Download ajinomoto acquires althea

Volume 18, Number 3
March 2013
API — Biomanufacturing
Ajinomoto Acquires Althea........................1
Angel Biotechnology is Disbanded...........2
API — Biomanufacturing in Brief.............2
Side Effects........................................................3
Commercial Dose Manufacturing.........3
Clinical Dose Manufacturing and
Packaging.....................................................4
API — Small Molecule ...............................5
Analytical Services........................................5
Phase II-IV Clinical Research...................5
Early Development.......................................6
Drug Discovery...............................................6
Captive Capacity............................................6
Commodity Suppliers..................................7
Medical Device CMOs.................................7
Regulatory Developments
New Approach to Cross-Contamination
Prevention in EU Provided in Draft
A P I — B i o m a n u fac t u r i n g
Ajinomoto Acquires Althea
Ajinomoto Co. Inc. (Tokyo, Japan) agreed to acquire contract biomanufacturer
Althea Technologies, Inc. (San Diego, Calif., USA) for $176 million. The price
is equal to more than three times Althea’s revenues of $53 million. Closing is
set for April 2013, at which point Althea Technologies will become a fully integrated subsidiary of Ajinomoto.
Ajinomoto is a developer and manufacturer of food and nutritional products
containing amino acids, with revenues of $15 billion. The company has a goal
of generating ¥30 billion ($325 million) by 2020 in revenues from what it terms
the “advanced biomedical business,” which is a diversification from its core food
business. It was attracted by the prospects of contract manufacturing, which it
puts at $2.3 billion, with double digit growth, and the opportunity to leverage
its amino acid-based technologies, including Corynex, its proprietary protein
expression system.
Althea Technologies, with 220 employees, provides microbial fermentation for
manufacture of biologics APIs, as well as commercial-scale fill/finish and related
formulation and analytical services. Fermentation capabilities go up to 1000 L
scale and include microbial and yeast hosts. Injectables capacity includes vials
(10 million per year) and prefilled syringes (25 million per year); lyophilization
capacity is to be added for 2014. The company was started by Magda Marquet
and Francois Ferret in 1998, and has private equity backing from several firms,
including Telegraph Hill Partners.
Guidelines.......................................................8
Outsourcing Events.................................... 11
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The Ajinomoto-Althea Technologies acquisition is reminiscent of
Fujifilm’s acquisition of the Merck BioManufacturing Network in
2011: a large Japanese company with heretofore little or no presence in biopharmaceuticals or contract manufacturing making a big, expensive
acquisition to gain entrance to the industry. While both companies have some
synergies to leverage, in both cases the buyers are clearly viewing the acquired
biomanufacturer as a platform for gaining a bigger role in the CMO industry.
The price paid is for Althea is truly impressive, especially as the company was
rumored to be experiencing some operational challenges in recent years. It had
the misfortune of bringing on substantial manufacturing capacity in 2008-2009,
just as the biologics development and manufacturing industry was experiencing a downturn. Nevertheless, the price will probably encourage private equity
investors, who have continued to pour money into the CMO industry despite its
volatile performance in recent years.
For more information on the business and
capabilities of Althea Technologies, click
on this box or go to www.pharmsource.com
and search by company name. If you need
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Actionable intelligence for bio/pharma sourcing
Angel Biotechnology
is
Disbanded
Angel Biotechnology (Edinburgh, Scotland) appears to be breaking up. According to various press
reports in the UK, the company has sold off its two of its main assets—its Edinburgh biomanufacturing facility and its collagen manufacturing business—and plans to auction off its biomanufacturing
facility in Cramlington, UK.
The situation is somewhat confusing because, despite being a publicly-traded company, Angel has
released little information directly. Its last major announcement was on February 2, 2013, when it disclosed that it had appointed outside administrators, which is a step in the bankruptcy process. A few
days previous, the company had announced that trading of its shares on the London Stock Exchange
had been suspended. At the end of January, it announced that its future depended on completing a joint
venture deal with Medica Materia Holding (MMH), a Russian biopharma company that has been Angel’s
main client and with which Angel had been in long-term negotiations to establish a joint venture.
