control parameters for specific excipient use
and include functionality-related characteristics. Various European
Pharmacopoeia monographs, for example, have listed relevant parameters specific to the intended use of the excipient, which can form
part of the regulatory filing process. Manufacturers are increasingly
expected to understand the functionality of excipients and their potential impact on the final drug product.
Second, acquired gelatin must meet specific certification expectations and environment, health, and safety (EH&S) requirements.
There are more than 15 regulatory references that form the basis of
global gelatin purchasing specifications, including those from FDA,
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
9
Excipient Quality
United States Pharmacopeia (USP), Japanese Phar- example, in 2013, when heavy levels of chromium
macopoeia (JP), Food Chemicals Codex (FCC), and were detected in gelatin capsules made in China,
World Organization for Animal Health (OIE).
the USP–National Formulary (NF) monograph
for pharmaceutical-grade gelatin was revised to
include testing for heavy metals. Some companies
Stringent raw material
purchasing specs and quality scrambled to comply with the new requirements,
which then had a negative impact on their customagreements are required,
ers. However, companies whose gelatin purchase
as well as a robust supplier
specifications included chromium restrictions
could maintain product supply without delaying
qualification program.
delivery of their customers’ products to market.
For example, there are specific regulations on
the sourcing of bovine raw materials for excipient Animal-sourced materials
use. While Bovine Spongiform Encephalopathy PharmTech: What issues are entailed with the use of
(BSE) is well under control as a disease, the OIE animal-sourced materials, as compared with synis leading a global movement to standardize BSE thetic or non-animal-derived materials?
regulations and establish a common guidance on
Talmon (Capsugel): Animal- and non-animal
prevention, control, and eradication of the disease. sourced materials are used as excipients in pharGlobal regulators base their regulatory framework maceutical products. Each of these forms offers its
on OIE guidance. In Europe, manufacturers of own unique characteristics, specifications, opporbovine material must provide certificates of suit- tunities, and challenges at various points in the
ability (CEP) issued by the European Directorate development process. The positives and negatives
for the Quality of Medicines (EDQM) to be in- associated with both forms must be well undercorporated into marketing authorization dossiers stood to ensure that any potential associated risks
for applicable medicinal products. This is just one are identified in advance and controlled.
example of the types of certifications required.
Gelatin, which is made from the hydrolysis of
Third, sourced gelatin must maintain specified collagen of bovine, porcine, or fish origin, is wellphysical/chemical and microbiological require- suited for the encapsulation of pharmaceutical
ments to provide appropriate encapsulation of in- ingredients because of its excellent gelling and
dividual APIs. These specifications cover a large film-forming characteristics that support the mannumber of criteria, including viscosity, pH level, ufacturing process. These characteristics are the
loss on drying, and particle sizes, among others.
result of the unique property of the gelatin polyThrough adherence to these three critical-to- mer, which exhibits a reversible temperature-based
quality attributes, companies with capsule and gelification, turning into liquid when heating and
encapsulation capabilities can help to minimize hardening in the cooling process.
the business continuation risks associated with
Hydroxypropyl methylcellulose (HPMC), which
gelatin raw materials and gelatin production. For is made from plant/cellulose-based material, is an
10
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
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Excipient Quality
alternative to gelatin for drug encapsulation. Recent
in-vivo and dissolution test results investigated the
clinical performance of second-generation HPMC
capsules compared to that of gelatin capsules, and
found that the second-generation HPMC capsule performance was equivalent to that of gelatin capsules (1).
The choice between gelatin and HPMC materials
is based on numerous factors including, for instance,
the targeted product profile, characteristics of the fill,
and consumer lifestyle considerations (i.e., dietary restrictions based on religious practices, such as halal
and kosher requirements, or on vegan or vegetarian
diets). For example, while gelatin sets the benchmark
for pH- and ionic strength-independent disintegration and product dissolution profiles, HPMC capsules maintain lower moisture absorption, more
flexibility, resistance to chemical crosslinking, and
a higher thermal stability than gelatin capsules, providing greater benefit for hygroscopic and moisturesensitive ingredients.
Ensuring supplier quality
PharmTech: How do you ensure supplier quality?
Talmon (Capsugel): First, stringent raw material purchasing specifications and quality agreements are required that cover a large number of criteria. Second,
a robust supplier qualification program is needed to
provide a sound framework to guarantee that hard
capsules meet the highest standards for quality, traceability, and integrity. At Capsugel, our multi-phase
program requires that our critical raw material suppliers undergo an intensive, year-long selection process
that includes 150 critical parameters for evaluation
to verify they meet the most stringent regulatory and
industry standards, the most important being unique
specifications related to dissolution profiles and impurities. The process includes the following:
12
• Step 1: Supplier screening and investigation. A review
of the quality system of the vendor, the state of
their manufacturing technology, the scope of
their product and service offerings, and a detailed understanding of their performance metrics, regulatory compliance, and raw material
traceability. For example, more than 15 regulatory agency regulations inform the basis of our
purchasing specs.
• Step 2: Quality evaluation. A review of supplier material quality compliance with the company’s
specifications.
• Step 3: Manufacturing suitability evaluation. An analysis of small-scale production trials and R&D
pilot, when relevant. This analysis ensures compatibility of materials with manufacturing processes and protocols and confirms both finished
capsule product quality and manufacturing efficiency performance levels.
• Step 4: On-site supplier audit. A thorough traceability analysis, from raw material delivery to finished goods release, including a detailed review
of quality systems. This audit also confirms
compliance of production equipment and compliance to current good manufacturing practice
(cGMP) requirements.
• Step 5: Scale-up and final approval. This step involves a full-scale manufacturing run of capsules to confirm that material consistently meets
specifications and is continuously suitable to our
full-scale production. This also requires an evaluation of the supplier’s ability to control product
integrity and proper documentation across the
entire supply chain.
Third, it is important that long-term supplier partnerships are supported by a continuous supplier
performance management program. This program
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
includes an ongoing evaluation process designed
to ensure supply-chain traceability and finished
capsules that comply with the highest integrity
standards. This program helps to maintain a
global network of qualified suppliers with whom
there are established long-term partnerships. Key
components of this program are constant testing
to the highest standards, updated with the most
advanced instrumentation for contaminants tests,
for example; regular in-depth onsite audits of suppliers; continuous monitoring at manufacturing
facilities, including performing incoming quality
control on each lot of raw material prior to its use;
and follow up on supplier performance. Finally, a
global sourcing strategy is needed to ensure consistent quality and security of supply.
PharmTech: How do you prepare for potential disruptions in the supply chain?
Talmon (Capsugel): The key to preventing supplychain disruptions is to develop long-term partnerships with suppliers across multiple production sites
to ensure that alternative resources can be ramped
quickly and effectively in the event of an unexpected
issue. Companies must always look one step ahead of
their current needs and the requirements of the regulatory environment and business market. This process
includes continuously screening potential new suppliers, monitoring industry and governmental standards
and trends, building and maintaining an extensive
knowledge base of international regulatory requirements, and participating in membership associations
and working groups. All of these efforts are aimed
at anticipating and rapidly implementing changes to
safeguard the integrity of supply chain and products.
PharmTech: Which supplier criteria are crucial?
