Chapter 8

Regulation of plasma products

The global plasma products industry is one of the most heavily regulated sectors
within pharmaceutical [Link] World Health Organization (WHO) has
observed that this is because all medicines regulators have faced ‘serious and complex
challenges at a scientific, technological and regulatory level to ensure that these
biological products are of good quality, safety and efficacy’.1
The manufacturing paradigm for plasma products, like all biological products derived
from human or animal tissue, differs significantly from that applicable to synthetically
derived [Link] manufacture of conventional medicines using chemically
consistent raw materials and standard manufacturing techniques can produce generic
bio-equivalent [Link] manufacture of plasma products, in comparison, entails
inherent variability in the following areas:
• Source material: Each batch of starting plasma may contain thousands of
plasma units from donors that have been pooled for processing. Each plasma
starting pool will contain a different protein profile, which is manufactured,
through intermediate product stages, to produce a suite of final products that
must conform with approved specifications unique to each product.
• Risk factors: The manufacture of plasma products, like all blood products,
carries the risk of transmission of blood-borne pathogens (including bacteria,
viruses and prions).This has been a tangible, not theoretical, risk, evident in the
past transmission of hepatitis C and the Human Immunodeficiency Virus (HIV)
through the blood supply, including through plasma products, prior to the
introduction of specific screening tests and other safety measures in the 1980s and
1990s. Although the risk of viral transmission has decreased considerably over the
past 20 years, the recognition that Transmissible Spongiform Encephalopathies
(TSEs), including variant Creutzfeldt-Jakob disease (vCJD), could be transmitted
by transfusion has sharpened the focus on regulatory requirements for addressing
emerging [Link] is significant focus by manufacturers and regulators on
the requisite measures to apply throughout the manufacturing chain so as to
provide assurance of the safety and quality of the final products.
• Manufacturing process: Although common manufacturing steps are
employed by fractionators, there are no standard universal manufacturing
procedures for specific final products. Each fractionator adopts unique
manufacturing procedures in order to maximise the yield, safety, quality and
clinical efficacy of final products. Each manufacturing process requires individual
assessment by regulators.
• Final products: The diversity of fractionation processes may mean differential
clinical efficacy for different brands of the same product. Because different brands
of the same product may have slightly different clinical properties and side effects,
regulators require each product brand to be trialled in the clinical setting prior to
marketing approval.

144 1 World Health Organization, Ensuring the Quality and Safety of Plasma Derived Medicinal Products, Information Sheet,World
Health Organization, Geneva, 2006, <[Link]
 Review of Australia’s Plasma Fractionation Arrangements

The issues identified here are fundamental to the safety, quality and efficacy of
plasma products. Because of the global consolidation of plasma product
manufacturers and an increasingly global market for these goods (see Chapter 3),
the regulatory response has also shifted towards international harmonisation of
[Link] WHO, while stating that individual countries should develop
national regulations for plasma products, asserts that these should be based on
current international standards and that national regulators should ‘actively
participate in initiatives towards international harmonisation of regulation’.2
Australia has played a key role in this process of regulatory harmonisation.
This chapter provides an overview of the Australian regulatory framework
implemented by the Therapeutic Goods Administration (TGA).The key issue of
the regulatory oversight of overseas-manufactured plasma products, and whether
this oversight should be strengthened if a toll fractionation model were adopted
for Australia, is specifically [Link] chapter also describes the international
model for regulation of the safety and quality of plasma products, and looks at
why some regulatory approaches are specific to Australia.

The Australian regulatory framework

The Therapeutic Goods Administration is part of the Australian Government
Department of Health and Ageing, with responsibility for administering the
Therapeutic Goods Act 1989 (Cwlth) (hereafter ‘the Act’).The TGA’s key objectives
in the regulation of therapeutic goods in Australia are to ensure that these goods:
• meet appropriate standards of safety, quality and efficacy
• are made available to the community in a timely manner.

The TGA currently regulates over 50 000 therapeutic goods, including

prescription and non-prescription medicines, medical devices, blood, and blood
and tissue [Link] number of goods regulated by the TGA is continually
increasing, as new therapies evolve, as new applications for existing therapeutic
goods are found, and as international markets continue to expand. Manufacturing
techniques are also changing and improving with the advent of new technologies.
In 2004–05, the TGA assessed over 11 000 applications for product registration,
listing or inclusion on the Australian Register of Therapeutic Goods (ARTG), and
for variations to existing registrations or listings, and tested a total of 2861 samples
of 1254 products, as part of post-market surveillance.
Plasma for fractionation and plasma products have been regulated by the TGA
since its inception in [Link] includes:
• plasma products derived from plasma collected and fractionated in Australia for
use in Australia
• plasma products derived from plasma collected and fractionated overseas for
use in Australia
• plasma products derived from overseas-sourced plasma fractionated in Australia
for use overseas.

2 World Health Organization, Ensuring the Quality and Safety of Plasma Derived Medicinal Products, 145
<[Link]
 Review of Australia’s Plasma Fractionation Arrangements

The Australian and New Zealand governments have commenced a consultation

process to establish a joint regulatory [Link] would see a new authority that
would replace both the TGA and the New Zealand Medicines and Medical Devices
Safety Authority (Medsafe). Legislation to establish the Australia New Zealand
Therapeutic Products Authority (ANZTPA) is expected to be introduced into
Parliament in [Link] no practical changes to the content of current regulations
for plasma products are planned as part of the proposed establishment of a trans-
Tasman therapeutic products agency, it is likely that under the new authority plasma
products would be regulated within a discrete biologicals framework.
Plasma products in Australia are currently regulated as registered [Link]
results in their being subject to an intensive level of pre- and post-market scrutiny.
The existing TGA regulatory model for plasma products includes:
• establishing standards and guidelines for the safety and quality of products
• pre-market product assessment before registration of a product on the ARTG and
marketing approval in Australia
• licensing of domestic manufacturers, and certification of overseas manufacturers of
the plasma products supplied in the Australian market
• controls on advertising and promotion
• post-market surveillance mechanisms, including Good Manufacturing Practice
(GMP) audits, monitoring of adverse events, sampling and analysis of products,
and recalls of defective products
• administrative and criminal penalties and sanctions for breaches of the Act
• special arrangements for the supply of products not approved for general
marketing, including through the Special Access Scheme and for clinical trials.

The key elements of this framework are pre-market product assessment against
relevant standards and guidelines for registration on the ARTG; manufacturer
licensing (for Australian manufacturers) and certification of overseas manufacturers
(either by the TGA or by an accepted overseas regulator); post-market product and
manufacturer surveillance; and enforcement of compliance following breaches. Some
plasma products, however (like other therapeutic products), can be supplied in
Australia as unregistered products, with their supply being considered on a case-by-
case basis under the Special Access Scheme.

Registration of plasma products

The Therapeutic Goods Administration undertakes a comprehensive assessment of
the safety, quality and efficacy of all domestic and imported plasma products before
they can be registered on the Australian Register of Therapeutic Goods and approved
for supply in the Australian market.
The TGA has access to independent expert advisory [Link] include the
Therapeutic Goods Committee (which provides advice on standards), the Australian
Drug Evaluation Committee (ADEC) (which provides advice on product safety,

146
 Review of Australia’s Plasma Fractionation Arrangements

quality and efficacy) and the Adverse Drug Reactions Advisory Committee
(which reviews adverse drug reactions).
The ADEC is composed mainly of practising specialist clinicians drawn from
outside the [Link] ADEC provides the TGA with expert advice on any issues
that have arisen during the evaluation process of a product, and recommends to
the TGA whether the product should be included in the ARTG.
The broad framework for the registration of all high-risk medicines, which
includes plasma products, is outlined in the Australian Regulatory Guidelines for
Prescription Medicines (June 2004).These guidelines describe:
• the Australian data requirements for applications for product registration
• the evaluation and decision-making process undertaken by the TGA on each
application.