On March 18, press sources revealed that Angel’s Edinburgh facility had been acquired by AB Technology for an undisclosed sum. AB Technology was established in 2012 by MMH and was to be the
vehicle for the joint venture. It was also revealed that a separate deal has been reached for the sale
of Angel’s Glasgow collagen manufacturing facility (Angel Biomedical) to a newly formed company
(Collbio Ltd., Manchester, UK), which will also take over Angel’s existing contract with Cardium
Therapeutics. Collbio is backed by life sciences finance firm Diagnostic Capital Ltd. and headed by
Stewart White, the former CEO of Angel Biotechnology.
Angel has been facing financial difficulties, as it has had problems reaching a viable level of revenues.
In its most recent financial statement (six months to September 2012), the company recorded a loss
of £2.9 million ($4.3 million) on revenues of only £1 million ($1.5 million). For the financial year
ended March 30, 2012, revenues were only £3.5 million ($5.25 million), with a loss of £1.3 million
($2.0 million).
In the context of the overall biomanufacturing market, the loss of Angel Biotechnology is immaterial. It had a small number of number of clients (fewer than five active, by our count) and limited
capacity. However, it seems to be reflective of the poor state of the biopharmaceutical development
industry in the UK, which suffers from very few successes and limited venture capital support. Other
UK-based biologics development and manufacturing organizations, including Eden Biodesign and
Cobra Biologics, have been acquired after suffering through difficult periods.
For more information on the business and capabilities of Angel Biotechnology, click on this box or go to www.pharmsource.
com and search by company name.
API — Biomanufacturing in Brief
Althea Technologies (San Diego, Calif., USA) entered an agreement to manufacture cGMP-compliant, gram-scale quantities of plasmid DNA expressing IL-12 for Profectus BioSciences (Baltimore,
Md., USA) in support of Profectus Biosciences’ continuing DNA vaccine development, backed by the
NIH. The IL-12 expression helps prompt an immune response once the DNA enters a cell, possibly
helping to overcome the poor delivery and immunogenicity of many DNA vaccines.
Rentschler Biotechnologie (Laupheim, Germany) appointed Frank Ternes as its new chief business
officer.
Sanofi (Paris, France) will manufacture APIs, such as peanut protein extract, for DBV Technologies’
Viaskin allergy treatment. As part of the agreement, Sanofi will scale up and validate the production
and commercial supply of the Viaskin APIs.
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S ide E f f e c t s
Side Effects identifies CMOs and CROs that might be impacted by key events affecting their clients,
including company acquisitions, product acquisitions and licenses, product approvals, late clinical
product terminations and FDA rejections.
Contractor
Pharma Company
Event
Product
Relationship
DUEXIS
Solid dose manufacturing
Omontys
Injectables manufacturing
Potentially positive
Sanofi-Adventis
Horizon Pharma
UK approval
Potentially negative
Baxter BioPharma Solutions
Affymax
Withdrawal of product
Source: PharmSource Lead Sheet
C o m m e r c ia l D o se Ma n u f a c t u r i n g
DPT Laboratories (San Antonio, Texas, USA) passed an FDA inspection at its sterile manufacturing
facility in Lakewood, N.J., USA, which manufactures small-volume parenterals, ophthalmic preparations, nasal sprays and sterile ointments. The inspection was a follow-up to confirm corrections were
made to GMP deficiencies cited in an August 2012 warning letter. The warning letter was officially
closed out on February 19, 2013.
DSM Pharmaceutical Products (Parsippany, N.J., USA) entered a three-year agreement to supply
sterile products for Eisai (Woodcliff Lake, N.J., USA), including commercial supplies of eribulin
mesylate and unnamed developmental drugs.
Hospira (Lake Forest, Ill., USA) recalled three of its generic injectable products—diazepam, furosemide and succinylcholine chloride (Quelicin)—due a potentially faulty seal, which could compromise
sterility. No adverse events had occurred at the time the recall was issued. The recalls come after
Hospira’s injectables manufacturing facility in Rocky Mount, N.C., USA, failed to pass an FDA reinspection after a 2010 warning letter. The agency listed 20 items requiring remediation, several of
which the company said are already in the process of being corrected.