Talmon (Capsugel): Supplier selection is guided by
several core principles, including the quality of the
suppliers’ products and services as well as their
product traceability and integrity framework. Additionally, suppliers’ quality systems, certifications
and cGMP, regulatory compliance, and EH&S
compliance are important. Finally, it is critical to
look for suppliers to maintain responsible sourcing initiatives and have viable business continuity
plans. All of these attributes are central to ensuring
that suppliers can consistently and reliably deliver.
PharmTech: What are best practices for working
with offshore suppliers?
Talmon (Capsugel): A robust framework is required
to ensure that offshore suppliers meet the global
expectations of companies and their customers. At
Capsugel, we have a global production footprint,
and our raw material sourcing efforts are globally
coordinated and managed.
We maintain supplier evaluation programs to
secure identification of potential sourcing risks
and development of appropriate mitigation plans
in close collaboration with our suppliers. Supplier
audit results, for example, are used to dictate the
frequency, as well as the depth and breadth of the
follow-up supplier audits we conduct.
In parallel, we also maintain a thorough business continuity risk assessment program across our
entire global supplier base. These assessments are
conducted along six main dimensions, including
supplier production capacity constraints; compliance to Capsugel quality expectations; compliance
to regulatory requirements; single-sourcing risks;
supplier financial health; and supplier intellectual
property risk and third-party misappropriation.
Reference
1. A.Shanley, “Establishing a New Performance Standard for
HPMC Capsules,” PharmTech.com, May 20, 2016, www.pharmtech.com/establishing-new-performance-hpmc-capsules PT
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
13
Batch Recordkeeping Management
Paperless Batch
Records for the Masses
Agnes Shanley
A cloud-based program
offers a less expensive
alternative to MES, bringing
the power of paperless batch
record management to small
and mid-sized companies.
Rick Soltero, founder and
CEO of InstantGMP, discusses
the need for paperless data
management that facilitates
cGMP compliance.
J
ust as the paperless office, a utopian vision of the 1970s, has
never quite taken shape, neither has the paperless pharmaceutical plant. Most large pharma companies have installed the
enterprise research planning (ERP) backbone and manufacturing execution systems (MES) software that is required for electronic
data management. Most small to mid-sized pharmaceutical firms,
however, continue to handle batch documentation the old-fashioned
way, which does not make data management any easier. In this reliance on paper, much potential power is lost: potentially reduced cycle
times and document management times are just the tip of the iceberg.
Smaller companies have not had too many choices for modernizing
data management. Either they could invest hundreds of thousands
of dollars on MES and ERP systems, and the same amount again on
their implementation, or they could use and try to customize “job
shop” software systems that were designed for other industries and
do not come out of the box meeting FDA’s 21 Code of Federal Regulations (CFR) Part 11 requirements. This lack of FDA compliance
would require users to generate thousands of standard operating
procedures (SOPs).
Within the past few years, cloud computing has brought the potential power of paperless batch recordkeeping to a growing number of smaller companies. Rick Soltero, an alumnus of AAI Pharma
and former director of R&D at Smith-Kline Beecham, turned an
interest in process control and programming into InstantGMP, a
company that offers cloud-based batch documentation software
designed to streamline quality control time to allow for management by exception.
14
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
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Batch Recordkeeping Management
Over the past two to three years, Soltero says, with. Today, when software packages tout the fact
more than 100 pharma companies have bought that they are Part 11 compliant, they are.
the software. Soltero talked about paperless data
PharmTech: How did you decide to start the commanagement issues and the company with Phar- pany?
maceutical Technology.
Soltero: InstantGMP started back in 2004. I saw
a need in pharmaceutical manufacturing for softStill a paper industry?
ware that could be used at multiple sites, and by
PharmTech: How much of the pharmaceutical indus- different people, simultaneously. At the time, there
try is still handling batch and other key manufac- weren’t any cloud-based software packages availturing and quality records on paper?
able that could be used by multiple sites and people,
Soltero: Even in this age of smartphones and at least not in a way that would allow one software
advanced communication, 50% of the industry is platform to reinforce GMPs.
still using paper. I believe this is because the opMy consulting company had to build a manutions available to smaller manufacturers are not facturing plant for a non-profit research organizaaffordable.
tion that was conducting Phase III clinical trials
in developing nations. Instead of taking the traditional manufacturing plant approach, which would
Most small- to mid-sized
have cost $6 million, we opted for an approach that
pharmaceutical firms
would depend on outsourcing and handing off the
continue to handle batch
project, after clinical trials were completed, to the
World Health Organization (WHO).
documentation the oldAt that point, technology had advanced to a
fashioned way, which does
point where remote data access via the Internet
not make data management
was possible. I wanted to create tools that would
any easier.
allow operations and quality staffers to create systems that did not rely on the presence of permaPharmTech: Does the continued use of paper also nent workers, and that could be used at more than
partly reflect a mindset issue? When FDA’s re- one company facility.
quirements for digital signatures, as set by 21 CFR
The facility needed quality systems that would
Part 11, came out about 10 years ago, they were a allow manufacturing data to be assessed remotely
source of misunderstanding and debate within the so that the client could minimize its dependence
industry. Has that changed?
on permanent staff.
Soltero: The environment has definitely changed,
Those quality systems, in turn, had to work with
and the industry’s understanding of digital signa- a 21 CFR Part 11-compliant database and docutures and records has crystallized. Now, the regu- ment management application, which included
lations for electronic signatures are very clearly controls for specifications, purchases, materials
written. They are easy to understand and comply receiving, inventory, and electronic batch records.
16
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
Quality systems were written while the business
rules were programmed into the application.
PharmTech: What are some best practices that can
be employed with the software system?
Soltero: The system will only record data from
materials that come from approved suppliers and
that have met all the required materials checks. It
also checks that specs have been approved and that
the status is acceptable. As a result, one cannot use
materials if they haven’t been approved. The process
stops when a gap is reached.
The software also performs quality review of
batch product records to ensure that requirements
have been met, signatures are in place, and documentation has been closed out, before reviews are
done by the quality assurance person. The reviewer
in the quality assurance department can then review these documents by exception, which saves a
significant amount of time.
We’ve designed every module with current good
manufacturing practice (cGMP) compliance in
mind. New features are judged not only based on
functionality but on how they comply with Part 11.
Data integrity
PharmTech: Pharmaceutical and ingredients manufacturers continue to have problems ensuring data
integrity. Does the software address this issue or
help facilitate compliance?
Soltero: We’ve designed the software to eliminate
the need to sign by hand or type in information.
In fact, all signatures are electronic. The company
scans barcodes on badges or materials, so one
needn’t try to figure out signatures, for instance, to
find out when materials were signed and by whom.
In addition, the software can be integrated with
balances and other equipment, and data can be
transferred electronically. Every item in inventory
has a bar code on it and can be brought up on a
computer screen.
PharmTech: Why did you feel that this approach
was needed?
Soltero: Not every pharma company is up to
speed in batch documentation. Many are still using
paper only. Big Pharma companies have electronic
systems, but not middle-sized companies, because
those systems are not affordable. An ERP system
from a company like SAP, for example, can cost
millions of dollars to buy and install.
We decided to use a cloud-enabled approach that
is easy and intuitive. Users can access the system
from anywhere by inputting their user name and
password. The result is more fluid operations than
possible in older systems.