The Australian data requirements for product registration cover:

• administrative information, including product labelling and packaging,
and evidence of manufacturer licensing or certification against GMP standards
• product quality data, including chemical, pharmaceutical and biological
studies
• product safety data, including preclinical, pharmacological and
toxicological studies
• clinical data, demonstrating clinical efficacy and capacity to meet
therapeutic claims, through clinical studies.

Applications for product registration are submitted to the TGA by an Australian

product [Link] sponsor is responsible for the accuracy of all data submitted
and for complying with all post-approval conditions specified by the [Link]
areas of obligation include responsibility for notifying the TGA of any change in
product registration details or manufacturing process that may affect the safety,
quality or clinical data previously submitted; and post-market responsibilities in
relation to registered products. In essence the Australian sponsor is legally
responsible for any unauthorised change in product registration details and for
meeting many of the requirements imposed by the Act. A sponsor must be an
Australian resident or an Australian incorporated body responsible for the
manufacture, import or export of the product, or who has the product
manufactured or imported on its behalf.
One critical issue raised with the Review has been the importance of
confidence in the TGA in terms of the evaluation of the safety, quality and
efficacy of domestic and imported plasma products. All products supplied in
Australia, regardless of origin, are assessed against the same standards and
guidelines for product registration.

147
 Review of Australia’s Plasma Fractionation Arrangements

The Australian Regulatory Guidelines for Prescription Medicines make it clear that:
• Applications for product registration must comply with statutory standards
established by Therapeutic Goods Orders made under the Act and monographs in
the British Pharmacopoeia.3 Australia applies the standards of the European
Pharmacopoeia by adoption of the British Pharmacopoeia.4 The Pharmacopoeia
sets minimum mandatory standards for the manufacture and quality of
pharmaceuticals for human and veterinary use. Specific monographs for final
products include standards for: the definition of active substances; specification of
the origin and quality of source materials (this includes standards for blood donor
selection and screening; in respect of donors, Australia also has specific requirements
in its own Therapeutic Goods Orders5); specifications for in-process testing and
final product release testing, specific reference tests and assays for the purity and
potency of products, and measuring residual impurities and permitted limits of
[Link] Pharmacopoeia includes specific monographs on human plasma for
fractionation, and for individual plasma derived products.6
• Applications for product registration should comply with the European Union
(EU) guidelines adopted in Australia by the TGA.7 Following consultation with the
Australian pharmaceutical industry, the TGA adopts specific guidelines published by
the European Medicines Agency (EMEA), to ensure that Australia’s technical data
requirements for product registration are closely aligned with those in the EU.
While the EU guidelines are not legally binding, sponsors must provide justification
for any data that does not conform with requirements in a guideline.

The key EMEA blood and plasma guidelines adopted in Australia are: the Note for
Guidance on Plasma-Derived Medicinal Products,8 the Guideline on Assessing the
Risk for Virus Transmission,9 the Guideline on the Scientific Data Requirements for a
Plasma Master File,10 and the Guideline on the Investigation of Manufacturing
Processes for Plasma-Derived Medicinal Products with Regard to vCJD Risk.11

3 Sections 3(1) and 10 of the Therapeutic Goods Act provide that where the Minister has not determined a specific standard to
apply to a therapeutic product under a Therapeutic Goods Order, then standards established in relevant monographs of the
British Pharmacopoeia will apply. Current standards for plasma products are set by the British Pharmacopoeia 2005, which is
harmonised with the European Pharmacopoeia 2005.
4 The TGA is an observer on several expert groups that advise the European Pharmacopoeia Commission on the maintenance
and development of the product monographs that make up the European Pharmacopoeia. Since 1997 the TGA has been an
observer on a specialist group concerned with plasma and related products.
5 Therapeutic Goods Order No. 74: Standards for Blood Components,Therapeutic Goods Administration, Canberra, 2006,
<[Link]
6 For a list of the European Pharmacopoeia monographs for plasma derived products, see Committee for Proprietary Medicinal
Products, Note for Guidance on Plasma-Derived Medicinal Products, revision 3 [CPMP/BWP/269/95 rev. 3], European Medicines
Agency, London, 2001, pp. 19–20 (Annexes I and II), <[Link]
7 See Therapeutic Goods Administration, European Union Guidelines Adopted in Australia,Therapeutic Goods Administration,
Canberra, 2006, <[Link]
8 Committee for Proprietary Medicinal Products, Note for Guidance on Plasma-Derived Medicinal Products, revision 3
[CPMP/BWP/269/95 rev. 3], <[Link]
9 Committee for Medicinal Products for Human Use, Guideline on Assessing the Risk for Virus Transmission [CPMP/BWP/5180/03],
European Medicines Agency, London, 2004, <[Link] (also adopted as new
Chapter 6 in the Note for Guidance on Plasma-Derived Medicinal Products (see note 6 above)).
10 Committee for Medicinal Products for Human Use, Guideline on the Scientific Data Requirements for a Plasma Master File (PMF),
revision 1 [EMEA/CPMP/BWP/3794/03Rev. 1], European Medicines Agency, London, 2006,
<[Link]
11 Committee for Medicinal Products for Human Use, Guideline on the Investigation of Manufacturing Processes for Plasma-Derived
Medicinal Products with Regard to vCJD Risk [CPMP/BWP/5136/03], European Medicines Agency, London, 2004,
148 <[Link]
 Review of Australia’s Plasma Fractionation Arrangements

Adoption of these guidelines has ensured provision to the TGA of extensive data
relevant to the safety and quality of plasma products, including:
• quality assurance of the starting plasma – through annual updates of the sponsor’s
Plasma Master File covering donor selection, screening of donations, audits of
collection centres, systems for tracing donors to finished products, storage and
transport of donations
• quality assurance of the manufacturing process – through testing and control of
intermediate products, specification, quality control and validation of the
purification and viral-inactivation and removal processes.

Assessment of product registration data essentially occurs at a fixed point in time.

Although the data provided in the application process address the quality assurance
and control systems built into the manufacturing process, the post-market
surveillance system provides for risk-based review of these systems through the
monitoring of adverse events; periodic product safety updates; product testing; annual
reviews of plasma master files; and GMP surveillance audits.
One issue for attention relates to the certification of product batch release by an
appropriately qualified person. At present, sponsors are not required to certify that
each batch of products for supply in Australia meets product registration
[Link] is already a requirement in the EU and the United States.
The TGA has experienced some difficulties in resolving issues related to product
quality with representatives of sponsors in Australia when these representatives do not
have a technical understanding of the product [Link] TGA will shortly enter
into formal consultation with industry on the proposal that all batches of imported
medicines should be released for supply only after an appropriately qualified person
has certified that the batch meets required specifications for quality and safety. It is
agreed that it is important to ensure that an appropriately qualified person is
responsible for certification of batch release.
A second issue relates to the TGA’s capacity to independently test [Link]
TGA employs a risk-based program of targeted testing of products in the
marketplace to ensure compliance with specifications and registration [Link] TGA
has occasionally found problems with batches of products that have passed testing by
the [Link] Review supports independent testing by the [Link]
extent of this testing would vary depending on the risk posed by the product and
TGA experience of the particular manufacturer. In the EU, there is a system of
Official Medicines Control Laboratories that test all batches of plasma products prior
to release in [Link] regulatory agencies of North America, which include the
Food and Drug Administration (FDA) and Health Canada, test products on a risk
management basis that is more targeted. It is anticipated that the presence of a
qualified person representing the sponsor will assist the TGA in the establishment of
a similar program for plasma derivatives in the Australian market.