Meanwhile, Hospira faces a lawsuit filed in New York by GlaxoSmithKline (Brentford, UK). The suit
is pursuing payment of more than $25 million in losses stemming from Hospira’s termination of an
influenza vaccine manufacturing agreement due to quality problems. Hospira declined to comment
on the lawsuit.
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IGI Laboratories (Buena, N.J., USA) entered an agreement to manufacture for Juventio (Chatham,
N.J., USA) finished doses of cosmetic and OTC products developed by IGI and using IGI’s Novasome
encapsulation technology. The three-year contract includes a $3 million minimum in purchases.
Irvine Pharmaceutical Services (Irvine, Calif., USA) is expanding its lyophilized/liquid filling,
formulation and biopharmaceutical development services at its Irvine site. The parenteral manufacturing facility will gain expanded sterile filling capacity, as well as added manufacturing capabilities.
Irvine plans to double its capacity by the second quarter of 2014.
Jubilant HollisterStier (Spokane, Wash., USA) received an FDA warning letter citing cGMP violations at its Kirkland, Quebec, Canada facility, including insufficient investigation of batch
discrepancies and failures, failure to establish batch acceptance criteria and lack of laboratory determination that each batch met specifications before release.
Patheon (Durham, N.C., USA) plans to close its Olds, Alberta, Canada soft gelatin capsule manufacturing site by the end of 2013, resulting in a savings of $8 million. Patheon acquired the facility when
it acquired Banner PharmaCaps in December 2012. A Patheon spokesperson told BPOR the move is
intended to help optimize all the capacity within the Patheon network. Products made at the Olds
facility will be transferred to other locations.
Pharma Tech Industries (Royston, Ga., USA) will provide filling, assembly and packaging services
for a powder-based, nasally delivered migraine relief medication for OptiNose (Yardley, Pa., USA).
The agreement will start with clinical supplies in support of OptiNose’s pending application to FDA
for approval; OptiNose has completed Phase III studies of the sumatriptan succinate product. Postapproval, Pharma Tech Industries will provide the same services at the commercial scale.
Pharmatek Laboratories (San Diego, Calif., USA) plans to expand its GMP facilities for highly
potent and cytotoxic compounds. The expansion, expected to be finished in the fourth quarter of
this year, will include three additional cGMP manufacturing suites and an automated packaging line
able to produce batch sizes of up to 10,000 bottles/day.
Tapemark (West St. Paul, Minn., USA) has expanded its transdermal patch manufacturing capabilities, adding formulation, blending and coating of patches to its existing converting and packaging
capacity. The additions allow Tapemark to offer comprehensive transdermal patch development and
manufacturing services.
C l i n i c a l D o se Ma n u f a c t u r i n g a n d P a c k a g i n g
Ashland Inc. (Wilmington, Del., USA) plans to expand its pharmaceutical R&D Center of Excellence in Wilmington, to include formulation development and GMP contract manufacturing capacity
for solid dispersions and oral solid dosages. Additions will include spray-drying and extrusion processes—previously located in Columbia, Md., USA—to support early-stage clinical trials. The new
facility is expected to be operational by summer 2014.
Capsugel (Morristown, N.J., USA) launched a new Dosage Form Solutions business, which will
expand the company’s lipid-based formulation offerings to meet growing customer demand for these
and other innovative formulations. The company will also continue to expand its targeted-release
capsule services.
In a related move, Capsugel also will acquire Encap Drug Delivery (Livingston, UK), adding Encap’s
liquid and semi-solid dose manufacturing capacity to its own. This acquisition is intended to boost
Capsugel’s semi-solid manufacturing services and help its new DFS unit mature.
Particle Sciences (Bethlehem, Pa., USA) has partnered with NETZSCH Premier Technologies, a
manufacturer of wet milling and dispersing equipment, to provide pharmaceutical nanomilling capabilities for wet-milled products, particularly sterile products.
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Quay Pharma (Deeside, UK) is expanding its clinical manufacturing facility in Deeside, UK to
include a new packaging and distribution area that will allow bulk product delivery. Quay is also
adding new equipment, including a state-of-the-art ion chromatography system to support two new
projects requiring specialist analytical capability. The addition will cost £100,000 ($152,341). Quay
provides clinical filling and labeling of primary and secondary packaging, such as bottle, tubes, blisters, and oral dosing syringes.