We are now extending the software by embedding equipment control features, allowing manufacturing and process equipment to be controlled
automatically through the cloud.
PharmTech: How do you ensure data security?
Soltero: Skeptics continue to question the security of cloud-based systems, but we use 128-bit
encrypted data, just like the military does. Nevertheless, Big Pharma companies are often reluctant
to rely on cloud software, so we have developed a
version of the software that they can run internally,
behind their own firewalls.
PharmTech: Can the software enable in-process control and use of process analytical technology (PAT)?
Soltero: We are currently building the capability
to facilitate PAT and allow users to monitor data
in real time and to handle multivariate data. The
software offers users a dynamic view so that they
Contin. on page 20
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
17
MPI RESEARCH
SPONSORED CONTENT
Robert H. DeWit, PhD, DABT
President
MPI Research
INDUSTRY COLLABORATION IS KEY
T
The drug development industry has always been fast
paced, by necessity. With new discoveries come new
regulatory considerations, new processes. When
the goal of an industry is to improve quality of life,
advancing quickly is not trendy—it’s a necessity.
INDUSTRY OUTLOOK
The tools and resources now available to us have allowed the
industry to advance at an unprecedented pace. In today’s landscape of increased consolidation, a sharpened focus on biologics,
and the emergence of new technologies, companies often struggle to effectively define themselves.
Consolidation, whether among contract research organizations, large pharma companies, or other
entities, seems to be today’s normal. However, it’s important our industry doesn’t get ahead of itself. Service expansion and consolidation should be done thoughtfully. Companies need to make
sure they truly understand the needs of a market before, for instance, buying out small shops. We
shouldn’t attempt to be all things to everyone. Niche operations with a complete dedication to certain
specialized areas should always have a role.
Rather than worrying so much about deal flow and valuations, we could all stand to focus more on
collaboration—among developers, CROs, government agencies, universities, etc. A collective decision to work just a bit more in concert could have a significant impact on quality of life. Plus, it is also in
everyone’s long-term business interests when compared to the innovation-stifling cloak-and-dagger
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If organizations throughout the industry were more open to working together to achieve the best
outcomes, drug and device development could advance at a more efficient and effective pace. To
truly prioritize our collective goal of improving quality of life, the industry also needs to prioritize collaboration.
One final charge for drug and device developers: work with organizations that employ a consultative model. In an industry that evolves as quickly as ours, it pays (literally) to work with people who
understand the practical details of new technologies and regulations. For example, the SEND initiative
is top of mind with many today. With the initial SEND requirement date quickly approaching in December, the industry is buzzing about SEND capabilities and ensuring readiness. Take the time to make
sure your development team not only knows “letter of the law” regarding requirements, but also has
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ABOUT ROBERT H. DEWIT, PHD, DABT
Robert H. DeWit, PhD, DABT, is the president of MPI Research. Dr. DeWit has more than 25 years of
global preclinical drug development and toxicology experience. Rob joins MPI Research after serving in leadership positions at the Southwest Michigan Innovation Center—first as president and CEO,
then as Assistant Dean of Western Michigan University’s School of Medicine. Throughout his career
Dr. DeWit has held scientific and leadership roles at Parke-Davis, The Upjohn Company, Pharmacia,
and Pfizer, bringing robust industry experience to MPI Research. Rob is a graduate of Calvin College,
and received his PhD from The University of Michigan, and is an active member of the American Association for the Advancement of Science, and both the national and regional chapters of the Society
of Toxicology.
Company Name
Phone
Email
Website
18
Pharmaceutical Technology
QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
:
:
:
:
MPI Research
269.668.3336
info@mpiresearch.com
www.mpiresearch.com
P h a r mTe c h . c o m
Batch Recordkeeping Management
Contin. from page 17
can define the most important fields and set it up
to capture any kind of information, operation, or
data related to these priorities. These fields become
the source of data for control.
A lot of pharmaceutical manufacturing equipment is already computer controlled (e.g., tablet
presses, blenders, compressors), so operators dial
in a setting when they use the equipment. What
we’re doing is building an interface to connect that
with the control panel.
Speeding up batch documentation review
PharmTech: What problems did you hope to address
with this approach?
Soltero: I wanted to reduce the time and effort required for quality review. I’ve been involved in manufacturing, from the clinical level through full-scale
commercial manufacturing, and in my experience,
reviewing batch documentation can take up to six
weeks. The reviewer must look through every piece
of documentation associated with a batch. We made
all that part of the software so that it can be accomplished in 20 seconds. This set-up allows the quality
department to review by exception.
PharmTech: How do you handle training with this
approach?
Soltero: Generally, using the traditional approach, it
takes a year to train an operator on cGMPs. For us,
training can be done quickly, especially since much
of the required training material is already embedded
in the software. If an operator needs to access a SOP,
it’s right there.
PharmTech: You mentioned the fact that you set companies up so that all badges and components are barcoded. That would assume a higher level of sophistication than can be found at many facilities today. How
20
do you get companies to the point where they can take
advantage of the benefits of this software?
Soltero: Part of the package is process consulting,
which helps clients take paper-based reports and map
them into the electronic systems to take full advantage of digital technology and streamline operations.
Training can be done in one day.
Some paper-bound companies came to us after a
regulatory inspection didn’t go well, and FDA issued
a 483 or warning letter. After they’d installed our software, some of these same companies reported that
FDA was satisfied during reinspection.
PharmTech: What are your plans for the platform?
Soltero: In the short term, we plan to make the use of
manufacturing and batch records more flexible. We
recognize the fact that every company has its own
unique way of doing things, so we are changing the
design to be user friendly enough to allow people to
retain some of their own originality when they move
from paper to digital practices.
We also want to make the software more intuitive
and to feature more responsive designs, so that the
software will be able to respond to any kind of device
being used, whether laptop, tablet, or smartphone. We
already have the designs for this capability in place.
The final step will be providing more artificial intelligence. We’re also building wizards to help people by
walking through key tasks.
One important plan is to incorporate more modern manufacturing tools into the software. People
talk about the teachings of Deming, statistical process control, and Six Sigma, but many people working in the pharmaceutical industry today haven’t
been trained in those approaches. We plan to have
those methodologies be part of the underpinnings
of the software. PT
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
Sterilization
Too Much by Half:
Misapplication of the Half-Cycle
Approach to Sterilization
James Agalloco
The half-cycle method for
validating sterilization can
have adverse effects on
materials if used for steam
sterilization. The author
reviews historical and
current thinking on
validation of sterilization
processes.
T
he expectations for validation of sterilization were first established in the 1970s, when at first large-volume parenteral
manufacturers and then the remainder of the pharmaceutical industry were obliged to scientifically support their
processes (1). In the past 40 years, numerous training sessions and
conferences have been given a
CONTINUOUS IMPROVEMENT
EDITORIAL
Editorial Director Rita Peters rita.peters@ubm.com
Senior Editor Agnes Shanley agnes.shanley@ubm.com
Managing Editor Susan Haigney susan.haigney@ubm.com
Science Editor Adeline Siew, PhD adeline.siew@ubm.com
Manufacturing Editor Jennifer Markarian jennifer.markarian@ubm.com
Science Editor Randi Hernandez randi.hernandez@ubm.com
Community Manager Caroline Hroncich caroline.hroncich@ubm.com
Art Director Dan Ward
Contributing Editors Jill Wechsler jillwechsler7@gmail.com; Jim Miller
info@pharmsource.com; Hallie Forcinio editorhal@cs.com; Susan J. Schniepp
sue.schniepp@mac.com; Eric Langer info@bioplanassociates.com;
and Cynthia A. Challener, PhD challener@vtlink.net
Correspondent Sean Milmo (Europe, smilmo@btconnect.com)
4 Could Greater Transparency Improve
Pharmaceutical Quality and Compliance?