Licensing and certification of manufacturers

The regulation of manufacturers in Australia is an essential part of the TGA’s
regulatory [Link] aim is to ensure that medicines are manufactured in
accordance with standards of GMP, in order to ‘build in’ safety, quality and efficacy.

149
 Review of Australia’s Plasma Fractionation Arrangements

The current Australian Code of Good Manufacturing Practice for Medicinal

Products (the Code of GMP) was introduced in August 2002.12 It is based on the
2002 Guide to Good Manufacturing Practice for Medicinal Products published by
the Pharmaceutical Inspection Cooperation Scheme (the PIC Scheme) and is a key
element in the movement towards international harmonisation of therapeutic goods
[Link] PIC Scheme Guide provides an international benchmark for
certification of medicine manufacturers.
The Australian Code of GMP is extracted from the PIC Scheme Guide and is the
mandatory standard for the regulation of medicine manufacturers in [Link]
Code provides a standard framework for assessing compliance with quality
management requirements in: the manufacture of medicines; standards for premises
and equipment; personnel; documentation; production and quality control; contract
manufacture; complaints handling; product recall; and self-inspection.
Australian manufacturers are assessed by the TGA against the Code of GMP before
being issued a manufacturing [Link] TGA subsequently undertakes (scheduled)
announced and (risk-based) unannounced audits to assess whether a domestic
manufacturer remains compliant with the Code. Generally, scheduled audits are
conducted every two years. A licence is perpetual, subject to satisfactory audit
outcomes, regular re-audits being conducted, and payment of an annual licence
charge. Licences can be suspended or revoked if audit outcomes are very
unsatisfactory.
Some of the key issues assessed in GMP audits of plasma fractionators are:
• critical process steps: control of plasma starting pools, virus inactivation and
removal, and aseptic processing
• prevention of contamination and cross-contamination in manufacture:
handling and segregation of materials, qualification of critical equipment, cleaning and
sanitation of facility and equipment
• process consistency: process validation and quality control.

Overseas manufacturers of medicines supplied in the Australian market are outside

the licensing jurisdiction of the Therapeutic Goods Act. However, under the Act, the
TGA must be satisfied that ‘if a step in the manufacture of the goods has been
carried out outside Australia ... the manufacturing and quality control procedures
used in the manufacture of the goods are acceptable’.13
Overseas manufacturers are certified by the TGA as part of the pre-market product
assessment and post-market approval conditions placed on Australian sponsors in the
product registration process. Certification is provided by:
• TGA acceptance of a certificate of GMP compliance issued by an overseas
regulator with which Australia has a Mutual Recognition Agreement (MRA) or
other accepted agreement; or by
• TGA certification of GMP compliance on the basis of an on-site audit of the
overseas manufacturer, when there is no other acceptable information available.

12 Therapeutic Goods Administration, Australian Code of Good Manufacturing Practice for Medicinal Products,Therapeutic Goods
Administration, Canberra, 2002, <[Link]
150 13 Therapeutic Goods Act 1989 (Cwlth), s. 25(1)(g); see also ss. 25(2), 26(1)(g), 26(2).
 Review of Australia’s Plasma Fractionation Arrangements

The TGA accepts certificates of GMP compliance through Mutual Recognition

Agreements. MRAs are legal instruments between Australia and one or more
countries. Prior to entering an MRA, each signatory is expected to assess the GMP
standards and audit procedures adopted in the other countries, in order to establish
regulatory equivalence. Other agreements, such as Memoranda of Understanding
(MOUs) or ‘cooperative agreements’, provide for exchange of information between
signatories but do not impose an obligation to accept certificates of GMP compliance,
generally because GMP regulatory equivalence has not been formally established for
signatory [Link] TGA has recently introduced a process of conducting
thorough ‘desk audits’ to assess the GMP reports for non-MRA countries.
Australia is currently signatory to four MRAs for GMP assessments of medicines:
(1) the European Union MRA (known as the EC MRA), coupled with the
European Free Trade Association MRA (EFTA MRA), and bilateral MRAs with
(2) New Zealand, (3) Canada (specifically excludes from its scope medicines derived
from human blood or plasma) and (4) Singapore. Since 1993 Australia has had an
MOU on GMP for medicines with Japan, and has also had a cooperative
information-sharing agreement with the United States, which expired in October
[Link] agreement, on GMP for pharmaceutical products, is currently in the
process of being renewed.
The EC MRA was entered with the European Community and covers the 15
countries that were members of the EC when the MRA came into effect.14 The
status of the 10 new members of the EU with regard to the MRA is under review
while the TGA is negotiating to establish GMP regulatory equivalence.15 A key
provision of the EC MRA is that, although parties should generally accept the
certificates of GMP compliance provided by other member countries, individual
members have a limited capacity, in exceptional circumstances, to conduct GMP
audits of manufacturers in the other [Link] TGA has used this provision
on one occasion. For this to occur, however, the TGA must notify the European
Commission, outlining very strong reasons. In such a case, the Australian product
sponsor must agree to pay for the audit.
The relevant European regulators for the overseas fractionators with facilities in
Europe at this time are shown in table 8.1.
The EFTA MRA was negotiated on terms almost identical to the EC MRA. It
extends the regime of the EC MRA to include Norway, Liechtenstein and Iceland.
The Pharmaceutical Inspection Convention (PIC) agreement, which applies to
Australia and Switzerland, differs from the EC MRA in that members do not have
the right to undertake their own GMP audits in exceptional circumstances. Under
Swiss law, Swissmedic (the national regulator) must lead any audit involving another
national regulatory authority.
The Pharmaceutical Inspection Cooperation Scheme (the PIC Scheme) was
established to promote harmonised GMP standards and guidance documents; to
promote consistent training and auditing practices across regulatory authorities; and

14 These were: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, the Netherlands,
Portugal, Spain, Sweden and the United Kingdom.
15 Ten new members joined the EU as of 1 May 2004: Cyprus, the Czech Republic, Estonia, Hungary, Latvia, Lithuania,
151
Malta, Poland, the Slovak Republic and Slovenia.
 Review of Australia’s Plasma Fractionation Arrangements

Table 8.1 European medicines regulators

Fractionator Regulators

Baxter • Austria – Ministry for Health and Women

• Belgium – Directoraat Generaal Geneesmiddelen (DGG) /
Direction Générale Médicaments (DGM)

BPL • United Kingdom – Medicines and Healthcare Products

Regulatory Agency (MHRA)

CSL Behring • Germany – Paul-Ehrlich-Institut

• Switzerland – Swiss Agency for Therapeutic Products
(Swissmedic)

LFB • France – Agence Française de Sécurité Sanitaire des Produits de

Santé (AFSSAPS) (French Health Products Safety Agency)

Octapharma • Austria – Ministry for Health and Women

• France – Agence Française de Sécurité Sanitaire des Produits de
Santé (AFSSAPS) (French Health Products Safety Agency)
• Germany – Paul-Ehrlich-Institut
• Sweden – Medical Products Agency / National Board of Health
and Welfare

Sanquin • Netherlands – Netherlands Medicines Inspectorate (Ministry)