API — Small Molecule
BASF (Florham Park, N.J., USA) has teamed with Bend Research (Bend, Ore., USA) to develop
novel excipients that will increase the bioavailability of poorly soluble drugs. The initial focus of the
partnership will be on optimizing new vinylpyrrolidone-based copolymers under development to
improve poorly soluble APIs.
Cedarburg Hauser Pharmaceuticals (Grafton, Wisc., USA), received DEA registration for its Denver,
Colo., USA facility to manufacture schedule II-IV controlled substances.
Micron Technologies (Malvern, Pa., USA), which provides micronization, milling and analytical services, has been acquired by private equity firm Arlington Capital Partners (Chevy Chase, Md., USA).
The goal of the sale is to expand Micron’s global capabilities and service offerings.
PharmaZell (Raubling, Germany) entered an agreement to acquire Abbott’s (Abbott Park, Ill., USA)
API manufacturing facility in Liestal, Switzerland for an undisclosed price. The site, which will help
PharmZell expand its API manufacturing services, includes 150 cubic meters of reactor space, as well
as QC laboratories, packaging clean rooms and warehouses.
A n a l y t i c a l S e r vi c es
Almac (Craigavon, UK) passed an FDA inspection of its Craigavon, UK analytical testing facilities
with no 483 observations or recommendations for improvements. The inspection was part of preapproval inspections for an unnamed client’s products—a respiratory inhaler and irritable bowel
treatment; Almac is the contract test laboratory for these products.
Almac is also expanding API manufacturing services at the same facility, doubling its cGMP API
capacity and increasing stability storage.
Blue Stream Laboratories (Cambridge, Mass., USA), an analytical laboratory specializing in characterization of recombinant glycoprotein and complex biologics, has added two new mass spectrometry
systems: the Agilent 6538 QTOF and the Thermo TSQ Vantage Triple Stage Quadrupole systems.
The two will boost Blue Stream’s capabilities for quantitative analyses of biosimilars, peptides and
other biologics.
SGS Life Science Services (Geneva, Switzerland) is adding integrated formulation and stability
testing services in a new 1,100-square-foot dedicated suite at its Wokingham, UK site for sample preparation and testing at one site. The expansion will be completed in the fourth quarter of this year.
P h ase I I - I V C l i n i c a l Resea r c h
Accelovance (Rockville, Md., USA) has acquired Radiant Development, the CRO division of Radiant
Research (Cincinnati, Ohio, USA). Terms of the acquisition were not disclosed.
inVentiv Health (Somerset, N.J., USA) has acquired what the company called a “significant” equity
stake in virtual clinical trial and e-informed consent company Myrtus (Burlington, Mass., USA).
©2013 PharmSource Information Services, Inc. 1-703-383-4903
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Synteract (Carlsbad, Calif., USA) has acquired Harrison Clinical Research (HCR – Munich, Germany)
to form a new multinational CRO that will be known as SynteractHCR and headquartered in San
Diego County, Calif. SynteractHCR will provide Phase I-IV clinical trial services in such areas as oncology, CNS, infections disease, endocrinology, cardiovascular and respiratory. Terms of the transaction
were not disclosed.
Trial Form Support (TFS – Lund, Sweden), a full-service CRO that specializes in oncology, CNS,
immunology and vaccines, infectious diseases and endocrinology, will acquire the contract research
arm of Semcon Caran (Goteborg, Sweden), which specializes in electronic data capture (EDC). The
deal, effective April 1, will allow TFS to offer new validated EDC capability to clients.
E a r ly D eve l o p m e n t
Agility Clinical (Carlsbad, Calif., USA), a CRO that focuses on pre-clinical and clinical research in the
orphan drug category, has teamed with European orphan drug development specialist PSR Orphan
Experts (Hoofddorp, The Netherlands) to expand its services into Europe.