Agnes Shanley
EXCIPIENT QUALITY
9 Ensuring Quality in
Pharmaceutical Raw Materials
Agnes Shanley
BATCH RECORDKEEPING MANAGEMENT
14 Paperless Batch Records for the Masses
Agnes Shanley
Address
485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA
Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com
SALES
Publisher Mike Tracey mike.tracey@ubm.com
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European Sales Manager Linda Hewitt linda.hewitt@ubm.com
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Executive Assistant Barbara Sefchick barbara.sefchick@ubm.com
Address
485 Route One South, Building F, Second Floor, Iselin, NJ 08830, USA
Tel. 732.596.0276, Fax 732.647.1235
PharmTech.com
Sr. Production Manager Karen Lenzen
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tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255
Audience Development Manager Rochelle Ballou rochelle.ballou@ubm.com
STERILIZATION
21 Too Much by Half: Misapplication
of the Half-Cycle Approach to Sterilization
James Agalloco
AGING FACILITIES
27 Is Global Regulatory
Gridlock Slowing Modernization?
Agnes Shanley
MICROBIAL TESTING
33 Microbiological Testing,
Time is of the Essence
Cynthia A. Challener
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Drives Human Performance Excellence
Clifford Berry
48 Extending QMS to Contract Partners
Agnes Shanley
51 Ad Index
Issue Editor: Agnes Shanley
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P h a r mTe c h . c o m
Continuous Improvement
Could Greater Transparency
Improve Pharmaceutical
Quality and Compliance?
Agnes Shanley
4
F
or years, leaders within the FDA, particularly Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), (1) have noted the need for FDA to break
with old “command-and-control” methods. A few years
ago, Woodcock proposed an incentive program that would reward
companies for strong compliance and product quality records, and
penalize those with lax practices. Results of a 2015 survey (2) of industry experts in California suggested that such a “scorecard” might
increase industry investment in quality.
Originally, mention of the scorecard brought immediate questions of whether FDA should supervise the effort. A number of
different ideas have been proposed, but a new approach was outlined at the Parenteral Drug Association (PDA) Annual Meeting
in September 2016 by Martin Van Trieste, former chief quality officer at Amgen, who retired in June 2016. Van Trieste had founded
Rx360, the industry supply-chain safety coalition that is working
to combat pharmaceutical counterfeiting, substandard drugs, and
illegal diversion.
He has been collaborating with veteran quality executive Richard
Love, founder of HarborView LLC, on software development and
new algorithms that are based on key pharmaceutical quality performance indicators. Their goal is a website, the first version of which
went live in November 2016, and a smartphone app that will help
consumers make informed buying decisions, and allow proactive
pharmaceutical manufacturers to use product quality as a sales and
marketing strategy. He discussed the concept with Pharmaceutical
Technology.
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
AMEREAGLE/SHUTTERSTOCK.COM
A new website and
methodology grades
manufacturers, and their
products, based on quality
and good business practices.
Founder Martin Van Trieste
explains the approach and
the thinking behind it.
A new approach
PharmTech: What inspired you to start working on
this project?
Van Trieste: The more I’ve thought about it, the
more I’ve seen that the industry needs a transformational approach to product quality and patient
safety. This is the age of the Internet. More power
must go to the pharma consumer, just as it has
to consumers in other sectors with sites such as
Angie’s List and Yelp. Transparency has a positive
impact on business, and the best performing companies tend to prosper.
PharmTech: Why isn’t the old approach working?
Van Trieste: In the old scenario, the head of quality defends what is needed to improve quality to
senior management, but the top manager generally
considers it an expense, or a cost of doing business,
rather than an investment in the future.
If the consumer of your products changes buying
habits based on product quality and the robustness of your supply chain, then product quality becomes a business issue. Sales and marketing teams
will see benefit, and invest more in product quality.
This would result in a real change in dynamics that
could be revolutionary.
We live in a very litigious society. Some consumer lawsuits have already been seen based on
product problems that involve purchasing agents,
pharmacy benefit managers, and buyer groups.
The basic questions behind some of these suits are
simple: ‘Why was I given a grade-D generic pharmaceutical product, which resulted in this adverse
reaction, rather than a grade-A generic? Was this
done just to save money?’ In today’s environment,
large companies will lose suits like this.
If market dynamics are introduced, it could spur
a logarithmic change in the industry’s approach
to quality and compliance. I’m a realist and recognize that this approach could take many years
to catch on, but I figured we could start with a ‘JD
Edwards’-type scorecard. Currently there is a lot
of motivation for improvement.
PharmTech: Today, the consumer at the typical retail pharmacy is not informed of the source of the
medication that is being used to fill his or her prescription. Shouldn’t that information be provided?
Van Trieste: We don’t have that level of transparency now, but I believe that the country of origin
for both actives and finished drugs should be revealed to the consumer. At the PDA conference, I
asked the audience a hypothetical question: ‘If you
could choose between three products, one made in
western Europe, one in India, and one in China,
which one would you choose?’
No hands went up for India or China. Whatever
else that says, it proves that consumers want sourcing information and something that tells you more
about how a drug was made.
PharmTech: So you are taking a ‘report card’ approach?
Van Trieste: Richard Love at HarborView and I are
developing software and an app that would allow
the consumer to take a photograph of a prescription bottle at the pharmacy. The system will be
set up so that it would check that photo against a
database, providing information on the company
that makes the drug and the factory where it was
made, to let people know whether it was manufactured at a well- or poorly-managed facility.
PharmTech: Is this a realistic idea, given how secretive pharmaceutical companies are?
Van Trieste: Pharma is lagging behind other industries in its use of information, and ‘big data’ for
the consumer. Think of Uber or Tesla. You don’t
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
5
Continuous Improvement
buy a Tesla from a dealership, and you can rate
your Uber experience instantly. Technology will
enable better quality.
PharmTech: Why do you think it is that country
and manufacturer of origin are not disclosed to
the consumer today?
Van Trieste: I’ve asked FDA, and they said that
such information could be considered a trade secret, and the agency cannot disclose trade secrets.
Back in the day when current good manufacturing practices (cGMPs) took effect, or even earlier,
in the 1930s when the Food Drug and Cosmetic
Safety Act was established, most drugs and APIs
were made in the United States, so our laws and
practices are based on the fact that most drugs
were produced in the US. But times have changed
and, today, consumers have a right to know.
PharmTech: What data can consumers realistically
be expected to check?
Van Trieste: Well, some data is already publicly
available. The tools that exist today for analyzing Big Data were not there, even three years ago.
They allow users to go through 483s, warning letters, and drug shortages documentation in a very
short amount of time.
So, we are developing a scorecard based mainly
on information that is publicly available, adding
on information from PDA’s quality-culture metrics.