• Belgium – Directoraat Generaal Geneesmiddelen (DGG) /
Direction Générale Médicaments (DGM)

to undertake peer assessment of audit practices.16 The PIC Scheme is not a GMP
regulatory equivalence scheme.
The frequency of GMP audits is comparable for Australian and overseas manufacturers
covered by GMP [Link] TGA has noted that the frequency of scheduled
audits in Australia, generally conducted every two years, is consistent with the PIC
Scheme standard.
With regard to the conduct of unannounced audits, the Review has considered the
implications of current differences between the situation for domestic manufacturers
and the situation for overseas manufacturers. Unannounced audits in Australia are one
component of GMP regulatory practice. Several factors can trigger an unannounced
audit (including tip-offs, issues associated with sample testing, a manufacturer’s GMP

16 For the PIC Scheme, see Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme, <[Link]
[Link]>.The PIC Scheme is a cooperative arrangement between 28 participating countries: Australia, Austria,
Belgium, Canada, the Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia,
Liechtenstein, Malaysia, the Netherlands, Norway, Poland, Portugal, Romania, Singapore, the Slovak Republic, Spain,
152 Sweden, Switzerland and the United Kingdom.
 Review of Australia’s Plasma Fractionation Arrangements

audit track record, and product recalls). Over the last five years, fewer than 5% of
GMP audits in Australia were unannounced.
The situation is different for overseas manufacturers. Under the MRAs to which it is
a signatory, Australia has very limited capacity to conduct its own GMP audits, but
can request that the relevant local regulator undertake an unscheduled [Link]
the TGA is able to conduct overseas audits under the MRAs, in practice all such
audits are announced in advance, because product sponsors must agree to pay for the
audits.
As of 31 October 2005, legislation has been in place within the EU countries so that
unannounced inspections can be undertaken when necessary. In some EU countries
(e.g. Portugal and the United Kingdom) some audits are unannounced, but attitudes
to such inspections vary widely within the EU. If the TGA were to rely upon the
MRAs in their current form, then unannounced audits may well be achievable
[Link] more pertinent issue is whether Australia should clarify with MRA
partners its role in these audits, particularly if a toll fractionation model were
implemented for Australia, giving rise to a strong national interest in the conduct of
GMP [Link] issue is discussed later in the chapter.
The Act provides strong civil and criminal penalties and sanctions for Australian
sponsors and manufacturers who fail to comply with product and manufacturing
standards.

Ensuring safety and quality of plasma products

The safety of blood and blood products has been a recurring theme internationally
over the last 25 [Link] transmission of hepatitis C and HIV through fresh blood
products and plasma derived products in the mid 1980s was a major catalyst for the
push towards international harmonisation of medicines regulation.
While strong regulatory consistency has been achieved between Australia and the
EU, there are still some areas where countries have adopted unique regulatory
[Link] section describes the pathogen ‘safety tripod’ adopted
internationally and some of the measures that are specific to Australia.
Figure 8.1 shows the pathogen safety tripod and the relative contribution of each leg
towards the reduction of risk of transmission of blood-borne [Link] figure sets
out reduction factors that are normally expressed on a logarithmic [Link] reason
is to imply that, although residual virus infectivity will never be reduced to absolute
zero, it may be greatly reduced to a negligible level.17 While selection of donors and
testing of donations each reduce the theoretical risk of transmission approximately
10–100 fold, the third leg of virus inactivation and removal reduces the risk of
transmitting a virus approximately another one hundred million [Link] illustrates
that the manufacturing process itself plays a central role in ensuring the safety of final
products. In combination these three steps significantly reduce the risk of
transmission of most current known viruses via plasma products.

17 See International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human
Use, Note for Guidance on Quality of Biotechnological Products:Viral Safety Evaluation of Biotechnology Products Derived from Cell
Lines of Human or Animal Origin, [CPMP/ICH/295/95], European Medicines Agency, London, 1997, p. 10, 153
<[Link]
 Review of Australia’s Plasma Fractionation Arrangements

Fig. 8.1 Pathogen safety tripod

Pathogen safety

Reduction
Selection

Testing
Log decrease in risk for plasma products through:
• selection 1–2 logs
• testing approximately 2 logs
• reduction 6–20 logs – higher for some viruses

Source: Adapted from information in:Thomas R. Kreil, ‘Differences between Blood and Plasma: Emerging Pathogens and the
Safety of Blood Products – What to Do, or Not, and Why?’, eSource (June 2006), p. 2,
<[Link]

The more recent challenge to the plasma products sector has been the recognition
that Transmissible Spongiform Encephalopathies, including variant Creutzfeldt-Jakob
disease, could be transmitted by [Link] there is currently no evidence that
vCJD or other prion diseases could be transmitted through plasma products, national
regulators have uniformly adopted a precautionary approach to reviewing the safety
tripod measures.
Prion proteins are normally present in many organs and tissues (including the brain,
spinal cord and eyes) of healthy humans and [Link] prion diseases are caused
by an abnormal folding and accumulation of prion proteins, which progressively
damages the [Link] TSE diseases – fatal degenerative diseases that affect both
humans and animals – include Creutzfeldt-Jakob disease (CJD) in humans, bovine
spongiform encephalopathy (BSE), or ‘mad cow disease’, in cattle, and scrapie in
sheep. Classical CJD occurs in approximately one person per million of the
population per year and it mainly affects older people.
In 1996, variant Creutzfeldt-Jakob disease was first identified in a younger cohort of
patients in the United Kingdom, exhibiting a number of distinctive features when
compared with classical CJD. Over 150 cases of vCJD have since been identified
worldwide, mostly in the United Kingdom but with significant numbers appearing
in [Link] is strong evidence that vCJD is causally linked to BSE,18 the
likelihood being that infection occurs as a result of eating BSE-contaminated beef

18 See R. [Link], M. Zeidler, G. E. Stewart, M. A. Macleod, J.W. Ironside, S. N. Cousens, J. Mackenzie, K. Estibeiro, A. J. E.
Green & R. S. G. Knight, ‘Diagnosis of New Variant Creutzfeldt-Jakob Disease’, Annals of Neurology, vol. 47, no. 5 (May
154 2000), pp. 575–82.
 Review of Australia’s Plasma Fractionation Arrangements

products. Recent reports strongly suggest that the transmission of vCJD has occurred
by blood transfusion from apparently healthy donors, prior to their development of
vCJD. As of 2006, there have been three overseas reports of possible transmission of
vCJD through the use of fresh blood products.19

Donor selection
Before potential blood or plasma donors can donate they are initially [Link]
purpose of this screening is to determine whether a person is in good health, in order
to safeguard both his or her health and the health of recipients. Collection centres
implement protocols in line with requirements in the European Pharmacopoeia,
assessing a donor’s medical history, general health and relevant lifestyle.
The assessment of each donor is carried out by a suitably qualified person working
under the supervision of a [Link] assessment involves an interview, a
questionnaire and further direct questions if [Link] screening process also
involves the provision of educational materials to all [Link] material explains
the donation process, the transmission of blood-borne infections, and the donor’s
responsibility in the prevention of such transmission.
The potential transmission of TSEs through the blood supply has led to many
countries introducing donor deferral measures as part of the donor selection process,

Table 8.2 Period of UK residency requiring donor deferral, by country

UK residency: cumulative period during 1980–96
Austria 6 months
Canada 6 months
Czech Republic 6 months
Finland 6 months
France 6 months
Germany 6 months
Greece 6 months
Ireland 5 years
Italy 6 months
New Zealand 6 months
Spain 12 months
Switzerland 6 months
United States 3 months