Calvert Laboratories (Scott Township, Pa., USA), a preclinical toxicology provider, has partnered with
drug formulation expert Particle Sciences (Bethlehem, Pa., USA) to pair Particle Sciences’ formulation development capability with Calvert Laboratories’ toxicology testing capacity.
Covance (Princeton, N.J., USA) entered an agreement to provide DNA/RNA sequencing, gene
expression analysis and genotyping analysis services to support M2Gen’s (Tampa, Fla., USA) cancer
research. All analyses will be conducted at Covance’s Seattle, Wash., USA facility.
Xceleron (Germantown, Md., USA) has teamed with JCL Bioassay (Hoffman Estates, Ill., USA) to
jointly offer clients highly sensitive analytical tools for preclinical and Phase I drug development in Asia,
Europe and North America. The agreement will pair Xceleron’s accelerator mass spectrometry (MS)
technology with JCL’s liquid chromatography-tandem MS services for bioavailability and other analyses.
Xceleron has also partnered with clinical pharmacology consulting firm Kinetigen (Research Triangle Park, N.C., USA) to improve Phase I drug pharmacokinetics analyses to clients. Xceleron will pair
its accelerator MS capabilities, which allow analysis across a broad range of asset classes and matrix
types, with Kinetigen’s expertise in complex pharmacokinetic analysis and overall clinical pharmacology strategy.
D r u g D is c o ve ry
Lonza (Basel, Switzerland) entered a contract to produce induced pluripotent stem cells (iPSCs) for
research by the National Institutes of Health (NIH) Center for Regenerative Medicine (CRM). The
three-year agreement has a value of up to $6.9 million. This is Lonza’s second contract to provide
iPSCs for NIH-CRM; the first was awarded in October 2012.
Cap t ive Capa c i t y
Baxter (Deerfield, Ill., USA) will buy Genmab’s (Copenhagen, Denmark) non-plasma-derived antibody manufacturing facility in Brooklyn Park, Minn., USA for $10 million. Baxter will continue to
employ the staff of 23 currently working at the 215,000-square-foot facility, which includes two segregated manufacturing trains, each with 1,000L and 10,000L bioreactors.
Kyowa Hakko Kirin (Tokyo, Japan) will begin construction of a ¥4.6 billion ($500 million) injectables
manufacturing plant at its Takasaki City site in May. The four-story, 4,106-square-meter facility will
focus on production of biopharmaceuticals in freeze-dried and liquid form. It is scheduled for completion in the second quarter of 2014, with operations starting in 2016 and commercial production
commencing by 2017.
©2013 PharmSource Information Services, Inc. 1-703-383-4903
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Merck (Whitehouse Station, N.J., USA) plans to sell its API manufacturing facility in Wicklow,
Ireland by the end of 2014. The company said it will transfer production of APIs—for such products
as allergy treatments Claritin and Clarinex and antifungal Noxafil—to other Merck facilities. Merck
also recently announced the sale of its API plant in Oss, the Netherlands to South Africa’s Aspen
Pharmacare (La Lucia Ridge, Durban).
Pfizer (New York, N.Y., USA) plans to sell its solid dose manufacturing operations in Illertissen,
Germany (near Laupheim). The site, which employs 400 staff, includes a highly automated facility
for production of highly potent solid dose products; the smoking cessation drug Chantix is produced
there currently. The announcement was made in late 2012, but no timetable for the sale has been
announced.
Sanofi (Paris, France) will invest €44 million ($56.6 million) in the Genzyme campus in Waterford,
Ireland, to enable manufacture of its Lantus (insulin glargine) product. The injectables manufacturing facility is expected to start production in 2016.
The Waterford site has two oral solid dose facilities, as well as an injectables manufacturing unit.
Genzyme recently completed a €150 million ($192.8 million) expansion that included a second
injectables filling line and three lyophilizers, as well as a softgel manufacturing capability. Genzyme
conducts dose manufacturing for most of its products at the Waterford site, including Myozyme,
Lumizyme, Cerezyme, Thymoglobulin, Cholestagel, Renvela and Renagel.
Teva (Petah Tikva, Israel) plans to sell its injectables manufacturing facility in Irvine, Calif., USA.