We’ve developed proprietary computer algorithms
to use that information.
PharmTech: What other data are you using for the
algorithms?
Van Trieste: We also incorporate manufacturing
data on process capability, and ask whether or not
the company has redundant sourcing for raw materials. Additional questions focus on inventory
levels. From these data, we issue a quality grade
6
that also indicates the probability of the given
manufacturer to have a drug shortage.
New tools for transparency
PharmTech: Tell us about the website.
Van Trieste: It is called medicine-i.com, and will
allow users to sift through compliance data as well
as data on the probability of shortages. I believe
that companies with good quality programs will
want to be in the system. For others, the program
will start some difficult internal conversations.
PharmTech: Will APIs and their suppliers be included in the grading process?
Van Trieste: APIs will be part of the calculation but
their manufacturers will not be graded. However,
if a finished drug manufacturer buys API from a
supplier, that supplier’s records will have been analyzed too (e.g., whether or not the company and
the facility were cited by FDA). The API manufacturer’s customer will receive a higher grade if their
API comes from a reputable company with a good
compliance history.
A website like this will improve transparency
and give consumers more power. Over time, retail
outlets will only want to stock products that have
been made by good suppliers.
PharmTech: How do you think the industry will
react to this program?
Van Trieste: I predict that one third of the industry
will want to be involved, one third will be against
the whole idea, and the other third will take their
usual ‘let’s wait and see what the others do’ approach to gage other companies’ response.
I do predict that pharma, as an industry, will resist
the idea, which is rather controversial for this segment.
But transparency is inevitable, and it has already happened in other industries. Resistance is futile!
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
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©2016 Patheon®. All rights reserved.
Continuous Improvement
PharmTech: How are you organizing the management of this program?
Van Trieste: I may not be the one to carry out the
idea, ultimately, but I want to bring it to a certain
level of development. Our algorithms will remain
our trade secret and the structure of the enterprise,
but the information within them will be made
public (e.g., number of shortages, which products,
length of time since last shortage, how the company is handling inventories, and whether they
have the drug on hand if need be).
Companies will also be penalized for failing to
build redundancy into their supplier networks.So,
for example, if Company X has had a drug shortage
in the past, if they are not measuring process capability, and if they rely on one supplier, the probability of their having a shortage is higher than it
is for the company with supply redundancy, 120
days of inventory, and process capability analysis.
Drug counterfeiting will not be part of the analysis.
A focus on quality
Amgen), but they still have a way to go. But at
least they’ve realized that, if you measure something, you can improve it.
PharmTech: What is the pharmaceutical industry’s
Sigma level today? Ten years ago, people were putting it at 3 or 3.5.
Van Trieste: I’d say the industry is probably still at
3.5 Sigma level as a whole, and roughly 80% of the
medicines sold today in the US are generic drugs.
In discussions about quality management, the Generic Pharmaceuticals Association has been most
vocal about the thousands of products that their
members manufacture, and how difficult it would
be to measure CpK (process capability) for each
product. Why is it that other industries have figured out how to do this for even the least expensive
products or components?
In the end, numbers tell the story. If a company is performing at Three Sigma, the cost of
poor quality accounts for 25% of manufacturing
costs. For a company operating at the Six-Sigma
level, it is only 2% of manufacturing costs. For a
large company with cost of goods sold of roughly
$1 billion per year, that can mean the difference
between $20 million and $250 million per year.
Pressure within the healthcare sector in general
should drive greater interest in reducing the cost
of poor quality through investment and best
practices.
PharmTech: Does the industry’s top management
have a grasp of the cost of poor quality?
Van Trieste: In 33 years, I’ve worked for various
companies and interacted with people at many
different companies in different capacities. One
group of companies is highly progressive. Quality and manufacturing leaders at these companies figured out a long time ago how to communicate the importance of investing in quality to References
C-level executives. There are progressive phar- 1. T. Sullivan, “FDA Drug Shortages: Fundamental Problem is the
Inability for the Market to Observe and Reward Quality,” Polimaceutical companies out there. But there is still
cymed.com, April 12, 2013, www.policymed.com/2013/04/fdaa lot of work to do. Other companies are not
drug-shortages-fundamental-problem-is-the-inability-for-theprogressive about quality and the industry is
market-to-observe-and-reward-quality.html
not at Six Sigma quality levels. There are some 2. C. Medina and F. Richmond, Therapeutic Innovation and Regulatory Science, 49 (5), pp 730-738 (2015). PT
companies that are close (e.g., Lilly, BMS and
8
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
Excipient Quality
Ensuring Quality in
Pharmaceutical Raw Materials
Agnes Shanley
Gelatin is widely used for
encapsulation, and requires
close attention to “criticalto-quality” attributes. JeanPhilippe Talmon, chief
procurement officer at
Capsugel, discusses best
practices.
G
elatin is commonly used for drug encapsulation. JeanPhilippe Talmon, chief procurement officer at Capsugel spoke to Pharmaceutical Technology about the
critical quality attributes of gelatin as an excipient in
capsule production, as well as measures that can be taken to ensure
an uninterrupted supply of quality raw materials.
RAWPIXEL.COM/SHUTTERSTOCK.COM
Critical to quality
PharmTech: What are the most important ‘critical-to-quality’ attributes for gelatin, for encapsulation?
Talmon (Capsugel): In today’s increasingly interconnected and highly
regulated global pharmaceutical market, adherence to ‘critical-toquality’ attributes is required to deliver best-in-class products.
First, sourced gelatin must comply with the different pharmaceutical and food regulations in all the markets where the end product
is sold. In global pharmacopeias, there are mandatory attributes to
assure the quality, identity, and purity of the excipients used in the
drug product. There are also non-mandatory attributes that provide information on control parameters for specific excipient use
and include functionality-related characteristics. Various European
Pharmacopoeia monographs, for example, have listed relevant parameters specific to the intended use of the excipient, which can form
part of the regulatory filing process. Manufacturers are increasingly
expected to understand the functionality of excipients and their potential impact on the final drug product.
Second, acquired gelatin must meet specific certification expectations and environment, health, and safety (EH&S) requirements.
There are more than 15 regulatory references that form the basis of
global gelatin purchasing specifications, including those from FDA,
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
9
Excipient Quality
United States Pharmacopeia (USP), Japanese Phar- example, in 2013, when heavy levels of chromium
macopoeia (JP), Food Chemicals Codex (FCC), and were detected in gelatin capsules made in China,
World Organization for Animal Health (OIE).
the USP–National Formulary (NF) monograph
for pharmaceutical-grade gelatin was revised to
include testing for heavy metals. Some companies
Stringent raw material
purchasing specs and quality scrambled to comply with the new requirements,
which then had a negative impact on their customagreements are required,
ers. However, companies whose gelatin purchase
as well as a robust supplier
specifications included chromium restrictions
could maintain product supply without delaying
qualification program.
delivery of their customers’ products to market.