19 See C. A. Llewelyn, P. E. Hewitt, R. S. G. Knight, K. Amar, S. N. Cousens, J. Mackenzie & R. [Link], ‘Possible Transmission
of Variant Creutzfeldt-Jakob Disease by Blood Transfusion’, Lancet, vol. 363, no. 9407 (7 February 2004), pp. 417–21; A. H.
Peden, M.W. Head, D. L. Ritchie, J. E. Bell & J.W. Ironside, ‘Preclinical vCJD after Blood Transfusion in a PRNP Codon
129 Heterozygous Patient’, Lancet, vol. 364, no. 9433 (7 August 2004), pp. 527–9; and ‘New Case of Transfusion-Associated
vCJD in the United Kingdom’, Eurosurveillance, vol. 11, no. 2 (2006),<[Link]
asp#references>. 155
 Review of Australia’s Plasma Fractionation Arrangements

in particular with regard to the donation of blood and plasma that could be affected
by a donor’s having lived in the United Kingdom for an extended period.20 In
Australia, persons who have spent six months or more in the United Kingdom
between 1980 and 1996 are not permitted to donate [Link] 8.2 sets out the
practice in other countries in regard to deferring donors who lived in the United
Kingdom during the period considered to represent the greatest risk.

Testing
Following collection, all donations are tested for relevant infectious disease markers.
In-vitro diagnostic (IVD) tests are regulated in Australia, the EU and North America.
The tests must meet sensitivity and specificity requirements prior to obtaining
regulatory approval. In Australia, IVD test performance is monitored through
laboratories’ participation in external quality assurance schemes.
Current tests used for infectious disease screening of blood and plasma donations are
based on the detection of a relevant antigen and/or antibody, and gene sequences. As
required by the British Pharmacopoeia, plasma donations are tested for infectious
disease markers at two stages: the individual donation and the first manufacturing
plasma pool. Each donation is tested for antibodies against human immunodeficiency
viruses 1 and 2 (HIV-1 and HIV-2), for hepatitis B surface antigen (HBsAg) and for
antibodies against hepatitis C (HCV).The first manufacturing plasma pool is tested
for HIV antibodies and HBsAg, and is also tested for HCV, using nucleic acid
amplification technology. In addition to the requirements of the British
Pharmacopoeia, the Therapeutic Goods Administration requires that donations are
tested for HIV-1 and HCV using nucleic acid amplification technology. If a repeat
positive result is found for any of these tests, the donation or pool must not be used.

Pathogen inactivation and removal

Inactivation and removal of infectious agents is the third and final stage of the
pathogen safety tripod. Inactivation and removal processes target viral and prion-
based agents.
The EMEA Note for Guidance on Plasma-Derived Medicinal Products states that
the fractionation and purification process adopted by manufacturers of plasma
products can contribute to the removal of viruses, quite separately from dedicated
viral-inactivation and removal [Link] capability is quite specific to the type of
manufacturing process [Link] two principal fractionation techniques are:
• Cold-ethanol fractionation (often referred to as Cohn fractionation).This
involves the addition of varying concentrations of ethanol to cooled plasma; this
process, together with variations in salt and pH, precipitates protein [Link]
fractions are further purified into individual plasma products. Cold-ethanol

20 In addition to restrictions on former UK residents, in August 2006 the US Food and Drug Administration (FDA) adopted a
draft guidance policy in which a donor deferral recommendation is made to collection establishments in respect of
individuals who have received a transfusion of blood or blood components in France since 1980 (Center for Biologics
Evaluation and Research, Guidance for Industry: Amendment (Donor Deferral for Transfusion in France since 1980) to ‘Guidance for
Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant
Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products’– Draft Guidance, US Food and Drug Administration, Rockville,
MD, 2006, <[Link] In Canada, potential donors who have spent a cumulative
total of six months or more in France between 1980 and 1996 are deferred from donating blood or plasma (see Health
Canada, Health Canada Issues Precautionary Directive for Deferral of Blood and Plasma Donors Who Have Spent Extended Periods of
Time in France, media release, 31 August 2000, Health Canada, Ottawa, <[Link]
156 cp/2000/2000_85_e.html>).
 Review of Australia’s Plasma Fractionation Arrangements

fractionation has been employed since the beginning of the plasma products
industry in the 1940s and continues to be the predominant methodology used by
fractionators around the world. Several variants of cold-ethanol fractionation are
employed by manufacturers, chiefly the Cohn-Oncley process in the United
States and the Kistler-Nitschmann process in Europe. Cold-ethanol fractionation
is well established, and products manufactured using this method have a long
history of safety and efficacy.
• Chromatography is a process by which the components of a mixture – in this
case, plasma – are separated according to size, charge, or other chemical
properties, via interaction with a solid medium such as a [Link] chemical
properties of the gel provide the basis for the separation. Chromatographic
techniques are increasingly being used in plasma fractionation, because higher
yields and greater purity can be achieved, less damage is caused to the plasma
proteins, and potentially a larger range of proteins can be extracted from the
starting plasma. Many products manufactured by CSL Bioplasma at its
Broadmeadows plant are purified predominantly by chromatographic techniques.
Other manufacturers of plasma derivatives do not have the same reliance on
chromatography as CSL Bioplasma. In general, other fractionators have
introduced one or more chromatography stages at the end of cold-ethanol
manufacturing processes following viral-inactivation procedures.

The European Medicines Agency (EMEA) recommends use of two distinct

inactivation/removal steps, which are designed to complement each other in their
mode of action. At least one of these steps should be effective against non-enveloped
[Link] EMEA recognises that ‘designing steps which will complement each
other and also be effective against a wide range of viruses including enveloped and
non-enveloped viruses of diverse physico-chemical characteristics, is not a
straightforward task’.21
The TGA requires a minimum of two effective viral-inactivation steps in the
manufacturing [Link] dual inactivation steps must target both:
• enveloped viruses (such as hepatitis B and C, HIV-1 and HIV-2, and West Nile
Virus) and
• non-enveloped viruses (such as hepatitis A and parvovirus B19).

The viral-inactivation procedures used by plasma fractionators vary between products

but may include solvent detergent, dry heat, pasteurisation, viral filtration and low
pH [Link] 8.3 provides an overview of the various viral-inactivation and
elimination methods.
Enveloped viruses are generally easier to inactivate than non-enveloped viruses,
because enveloped viruses can be inactivated through solvent detergent processes and
a number of heat treatment processes.
It is arguable that the most effective of the viral-elimination processes for non-
enveloped viruses is nanofiltration. Nanofiltration is a filtration process that can
remove small particles such as a virus. However, nanofiltration is not appropriate for
all plasma products. For example, nanofiltration for the removal of non-enveloped

21 Committee for Proprietary Medicinal Products, Note for Guidance on Plasma-Derived Medicinal Products, revision 3
[CPMP/BWP/269/95 rev. 3], p. 15, <[Link] 157
 Review of Australia’s Plasma Fractionation Arrangements

Table 8.3 Viral-inactivation and elimination methods

Treatment Advantages Points to consider

Solvent • Extremely efficient against enveloped • Requires a subsequent
detergent viruses manufacturing step to
• Relatively simple equipment eliminate the solvent
• Non-denaturing effect on proteins detergent agents
• High recovery of protein functional • Not effective against non-
activity lipid-enveloped viruses (e.g.
parvovirus or hepatitis A virus)

Pasteurisation • Potential to inactivate enveloped and • Protein stabilisers may

non-lipid-enveloped viruses, including protect viruses
hepatitis A virus • Does not inactivate parvovirus
• Relatively simple equipment • Low recovery of fragile
coagulation factors
• Potential generation of
neoantigens