The 70,000-square-foot facility has six filling lines and at least three lyophilization units, and is
capable of manufacturing cytotoxic products. In 2009, the facility was the target of an FDA warning
letter stemming from contamination problems in the manufacture of propofol, a generic anesthesia
product. Teva reportedly spent $375 million to remediate the facility, but has moved most of its products from that plant to another injectables site in Hungary. The company reportedly will leave some
products at the facility to be manufactured by buyer.
Industry sources indicate that there is likely to be considerable interest in the facility, including from
CMOs, as injectables capacity is much in demand. However, CMOs are likely to be put off by the low
utilization and need to absorb much of the fixed costs of the facility until they can build up a sufficient volume of contract production.
C o m m o di t y S u pp l ie r s
Qualicaps (Irving, Texas, USA) is investing $26 million to expand its hard gelatin capsule manufacturing facility in Whitsett, N.C., USA. The three-year project was partly funded by a grant of up to
$235,000 from the One North Carolina Fund, which is contingent upon proof of job creation and a
local funding match. The expansion is expected to create 123 jobs.
SAFC (St. Louis, Mo., USA) is expanding its Irvine, Scotland cell culture media manufacturing plant
to add large-scale dry powder milling and blending capability, capable of producing more than 1,000
metric tons of DPM per year, along with an additional 60,000-plus square feet of warehousing space.
SAFC is undertaking the expansion, set to be finished in the first quarter of 2014, to meet growing
demand in Europe and the Asia Pacific market.
Medi c a l D evi c e CMOs
Rexam (Suresnes, France) is expanding its La Verpilliere, France packaging facility, adding approximately 25,833 square feet of clean room space for production of insulin injection pens for Eli Lilly
(Indianapolis, Ind., USA).
©2013 PharmSource Information Services, Inc. 1-703-383-4903
Bio⁄Pharmaceutical Outsourcing Report 7 of 11
Actionable intelligence for bio/pharma sourcing
Re g u l at o ry D eve l o p m e n t s
New Approach to Cross-Contamination Prevention
Provided in Draft Guidelines
in
EU
Draft EMA guidance on avoiding cross-contamination of products made in shared facilities could
require some pharmaceutical manufacturers, including some CMOs, to revisit their cross-contamination risk assessments and revalidate their cleaning procedures.
According to the EMA website, the draft suggests how companies may best comply with GMP revisions designed to prevent residual APIs from one product contaminating another, potentially placing
patients at risk. CMOs, which typically make multiple pharmaceuticals for multiple clients, would be
among the companies most affected by the recommendations in the document.
As BPOR went to press, EMA also released proposed revisions to four GMP guideline chapters, two
of which address cross-contamination prevention requirements. These documents were developed
in tandem to address changes to GMP regulations, including the new, tougher contamination prevention requirements, according to an EMA source. The cross-contamination guidance was released
first—at the end of January—and the more recently published proposed guidelines, which provide
the basis for EU harmonization by explaining how to interpret and apply GMP regulations, specifically reference that document.
The revised Chapter 5 of the GMP guidelines explains the regulatory foundation for what Doug
Rufino, Patheon vice president of quality, North America, called the key element of the draft
guidance: the requirement that manufacturers of multiple products must consider available pharmacological and toxicological data as part of their contamination risk assessment. Historically, a simple
numerical value—typically 10ppm or 1/1,000 of the lowest clinical dose, whichever was lower—has
been used.
The proposed GMP guidelines state that “a toxicological evaluation should be the basis for the establishment of threshold values in relation to the products manufactured (see Guideline on setting health
based exposure limits for use in risk identification in the manufacture of different medicinal products in shared
facilities). Where the toxicological evaluation supports a threshold value, this should be used as an
input parameter in risk assessment.”
Some companies, such as Patheon, already consider pharmacological and toxicological data, Rufino
told BPOR. For these firms, the provisions in the draft cross-contamination guidance will not have
a significant impact. “It appears that the guidance document may be moving towards an approach
similar to Risk-MaPP (e.g., using toxicity data instead of 1/1,000 of the lowest clinical dose), which is
good,” he said.