For example, there are specific regulations on
the sourcing of bovine raw materials for excipient Animal-sourced materials
use. While Bovine Spongiform Encephalopathy PharmTech: What issues are entailed with the use of
(BSE) is well under control as a disease, the OIE animal-sourced materials, as compared with synis leading a global movement to standardize BSE thetic or non-animal-derived materials?
regulations and establish a common guidance on
Talmon (Capsugel): Animal- and non-animal
prevention, control, and eradication of the disease. sourced materials are used as excipients in pharGlobal regulators base their regulatory framework maceutical products. Each of these forms offers its
on OIE guidance. In Europe, manufacturers of own unique characteristics, specifications, opporbovine material must provide certificates of suit- tunities, and challenges at various points in the
ability (CEP) issued by the European Directorate development process. The positives and negatives
for the Quality of Medicines (EDQM) to be in- associated with both forms must be well undercorporated into marketing authorization dossiers stood to ensure that any potential associated risks
for applicable medicinal products. This is just one are identified in advance and controlled.
example of the types of certifications required.
Gelatin, which is made from the hydrolysis of
Third, sourced gelatin must maintain specified collagen of bovine, porcine, or fish origin, is wellphysical/chemical and microbiological require- suited for the encapsulation of pharmaceutical
ments to provide appropriate encapsulation of in- ingredients because of its excellent gelling and
dividual APIs. These specifications cover a large film-forming characteristics that support the mannumber of criteria, including viscosity, pH level, ufacturing process. These characteristics are the
loss on drying, and particle sizes, among others.
result of the unique property of the gelatin polyThrough adherence to these three critical-to- mer, which exhibits a reversible temperature-based
quality attributes, companies with capsule and gelification, turning into liquid when heating and
encapsulation capabilities can help to minimize hardening in the cooling process.
the business continuation risks associated with
Hydroxypropyl methylcellulose (HPMC), which
gelatin raw materials and gelatin production. For is made from plant/cellulose-based material, is an
10
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
Adare Pharmaceuticals:
Patients and our partners
are at the heart of
everything we do
Adare is a global specialty pharmaceutical company inspired
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not fully addressed by current medications. We use our unique
combination of experience, proprietary capabilities, and
resources to create meaningful products for them.
Our entrepreneurial and performance-driven culture
encourages us to take risks, identify promising ideas, and see
those opportunities through to completion. Our collaborative
spirit and dedication to developing strong partnerships
provide Adare and our partners with significant advantages in
competitive markets.
Adare can help you overcome complex formulation
challenges and add valuable IP to commercialized products
and products in development. Over 40 products incorporating
Adare taste masking, customized drug release, and
bioavailability enhancement proprietary technologies have
been commercialized around the world.
Adare also has an extensive patent portfolio, which includes
more than 360 granted patents and 225 pending patent
applications.
Experience a partnership focused on the needs of patients
and your company’s goals. Schedule a meeting with us at
BusDev@adarepharma.com.
Discover how our taste masking, customized drug release,
and bioavailability enhancement experts can help solve
your complex formulation challenges. Email us at
BusDev@adarepharma.com.
Visit www.AdarePharma.com
©2016 Adare Pharmaceuticals, Inc.
Excipient Quality
alternative to gelatin for drug encapsulation. Recent
in-vivo and dissolution test results investigated the
clinical performance of second-generation HPMC
capsules compared to that of gelatin capsules, and
found that the second-generation HPMC capsule performance was equivalent to that of gelatin capsules (1).
The choice between gelatin and HPMC materials
is based on numerous factors including, for instance,
the targeted product profile, characteristics of the fill,
and consumer lifestyle considerations (i.e., dietary restrictions based on religious practices, such as halal
and kosher requirements, or on vegan or vegetarian
diets). For example, while gelatin sets the benchmark
for pH- and ionic strength-independent disintegration and product dissolution profiles, HPMC capsules maintain lower moisture absorption, more
flexibility, resistance to chemical crosslinking, and
a higher thermal stability than gelatin capsules, providing greater benefit for hygroscopic and moisturesensitive ingredients.
Ensuring supplier quality
PharmTech: How do you ensure supplier quality?
Talmon (Capsugel): First, stringent raw material purchasing specifications and quality agreements are required that cover a large number of criteria. Second,
a robust supplier qualification program is needed to
provide a sound framework to guarantee that hard
capsules meet the highest standards for quality, traceability, and integrity. At Capsugel, our multi-phase
program requires that our critical raw material suppliers undergo an intensive, year-long selection process
that includes 150 critical parameters for evaluation
to verify they meet the most stringent regulatory and
industry standards, the most important being unique
specifications related to dissolution profiles and impurities. The process includes the following:
12
• Step 1: Supplier screening and investigation. A review
of the quality system of the vendor, the state of
their manufacturing technology, the scope of
their product and service offerings, and a detailed understanding of their performance metrics, regulatory compliance, and raw material
traceability. For example, more than 15 regulatory agency regulations inform the basis of our
purchasing specs.
• Step 2: Quality evaluation. A review of supplier material quality compliance with the company’s
specifications.
• Step 3: Manufacturing suitability evaluation. An analysis of small-scale production trials and R&D
pilot, when relevant. This analysis ensures compatibility of materials with manufacturing processes and protocols and confirms both finished
capsule product quality and manufacturing efficiency performance levels.
• Step 4: On-site supplier audit. A thorough traceability analysis, from raw material delivery to finished goods release, including a detailed review
of quality systems. This audit also confirms
compliance of production equipment and compliance to current good manufacturing practice
(cGMP) requirements.
• Step 5: Scale-up and final approval. This step involves a full-scale manufacturing run of capsules to confirm that material consistently meets
specifications and is continuously suitable to our
full-scale production. This also requires an evaluation of the supplier’s ability to control product
integrity and proper documentation across the
entire supply chain.
Third, it is important that long-term supplier partnerships are supported by a continuous supplier
performance management program. This program
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
includes an ongoing evaluation process designed
to ensure supply-chain traceability and finished
capsules that comply with the highest integrity
standards. This program helps to maintain a
global network of qualified suppliers with whom
there are established long-term partnerships. Key
components of this program are constant testing
to the highest standards, updated with the most
advanced instrumentation for contaminants tests,
for example; regular in-depth onsite audits of suppliers; continuous monitoring at manufacturing
facilities, including performing incoming quality
control on each lot of raw material prior to its use;
and follow up on supplier performance. Finally, a
global sourcing strategy is needed to ensure consistent quality and security of supply.
PharmTech: How do you prepare for potential disruptions in the supply chain?
Talmon (Capsugel): The key to preventing supplychain disruptions is to develop long-term partnerships with suppliers across multiple production sites
to ensure that alternative resources can be ramped
quickly and effectively in the event of an unexpected
issue. Companies must always look one step ahead of
their current needs and the requirements of the regulatory environment and business market. This process
includes continuously screening potential new suppliers, monitoring industry and governmental standards
and trends, building and maintaining an extensive
knowledge base of international regulatory requirements, and participating in membership associations
and working groups. All of these efforts are aimed
at anticipating and rapidly implementing changes to
safeguard the integrity of supply chain and products.
PharmTech: Which supplier criteria are crucial?
Talmon (Capsugel): Supplier selection is guided by
several core principles, including the quality of the
suppliers’ products and services as well as their
product traceability and integrity framework. Additionally, suppliers’ quality systems, certifications
and cGMP, regulatory compliance, and EH&S
compliance are important. Finally, it is critical to
look for suppliers to maintain responsible sourcing initiatives and have viable business continuity
plans. All of these attributes are central to ensuring
that suppliers can consistently and reliably deliver.