Vapour-heat • May inactivate enveloped and non-lipid- • Possible risk of transmission of

enveloped viruses, including hepatitis hepatitis C virus and hepatitis
A virus G virus
• Does not inactivate parvovirus

Terminal • May inactivate enveloped and non-lipid- • Does not inactivate parvovirus
dry-heat enveloped viruses, including hepatitis • 10–20% loss of coagulation
A virus factor activity
• Treatment applied on the final container • Requires strict control of
residual moisture content

Acid pH • Effective against enveloped viruses • Restricted to IgG

• Relatively simple equipment • Limited efficacy against non-
lipid-enveloped viruses

Nanofiltration • Elimination of viruses based on size- • Non-applicable to high

on 15 nm exclusion effect molecular weight protein
membranes • Eliminates all major viruses, including concentrate (without
hepatitis A virus and parvovirus significant protein loss)
• May possibly eliminate prions
• Filter’s integrity and removal capacity is
validated after use
• High recovery of protein activity
• Non-denaturing for proteins
• Risks of downstream contamination are
limited when filtration is performed prior to
aseptic filling
• Filters are commercially available; no royalties

Nanofiltration • Similar to 15 nm membranes • Elimination of small viruses

on 35 nm • Applicable to some Factor VIII and von not total
membranes Willebrand factor concentrates
Source: Derived from information in: A. Farrugia, Guide for the Assessment of Clotting Factor Concentrates for the
Treatment of Hemophilia,World Federation of Hemophilia, Montreal, 2003, p. 8, also available online at
<[Link]

22 Farrugia table adapted from: F. Ala,T. Burnouf & M. M. El-Nageh, Plasma Fractionation Programmes for Developing Countries:
Technical Aspects and Infrastructural Requirements,WHO Regional Publications, Eastern Mediterranean Series, no. 22,World
158 Health Organization, Alexandria, 1999; and T. Burnouf & M. Radosevich, ‘Reducing the Risk of Infection from Plasma
Products: Specific Preventative Strategies’, Blood Reviews, vol. 14, no. 2 (June 2000), pp. 94–110.
 Review of Australia’s Plasma Fractionation Arrangements

viruses cannot be used in the case of Factor VIII plasma products, because Factor VIII
is such a large protein that it may also be removed by the nanofiltration process.
In the cleaning undertaken between batches of plasma, harsh chemical and physical
treatments are used to eliminate prions from the equipment used in fractionation.
These treatments cannot be used on the gels employed in chromatographic
[Link] is because the gels are made up of polymerised sugars, and similar
substances, that cannot withstand these processes. Other processes are used to clean
gels; these treatments are effective for the inactivation of viruses but less effective for
the inactivation of prions.
The TGA introduced segregation of Australian plasma as a regulatory requirement
because of the risk of prion contamination from multiple plasma sources. Given that
CSL Bioplasma fractionates plasma from a number of countries, including countries
with a BSE status inferior to that of Australia, the TGA considered that the application
of segregation as a precautionary measure based on scientific uncertainty around prion
infectivity was justified. Due to the particular manufacturing procedures used
predominantly by CSL Bioplasma at its Broadmeadows plant (i.e. chromatography and
not cold-ethanol fractionation), segregation in this instance has meant using separate
chromatography columns for fractionating Australian [Link] use of separate
equipment provides an effective barrier between plasma starting pools from different
sources, to negate the potential risk of prions being transferred from one pool to
another during [Link] segregation measures adopted at different fractionation
plants (all of which typically fractionate plasma from multiple countries) are not
necessarily identical, and measures to minimise risk are determined with reference to
the production technology in use at a particular facility.
It is generally thought that the risk of transmission of vCJD by plasma products is
low because the manufacturing processes (particularly those involving cold-ethanol
fractionation) remove prions to a significant extent from the fractions that are
separated to obtain therapeutic products.23 However, there is a level of uncertainty,
because science has yet to develop a testing procedure that is sensitive enough to
detect prions in donor blood and therefore able to accurately test the effectiveness of
prion inactivation. In addition, although none of the patients exposed to plasma
products sourced from potentially contaminated plasma have developed prion disease,
the incubation periods are such that low-titre inocula, as would occur with plasma
products, may have transmitted as yet undetected disease. It is partly because of these
uncertainties that current regulatory practice around the world is to recall any plasma
product made from a plasma pool containing a donation from a person who
subsequently develops vCJD, regardless of the theoretical extent to which the
production process may have rendered the final product non-infectious. It should be
acknowledged that under these circumstances most of the product would have been
used by the time the donor became ill.
The TGA uses international best-practice guidelines, and the advice of the Australian
National Health and Medical Research Council (NHMRC) Transmissible

23 For a comparison of fractionation techniques in this respect, see P. R. Foster, A. [Link], C. McLean, B. D. Griffin,
J. C. Hardy, A. Bartley, S. MacDonald & A. C. Bailey, ‘Studies on the Removal of Abnormal Prion Protein by Processes
Used in the Manufacture of Human Plasma Products’, Vox Sanguinis, vol. 78, no. 2 (March 2000), pp. 86–95.
159
 Review of Australia’s Plasma Fractionation Arrangements

Spongiform Encephalopathies Advisory Committee (TSEAC),24 in minimising any

risk of prion transmission through plasma products. Each plasma product on the
Australian market is assessed for this risk regardless of its origin. As mentioned in
Chapter 6, the TGA recently introduced a policy that has created a restricted donor
pool for the production of the plasma derived Factor VIII product Biostate. Biostate
is principally used to treat people with haemophilia A who have developed inhibitors
to recombinant clotting factors, and people with von Willebrand’s [Link] have
been no reported cases of vCJD in recipients of plasma [Link] consensus of
expert opinion, however, is that people with haemophilia and von Willebrand’s
disease who require treatment with plasma products are under a higher theoretical
risk than recipients of other products because of their lifelong reliance on these
products to maintain their health.
TSEAC’s risk assessment found that although the theoretical risks of vCJD
transmission were very small and that Biostate has an excellent safety record with no
cases of transmission of pathogens, further precautions should be taken to reduce that
already small [Link] many Factor VIII purification methods clear prions to a
large extent,25 the manufacturing process used by CSL to manufacture Biostate was
judged by TSEAC to result in a small residual risk.26 TSEAC’s requirements for prion
clearance guide the TGA in its approval of plasma products, whereby an overseas
product27 has been approved which has a prion clearance reflective of TSEAC’s
advice.28
Following the increased access to government-funded recombinant Factor VIII and
the consequent reduction in demand for Biostate, it was possible to introduce a new
precautionary measure to further reduce the theoretical risk. A plasma collection
policy was introduced in June 2005 and came into full effect after 1 April 2006 to
ensure that plasma used in the production of Biostate was sourced from donors who
had not lived or travelled outside Australia and New Zealand since 1980.29 Such
donors have an extremely low risk of being exposed to vCJD because there have
been no confirmed cases of BSE or vCJD in either [Link] this measure an
additional level of protection against the theoretical risk of prion transmission is
available to protect people who receive Biostate.