Establishment of Threshold Values
Among the most significant suggestions in the draft guidance related to that requirement is for
drug makers to develop a “threshold value” for each product made in a given plant. This could be a
permitted daily exposure (PDE) or a threshold of toxicological concern (TTC), based on pharmacological and toxicological data from clinical and non-clinical studies.
The guidance defines a PDE as “a substance-specific dose that is unlikely to cause an adverse effect if an
individual is exposed at or below this dose every day for a lifetime.” The PDE should be determined by:
◆◆ Hazards identified after reviewing contamination data;
◆◆ Evaluation of “critical effects;”
◆◆ Determination of a no-observed-effect level of the findings that are considered to be critical
effects; and
◆◆ Other adjustment factors to account for uncertainties.
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A TTC—which the EMA expects companies to use for any genotoxic active substance—represents
the genotoxic impurity exposure level linked to a theoretical cancer risk of one additional cancer in
100,000 patients exposed to the substance over a lifetime. For these products, any level of exposure is
considered to carry a risk.
If a company lacks sufficient data to develop a PDE or TTC for a particular product, that drug would
have to be made in a dedicated facility, according to the draft guidance. Certain antibiotics and highpotency compounds like cytotoxic drugs already face this requirement.
Thomas Beck, director of quality assurance/quality control at Recipharm noted that this could prove
problematic for CMOs. “The original clinical data is not always submitted to the CMO, since they only
manufacture the product,” he told BPOR. “The owner of the product also changes during the life
cycle; this makes it much more complex to get data to evaluate the PDE.”
In addition to needing to get original clinical data from their clients to develop the PDE, CMOs will
need to employ a new skill—toxicology—that normally sits within the product owner, Beck noted.
Firms will also have to conduct a complete new assessment and revalidation, he added.
The draft guide also describes how manufacturers should present PDE and TTC data in newly
required reports to regulatory inspectors, including a suggested report template.
Validation of Cleaning Procedures
The regulations call for a quality risk management approach based on the toxicological evaluation
and potential contamination risk—including such factors as facility and equipment design, API characteristics, process characteristics, personnel flow and cleaning processes—according to the proposed
GMP guidelines.
Though specifically mentioned in the regulations and draft guidance, cleaning procedures are likely
to remain the same for many facilities, however. “Once the assessment is done and revalidation completed, cleaning is probably the same,” Beck said.
Joachim del Boca, vice president of regulatory affairs/quality compliance at Vetter, agreed, but added
that validation may need to be extended to the entire cleanroom. “Currently, validation is done on
equipment with direct contact with the substances. But the validation needs to be extended in case of
any residue anywhere in the room,” he said.
Rufino took it a step further, suggesting that “validation departments will need to evaluate their
current cleaning validation practices/calculations and target values to determine if they are safe from
a pharmacological and toxicological perspective.”
If in-house testing shows any residue in the production area, cleaning procedures may need to be
intensified, del Boca added. Special gowning, weighing processes in isolators and specialized waste
handling are other procedures that may need to change in light of the new guidance, he added.
Recommended Designs and Procedures
Chapter 5 of the proposed GMP guidelines also lays out requirements for drug production, with a
section dedicated to prevention of cross contamination. The guidelines say firms should use “robust
design of the premises, equipment and processes,” plus “appropriate procedures and technical or
organizational measures, including reproducible cleaning and decontamination processes of validated
effectiveness” to reduce or eliminate the risk of cross-contamination. Some technical and organizational measures suggested include:
◆◆
◆◆
◆◆
◆◆
Dedicated facilities;
Self-contained production areas;
Use of “closed systems” for processing and for material/product transfer between equipment;
Localized dust extraction;
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◆◆
◆◆
Use of disposable technologies and/or equipment designed for ease of cleaning;
Use of protective clothing inside areas with a high cross-contamination risk;
Cleaning verification after each product campaign;
Comprehensive sampling protocol after cleaning of critical surfaces; and
Air sampling and wipe/swab sampling in areas adjoining the working area.
Any such measures applied must be checked periodically for effectiveness. The GMP guidelines do
not define a set period for evaluating the effectiveness of these or other measures to prevent crosscontamination.