PharmTech: What are best practices for working
with offshore suppliers?
Talmon (Capsugel): A robust framework is required
to ensure that offshore suppliers meet the global
expectations of companies and their customers. At
Capsugel, we have a global production footprint,
and our raw material sourcing efforts are globally
coordinated and managed.
We maintain supplier evaluation programs to
secure identification of potential sourcing risks
and development of appropriate mitigation plans
in close collaboration with our suppliers. Supplier
audit results, for example, are used to dictate the
frequency, as well as the depth and breadth of the
follow-up supplier audits we conduct.
In parallel, we also maintain a thorough business continuity risk assessment program across our
entire global supplier base. These assessments are
conducted along six main dimensions, including
supplier production capacity constraints; compliance to Capsugel quality expectations; compliance
to regulatory requirements; single-sourcing risks;
supplier financial health; and supplier intellectual
property risk and third-party misappropriation.
Reference
1. A.Shanley, “Establishing a New Performance Standard for
HPMC Capsules,” PharmTech.com, May 20, 2016, www.pharmtech.com/establishing-new-performance-hpmc-capsules PT
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
13
Batch Recordkeeping Management
Paperless Batch
Records for the Masses
Agnes Shanley
A cloud-based program
offers a less expensive
alternative to MES, bringing
the power of paperless batch
record management to small
and mid-sized companies.
Rick Soltero, founder and
CEO of InstantGMP, discusses
the need for paperless data
management that facilitates
cGMP compliance.
J
ust as the paperless office, a utopian vision of the 1970s, has
never quite taken shape, neither has the paperless pharmaceutical plant. Most large pharma companies have installed the
enterprise research planning (ERP) backbone and manufacturing execution systems (MES) software that is required for electronic
data management. Most small to mid-sized pharmaceutical firms,
however, continue to handle batch documentation the old-fashioned
way, which does not make data management any easier. In this reliance on paper, much potential power is lost: potentially reduced cycle
times and document management times are just the tip of the iceberg.
Smaller companies have not had too many choices for modernizing
data management. Either they could invest hundreds of thousands
of dollars on MES and ERP systems, and the same amount again on
their implementation, or they could use and try to customize “job
shop” software systems that were designed for other industries and
do not come out of the box meeting FDA’s 21 Code of Federal Regulations (CFR) Part 11 requirements. This lack of FDA compliance
would require users to generate thousands of standard operating
procedures (SOPs).
Within the past few years, cloud computing has brought the potential power of paperless batch recordkeeping to a growing number of smaller companies. Rick Soltero, an alumnus of AAI Pharma
and former director of R&D at Smith-Kline Beecham, turned an
interest in process control and programming into InstantGMP, a
company that offers cloud-based batch documentation software
designed to streamline quality control time to allow for management by exception.
14
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
SIMON MAYER/SHUTTERSTOCK.COM
High costs a factor
WWW.CAPSUGEL.COM
ENGINEERING
MEDICINES TO LIFE
RISING TO THE CHALLENGE
Tomorrow’s complex medicines face challenges to overcome low
bioavailability and optimize drug delivery. This calls for a partner with
the credibility, ingenuity and flexibility to deliver both the product and
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With a unique range of technology and integrated product development
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© 2016 CAPSUGEL BELGIUM NV ALL RIGHTS RESERVED.
Batch Recordkeeping Management
Over the past two to three years, Soltero says, with. Today, when software packages tout the fact
more than 100 pharma companies have bought that they are Part 11 compliant, they are.
the software. Soltero talked about paperless data
PharmTech: How did you decide to start the commanagement issues and the company with Phar- pany?
maceutical Technology.
Soltero: InstantGMP started back in 2004. I saw
a need in pharmaceutical manufacturing for softStill a paper industry?
ware that could be used at multiple sites, and by
PharmTech: How much of the pharmaceutical indus- different people, simultaneously. At the time, there
try is still handling batch and other key manufac- weren’t any cloud-based software packages availturing and quality records on paper?
able that could be used by multiple sites and people,
Soltero: Even in this age of smartphones and at least not in a way that would allow one software
advanced communication, 50% of the industry is platform to reinforce GMPs.
still using paper. I believe this is because the opMy consulting company had to build a manutions available to smaller manufacturers are not facturing plant for a non-profit research organizaaffordable.
tion that was conducting Phase III clinical trials
in developing nations. Instead of taking the traditional manufacturing plant approach, which would
Most small- to mid-sized
have cost $6 million, we opted for an approach that
pharmaceutical firms
would depend on outsourcing and handing off the
continue to handle batch
project, after clinical trials were completed, to the
World Health Organization (WHO).
documentation the oldAt that point, technology had advanced to a
fashioned way, which does
point where remote data access via the Internet
not make data management
was possible. I wanted to create tools that would
any easier.
allow operations and quality staffers to create systems that did not rely on the presence of permaPharmTech: Does the continued use of paper also nent workers, and that could be used at more than
partly reflect a mindset issue? When FDA’s re- one company facility.
quirements for digital signatures, as set by 21 CFR
The facility needed quality systems that would
Part 11, came out about 10 years ago, they were a allow manufacturing data to be assessed remotely
source of misunderstanding and debate within the so that the client could minimize its dependence
industry. Has that changed?
on permanent staff.
Soltero: The environment has definitely changed,
Those quality systems, in turn, had to work with
and the industry’s understanding of digital signa- a 21 CFR Part 11-compliant database and docutures and records has crystallized. Now, the regu- ment management application, which included
lations for electronic signatures are very clearly controls for specifications, purchases, materials
written. They are easy to understand and comply receiving, inventory, and electronic batch records.
16
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
Quality systems were written while the business
rules were programmed into the application.
PharmTech: What are some best practices that can
be employed with the software system?
Soltero: The system will only record data from
materials that come from approved suppliers and
that have met all the required materials checks. It
also checks that specs have been approved and that
the status is acceptable. As a result, one cannot use
materials if they haven’t been approved. The process
stops when a gap is reached.
The software also performs quality review of
batch product records to ensure that requirements
have been met, signatures are in place, and documentation has been closed out, before reviews are
done by the quality assurance person. The reviewer
in the quality assurance department can then review these documents by exception, which saves a
significant amount of time.
We’ve designed every module with current good
manufacturing practice (cGMP) compliance in
mind. New features are judged not only based on
functionality but on how they comply with Part 11.
Data integrity
PharmTech: Pharmaceutical and ingredients manufacturers continue to have problems ensuring data
integrity. Does the software address this issue or
help facilitate compliance?
Soltero: We’ve designed the software to eliminate
the need to sign by hand or type in information.
In fact, all signatures are electronic. The company
scans barcodes on badges or materials, so one
needn’t try to figure out signatures, for instance, to
find out when materials were signed and by whom.
In addition, the software can be integrated with
balances and other equipment, and data can be
transferred electronically. Every item in inventory
has a bar code on it and can be brought up on a
computer screen.
PharmTech: Why did you feel that this approach
was needed?
Soltero: Not every pharma company is up to
speed in batch documentation. Many are still using
paper only. Big Pharma companies have electronic
systems, but not middle-sized companies, because
those systems are not affordable. An ERP system
from a company like SAP, for example, can cost
millions of dollars to buy and install.