24 As opposed to the FDA’s TSEAC, which is charged with providing similar advice to the FDA; see
<[Link]
25 T. Kriel, ‘Industry TSE Clearance Studies for Plasma-Derived Factor VIII’, presentation, September 2006,
<[Link]
26 S. Caris, ‘New Donor Requirements for Plasma Derived Factor VIII in Australia’, National Haemophilia, no. 153,
March 2006, p. 6, <[Link]
27 Australian Register of Therapeutic Goods entry for Octanate, <[Link]
[Link]/MEDpublic?SearchView&Query=octanate&start=1&searchOrder=4&searchMax=1000&search
WV=0&searchFuzzy=0>.
28 A. Neisser-Svae, et al., ‘Prion Protein Removal during Manufacturing of High-Purity VWF/FVIII Concentrates’,
Haemophilia, vol. 12 (suppl. 2), 2006, p. 20, 05 PO 122.
29 Caris, ‘New Donor Requirements for Plasma Derived Factor VIII in Australia’.
160
 Review of Australia’s Plasma Fractionation Arrangements

Regulatory issues arising with toll fractionation

In the event that Australian governments agree to an option for future fractionation
arrangements that results in the overseas processing of Australian plasma, either (a) new
products would need to be registered on the Australian Register of Therapeutic Goods,
or (b) variations in registration details of products already on the ARTG would be
required, given the change in the use of Australian plasma in their manufacture for
supply to this country.
Under a toll fractionation model, the Therapeutic Goods Administration would
continue to monitor safety, quality and efficacy through the product registration
process, and then on an ongoing basis through post-market surveillance via the
monitoring of adverse reactions; periodic product safety updates; product testing; annual
reviews of plasma master files; and GMP surveillance [Link] are six issues that
may need resolution:
1. product registration
2. compliance with European provisions regarding eligibility criteria for donors
3. GMP auditing in MRA countries
4. GMP auditing in non-MRA countries
5. costs of overseas audits
6. contractual provisions.

Two important considerations in regard to the overseas fractionation of Australian

plasma are: whether there is equivalence of manufacturing requirements between
Australia and the countries where manufacturing takes place; and whether the
regulatory authorities in those countries will monitor compliance with manufacturing
standards to a level that satisfies the TGA for the purposes of meeting the provisions of
the Therapeutic Goods [Link] issues arise for toll fractionation particularly because
the plasma products made under toll fractionation arrangements would be supplied to
the Australian market only, rather than for use in the country of manufacture. Also, the
regulator in the country of manufacture may exercise a different level of oversight for
products for export only, as distinct from products for the home market.

Product registration
The TGA currently places specific requirements on the domestic fractionator in
relation to the manufacturing process, through the Manufacturing Principles. Currently,
the Manufacturing Principles include the provision that any fractionation plant that is
used to process Australian plasma into products for use in Australia shall not be used to
process any plasma collected outside of Australia unless the TGA is satisfied that the
overseas-sourced plasma will not contaminate Australian product with blood-borne
[Link] Manufacturing Principles specify that the TGA is to do this by
evaluation of the Plasma Master File of the overseas-sourced plasma and consideration
of the fractionation plant’s processes.
While the Manufacturing Principles do not apply outside Australia’s jurisdiction, under
Section 25 of the Act the TGA is required, when evaluating applications of overseas-
manufactured products, to take into account whether ‘the manufacturing and quality
control procedures used in the manufacture of the goods are acceptable’.

161
 Review of Australia’s Plasma Fractionation Arrangements

Compliance with European provisions regarding eligibility criteria

for donors
Directive 2004/33/EC issued by the European Commission currently requires that
blood and blood components imported from third countries, including starting
plasma for fractionation, must be sourced from a donor pool that meets EU
eligibility criteria for donors of whole blood and blood components. Australian
recovered plasma would technically be rendered noncompliant with the Directive
because its minimum haemoglobin levels for whole blood donors are lower than
those of the [Link] TGA has been in contact with the EMEA on this [Link]
intent of the provisions for haemoglobin levels is to protect donor health and have
no bearing on the safety and quality of starting plasma and finished [Link]
European Commission and the EMEA are aware of this issue. It is the TGA’s
understanding that, in the event that Australian plasma were fractionated in Europe,
shipments would not be impeded on the basis of this potential breach that currently
exists under the Directive.
In the event that Australia moves to a tender process for future fractionation
contracts, negotiations between Australian and European regulatory agencies would
need to be held to identify and resolve any regulatory requirements that do not
apply to the safety and quality of plasma and finished products but could nonetheless
have the effect of impeding the shipment or processing of Australian plasma at a
manufacturing facility in Europe. It could be a requirement for tenderers to
demonstrate that there were no such impediments in their country.

GMP auditing in MRA countries

The MRAs covering plasma derived products with the European Union, and the
PIC agreement with Switzerland, are most pertinent, as these include countries with
fractionation plants. Some of the key elements of the EC/EFTA MRAs and PIC
agreement for the purposes of this discussion are:
• GMP inspections of overseas fractionation plants are carried out by an overseas
regulator in accordance with their GMP requirements, which are agreed to be
equivalent to those of Australia.
• The TGA can request the overseas regulator to carry out an inspection to certify
that the manufacturer is appropriately authorised to manufacture the products, is
regularly inspected and complies with the national GMP requirements of the
overseas regulator. Certificates are generally issued within 30 days; however, this
may be extended to 60 days in exceptional circumstances. Each regulator is
obliged to recognise the conclusions of the audits.
• The TGA can request an inspection report of the last inspection of the
manufacturing [Link] the last inspection is more than two years old or where
there is a particular need to inspect the site, an up-to-date and detailed report
may be requested. A report may comprise a Site Master File and a narrative
report describing the most recent audit and any GMP deficiencies, or it may
respond to specific queries by the TGA. However, the details in the inspection
reports can be quite [Link] same timing for delivery of inspection reports
applies as described above. Each regulator is obliged to recognise the conclusions
of the audits.

162
 Review of Australia’s Plasma Fractionation Arrangements

• Under the EC/EFTA MRAs the TGA may conduct an audit of an overseas
manufacturer but only in exceptional circumstances. It must identify its reasons
for doing so to the overseas regulator and the overseas regulator may join the
inspection. Costs may be recovered by the TGA from the Australian sponsor in
such circumstances.
• The overseas regulator must communicate to the TGA with appropriate urgency
a suspension or withdrawal of product based on noncompliance with the GMP
and which could affect the protection of public health.30

The current provisions in the EC/EFTA MRAs permit the TGA to conduct an
audit in exceptional circumstances. In Switzerland the local regulator must lead the
audit. If Australia were to move to overseas toll fractionation this might be
considered to be a previously unanticipated circumstance requiring an increased
ability for the TGA to conduct joint audits with regulators in MRA [Link]
is because plasma products are considered high-risk, the products would be for the
Australian market only, and because Australia would be completely reliant for its
supply of plasma products on manufacturing sites outside Australian jurisdiction, in
contrast to the current [Link] Australia–EC/EFTA MRAs could be
renegotiated to enable joint inspections by the TGA and designated EC/EFTA GMP
Inspectorates of manufacturers of high-risk products, such as fractionated products, in
appropriate [Link] would maintain Australia’s commitment to regulatory
harmonisation while enabling the TGA to have input into the scope and depth of
the audit. It is noted that a joint audit program would require ongoing negotiations
with the relevant European regulatory authorities. Amendments tend to take a long
time to negotiate and implement, and would need to involve a detailed examination
of how these amendments would operate in practice.