Some experts suggested that the new model outlined in the GMP guidelines and cross-contamination guidance could trigger the use of more dedicated equipment at some facilities, even if the
current equipment is easy to clean. For small-scale operations, the guidance may also encourage
more use of small, disposable contact parts, but “this is not applicable for commercial manufacturing, since the scale is in cubic meters and tons, rather than milliliters and grams,” Beck said.
Del Boca agreed that the guidance could increase the use of disposable contact parts, and noted that
waste disposal procedures will be important for these parts in order to protect the whole room from
potential contamination. For instance, Vetter places used disposable parts in a sealed container or
bag, and uses a special waste handling company to dispose of them.
While Rufino agreed use of disposable contact parts will continue to be beneficial, he noted that
engineering controls may be even more important. The facility itself and other non-product contact
surfaces will remain a potential source contamination, he cautioned, so “cleaning validation and
associated carry-over concerns will remain a critical element.”
Chapter 3 of the proposed GMP guidelines, covering premise and equipment requirements, also
mentions the draft guidance and the regulatory requirement to include a toxicological evaluation as
part of risk management. According to this portion of the draft regulations, dedicated facilities will
be required for products that present a risk that cannot be adequately controlled by technical and/
or operational measures, when scientific data does not support threshold values or when those values
fall below levels of detection, based on the toxicological evaluation.
Del Boca noted that firms accustomed to dealing with ANVISA in Brazil may have an edge in
meeting the new regulatory requirements and recommendations in the guidance.
“This is new in Europe,” he explained. “But we are used to this from ANVISA, which already requires
segregation of some high-potency substances, such as hormones, in order to get GMP certification.”
Other topics addressed in the proposed GMP guidelines include:
◆◆ The manufacturer’s legal obligation to ensure that APIs are produced in compliance with GMPs
and to assure supply chain traceability;
◆◆ Testing requirements for starting materials;
◆◆ Notification to regulatory authorities of potential drug shortages;
◆◆ Expectations regarding technology transfer of analytical methods;
◆◆ Incorporation of quality risk management principles during defect and complaint investigations;
◆◆ The decision-making process for recalls or mitigation actions, including identification of the
cause of the problem; and
◆◆ Requirements for reporting quality defects to regulators.
EMA will accept comments on the draft guidance—entitled Guideline on setting health based exposure
limits for use in risk identification in the manufacture of different medicinal products in shared facilities—until
June 30. Comments on the proposed GMP guidelines are due July 18.
©2013 PharmSource Information Services, Inc. 1-703-383-4903
Bio⁄Pharmaceutical Outsourcing Report 10 of 11
Actionable intelligence for bio/pharma sourcing
O u t s o u r c i n g E ve n t s
PDA Annual Meeting 2013
April 15-17, 2013,
Orlando, Fla. USA
www.pdaannualmeeting.org
MD&M East 2013
June 17-20, 2013,
Philadelphia, Pa., USA
www.canontradeshows.com/expo/east13/
Partnerships in Clinical Trials
April 22-24, 2013,
Orlando, Fla., USA
www.clinicaltrialpartnerships.com
DIA 2013 Annual Meeting
June 23-27, 2013,
Boston, Mass., USA
www.diahome.org
BIO 2013 Annual Convention
April 22-25, 2013,
Chicago, Ill., USA
www.bio.org/events
Contract Pharma 12th Annual Conference and
Tabletop Exhibition
September 19-20, 2013,
New Brunswick, N.J., USA
www.conference.contractpharma.com
INTERPHEX 2013
April 23-25, 2013,
New York, N.Y., USA
www.interphex.com
ACP-LS Annual Meeting
September 19-20, 2013,
Philadelphia, Pa., USA
www.acp-ls.org/annual-meeting
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EDITORIAL ADVISORY BOARD MEMBERS
John Budzinski, PhD
Martin L. Jeiven, MS
Paul C. Stuart
Phelix Pharma Outsourcing Consultants, Inc.
President, Jeiven Pharmaceutical Consulting, Inc.
Mak Jawadekar, PhD
Howard L. Levine, PhD
Vice President, Clinical Supply Chain
Pfizer Worldwide Research and Development
Consultant in Drug Development
President, BioProcess Technology Consultants
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