We decided to use a cloud-enabled approach that
is easy and intuitive. Users can access the system
from anywhere by inputting their user name and
password. The result is more fluid operations than
possible in older systems.
We are now extending the software by embedding equipment control features, allowing manufacturing and process equipment to be controlled
automatically through the cloud.
PharmTech: How do you ensure data security?
Soltero: Skeptics continue to question the security of cloud-based systems, but we use 128-bit
encrypted data, just like the military does. Nevertheless, Big Pharma companies are often reluctant
to rely on cloud software, so we have developed a
version of the software that they can run internally,
behind their own firewalls.
PharmTech: Can the software enable in-process control and use of process analytical technology (PAT)?
Soltero: We are currently building the capability
to facilitate PAT and allow users to monitor data
in real time and to handle multivariate data. The
software offers users a dynamic view so that they
Contin. on page 20
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
17
MPI RESEARCH
SPONSORED CONTENT
Robert H. DeWit, PhD, DABT
President
MPI Research
INDUSTRY COLLABORATION IS KEY
T
The drug development industry has always been fast
paced, by necessity. With new discoveries come new
regulatory considerations, new processes. When
the goal of an industry is to improve quality of life,
advancing quickly is not trendy—it’s a necessity.
INDUSTRY OUTLOOK
The tools and resources now available to us have allowed the
industry to advance at an unprecedented pace. In today’s landscape of increased consolidation, a sharpened focus on biologics,
and the emergence of new technologies, companies often struggle to effectively define themselves.
Consolidation, whether among contract research organizations, large pharma companies, or other
entities, seems to be today’s normal. However, it’s important our industry doesn’t get ahead of itself. Service expansion and consolidation should be done thoughtfully. Companies need to make
sure they truly understand the needs of a market before, for instance, buying out small shops. We
shouldn’t attempt to be all things to everyone. Niche operations with a complete dedication to certain
specialized areas should always have a role.
Rather than worrying so much about deal flow and valuations, we could all stand to focus more on
collaboration—among developers, CROs, government agencies, universities, etc. A collective decision to work just a bit more in concert could have a significant impact on quality of life. Plus, it is also in
everyone’s long-term business interests when compared to the innovation-stifling cloak-and-dagger
attitude that often exists around data or technologies that prove useless when kept in a vacuum.
If organizations throughout the industry were more open to working together to achieve the best
outcomes, drug and device development could advance at a more efficient and effective pace. To
truly prioritize our collective goal of improving quality of life, the industry also needs to prioritize collaboration.
One final charge for drug and device developers: work with organizations that employ a consultative model. In an industry that evolves as quickly as ours, it pays (literally) to work with people who
understand the practical details of new technologies and regulations. For example, the SEND initiative
is top of mind with many today. With the initial SEND requirement date quickly approaching in December, the industry is buzzing about SEND capabilities and ensuring readiness. Take the time to make
sure your development team not only knows “letter of the law” regarding requirements, but also has
a practical understanding of how to navigate the real-world process. A little experience can and will
have a significant impact on your timeline, budget, and chances for success.
ABOUT ROBERT H. DEWIT, PHD, DABT
Robert H. DeWit, PhD, DABT, is the president of MPI Research. Dr. DeWit has more than 25 years of
global preclinical drug development and toxicology experience. Rob joins MPI Research after serving in leadership positions at the Southwest Michigan Innovation Center—first as president and CEO,
then as Assistant Dean of Western Michigan University’s School of Medicine. Throughout his career
Dr. DeWit has held scientific and leadership roles at Parke-Davis, The Upjohn Company, Pharmacia,
and Pfizer, bringing robust industry experience to MPI Research. Rob is a graduate of Calvin College,
and received his PhD from The University of Michigan, and is an active member of the American Association for the Advancement of Science, and both the national and regional chapters of the Society
of Toxicology.
Company Name
Phone
Website
18
Pharmaceutical Technology
QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016
:
:
:
:
MPI Research
269.668.3336
info@mpiresearch.com
www.mpiresearch.com
P h a r mTe c h . c o m
Batch Recordkeeping Management
Contin. from page 17
can define the most important fields and set it up
to capture any kind of information, operation, or
data related to these priorities. These fields become
the source of data for control.
A lot of pharmaceutical manufacturing equipment is already computer controlled (e.g., tablet
presses, blenders, compressors), so operators dial
in a setting when they use the equipment. What
we’re doing is building an interface to connect that
with the control panel.
Speeding up batch documentation review
PharmTech: What problems did you hope to address
with this approach?
Soltero: I wanted to reduce the time and effort required for quality review. I’ve been involved in manufacturing, from the clinical level through full-scale
commercial manufacturing, and in my experience,
reviewing batch documentation can take up to six
weeks. The reviewer must look through every piece
of documentation associated with a batch. We made
all that part of the software so that it can be accomplished in 20 seconds. This set-up allows the quality
department to review by exception.
PharmTech: How do you handle training with this
approach?
Soltero: Generally, using the traditional approach, it
takes a year to train an operator on cGMPs. For us,
training can be done quickly, especially since much
of the required training material is already embedded
in the software. If an operator needs to access a SOP,
it’s right there.
PharmTech: You mentioned the fact that you set companies up so that all badges and components are barcoded. That would assume a higher level of sophistication than can be found at many facilities today. How
20
do you get companies to the point where they can take
advantage of the benefits of this software?
Soltero: Part of the package is process consulting,
which helps clients take paper-based reports and map
them into the electronic systems to take full advantage of digital technology and streamline operations.
Training can be done in one day.
Some paper-bound companies came to us after a
regulatory inspection didn’t go well, and FDA issued
a 483 or warning letter. After they’d installed our software, some of these same companies reported that
FDA was satisfied during reinspection.
PharmTech: What are your plans for the platform?
Soltero: In the short term, we plan to make the use of
manufacturing and batch records more flexible. We
recognize the fact that every company has its own
unique way of doing things, so we are changing the
design to be user friendly enough to allow people to
retain some of their own originality when they move
from paper to digital practices.
We also want to make the software more intuitive
and to feature more responsive designs, so that the
software will be able to respond to any kind of device
being used, whether laptop, tablet, or smartphone. We
already have the designs for this capability in place.
The final step will be providing more artificial intelligence. We’re also building wizards to help people by
walking through key tasks.
One important plan is to incorporate more modern manufacturing tools into the software. People
talk about the teachings of Deming, statistical process control, and Six Sigma, but many people working in the pharmaceutical industry today haven’t
been trained in those approaches. We plan to have
those methodologies be part of the underpinnings
of the software. PT
Pharmaceutical Technology QUALITY THROUGHOUT THE SUPPLY CHAIN NOVEMBER 2016 P h a r mTe c h . c o m
Sterilization
Too Much by Half:
Misapplication of the Half-Cycle
Approach to Sterilization
James Agalloco
The half-cycle method for
validating sterilization can
have adverse effects on
materials if used for steam
sterilization. The author
reviews historical and
current thinking on
validation of sterilization
processes.
T
he expectations for validation of sterilization were first established in the 1970s, when at first large-volume parenteral
manufacturers and then the remainder of the pharmaceutical industry were obliged to scientifically support their
processes (1). In the past 40 years, numerous training sessions and
conferences have been given a