GMP auditing in non-MRA countries

The only non-MRA country with any major commercial fractionators that could
undertake toll fractionation of Australian plasma is the United [Link] Review
undertook liaison with the Food and Drug Administration (FDA) to ascertain the
regulatory issues that would arise from toll fractionation in the United States.
The United States Federal Food, Drug, and Cosmetic Act (the FDC Act) specifies
provisions for the importation of components, including plasma, that are used in the
manufacture of therapeutic goods (e.g. drugs) when the finished drug products are to
be exported rather than distributed in the United [Link] is referred to as ‘Import
for Export’ (IFE). Blood, blood components, and plasma have special requirements
under the IFE provisions. If a company were fractionating plasma imported from
Australia at a plant in the United States, the company would need FDA permission
under the plasma-specific IFE provisions of the FDC Act to import shipments of
plasma and would also need to comply with the export provisions of the FDC Act to
export finished products to [Link] neither the imported plasma nor the
exported finished products would require FDA-approved biologics licences, a
number of the IFE provisions are directed at promoting the safety and quality of
products so as not to present a health risk to the country of export under such
arrangements.31

30 See Guide to the MRAs in Operation [EMEA/MRA/22/03 Final], European Medicines Agency, London, 2003,
<[Link] guide published by the EMEA relates to the MRAs
between the EU and the respective parties to agreements and is dated 8 May 2003. 163
31 See, for example, the requirements in Section 802 of the Federal Food, Drug and Cosmetic Act.
 Review of Australia’s Plasma Fractionation Arrangements

The scope of regulatory oversight by the FDA for a toll fractionation arrangement
would depend on the facts and circumstances of each particular arrangement.32 For
example, if the IFE arrangement involved a US licensed manufacturer, the FDA
would inspect, according to its standard policies and procedures, the facilities,
including areas and systems involving IFE manufacturing. (This could be either a
comprehensive or a streamlined evaluation, depending on the level of inspectional
coverage that is deemed appropriate according to perceived risk.) The Review was
also interested in whether, if regulatory breaches relating to production for the
United States market resulted in the FDA revoking or suspending a fractionator’s
licence, this would automatically result in suspension of toll fractionation activities at
the [Link] a US licence is not necessary for IFE arrangements to exist, action
taken by the FDA would be based on the FDA’s assessment of the particular
circumstances and factors leading to the revocation or suspension of a licence. In
practice, the FDA would notify relevant foreign regulators of action against a plant
and a formal cooperation agreement between the FDA and the TGA could
potentially specify how this could take place.
With regard to whether the TGA could conduct unannounced inspections of
facilities in the United States, there are no FDA policies or procedures that require or
recommend the TGA to pre-announce an inspection to the company. Conversely,
FDA regulations do not require manufacturers to allow such inspections. Provisions
in the contract with the fractionator could be employed to facilitate auditing of a US
plant by the TGA (contractual provisions are discussed in greater detail below).
Such an understanding could be memorialised in an Agency-to-Agency
arrangement. As noted above, the information-sharing agreement between the TGA
and the FDA has expired and the agencies are in the process of reviewing it.

Costs of overseas audits

Undertaking an overseas audit of a toll fractionation facility is costly. It is estimated
by the TGA that an audit could cost approximately A$100 [Link] TGA will
establish a schedule of fees specifically for plasma products. Given the high cost of
overseas audits, the TGA should consider the need to amend the Therapeutic Goods
Regulations so that fees may be imposed on a sponsor to recover the costs of GMP
auditing by the [Link] would arguably be best undertaken through amendments
to the regulations imposing a fee on the sponsor, but it should be noted that the
MRAs also address the issue of costs of inspections and any amendments to the
regulations would need to take this into account.
It is noted that an overemphasis on frequent and/or unannounced site audits may
bring risks of disruption to production and that any special, or unscheduled, audits
should be justified by an assessment of product risk.

Contractual provisions
When used in conjunction with other mechanisms, such as regulatory provisions and
risk management strategies, contractual provisions in supply contracts between
Australian product sponsors and the National Blood Authority (NBA) could be a

32 The FDA has issued a draft Guidance for Industry document on Exports and Imports under the FDA Export Reform and
Enhancement Act of 1996 which, when finalised, will explain the basic requirements and procedures for exporting and
164 importing biologicals and other therapeutic goods, including those that may not be sold or distributed in the United States:
<[Link]
 Review of Australia’s Plasma Fractionation Arrangements

useful mechanism for reinforcing the roles and responsibilities of the parties, and of
third parties such as the TGA, in relation to ensuring the safety, quality and efficacy of
plasma products. By way of example, the Plasma Products Agreement with CSL
Limited includes a number of provisions that reinforce CSL’s obligations under the
Therapeutic Goods Act and provide for remedial action if a unit of product does not
meet the standards for safety, quality and efficacy, or any other requirements, associated
with the product’s registration or listing. It must be noted, however, that, as will be
discussed in Chapter 9, legal and practical impediments may be encountered in
enforcing a contract involving a manufacturer in another country. It must also be noted
that major risks arising from an overseas toll fractionation process, such as threats to the
security of supply of plasma and finished products during transportation phases, need to
be addressed by mechanisms other than the regulatory framework for the safety, quality
and efficacy of [Link] issue is also discussed further in Chapter 9.
The Review considers that should Australia adopt an overseas toll fractionation
arrangement there are a number of provisions that should be included in a supply
contract with an Australian sponsor in relation to the provision of fractionation services
by an overseas [Link] would include:
• requiring that the company comply with all Therapeutic Goods Act requirements
and other relevant Australian laws; and/or
• performance standards designed to ascertain and measure certain aspects of quality
control; and/or
• requiring the company to have, maintain and implement an approved risk
management plan, which properly deals with the risks associated with ensuring safe,
high-quality products (i.e. identifies those risks, the likelihood of occurrence, the
impact of occurrence, and strategies to minimise the likelihood or impact of
occurrence).

The contract provisions on compliance with the Act will rely on the TGA’s regulatory
monitoring regime (including activities by overseas regulators, as part of international
agreements).The TGA would need to report noncompliance to the NBA so that the
NBA could implement or ensure the implementation of appropriate contractual
protections (these could include change in payments, withdrawal of a product, supply
planning changes).
The contract could also require the company to ensure that it does not enter into any
subcontract (in connection with the contract to fractionate Australian plasma) without
first complying with certain conditions and NBA approval and Therapeutic Goods Act
compliance.
In addition to imposing quality requirements, the contract would also need to include:
• reporting mechanisms (to be adhered to by the sponsor and/or the manufacturer)
with regard to TGA requirements/performance measures
• provision for audits of the manufacturing process to be conducted and for access to
relevant premises
• undertakings about:
who is to conduct the overseas audits (TGA or an equivalent overseas regulator),
how often and how they are to be conducted, and who is to bear the cost

165
 Review of Australia’s Plasma Fractionation Arrangements

• contractual remedies for failure to permit the conduct of audits, such as:
(a) the ability for the Commonwealth to terminate the contract; and/or
(b) reduction in/suspension of payments if the manufacturer does not permit
and facilitate auditing; and/or
(c) provision for the conduct of tests of the products received in Australia,
pursuant to TGA [Link] contract would need to specify who
would conduct such tests, who pays for the conduct of the tests, and the
consequences of a product failing any such test.

Conclusion
Plasma products are biologicals that carry an inherent risk of pathogen
[Link] are regulated as high-risk medicines by the Therapeutic Goods
[Link] TGA regulates the safety, quality and efficacy of domestic and
imported plasma products in the Australian market.
The infectious disease safety of plasma products is ensured through donor selection
and testing of starting plasma, followed by inactivation and removal of pathogens
during the fractionation [Link] third step has the greatest effect upon the
safety of finished plasma products. In well-regulated environments, plasma products
have a long record of safety and for over ten years there have been no international
reports that plasma derivatives have transmitted a blood-borne pathogen.
Through the product registration process, the TGA requires acceptable evidence of
manufacturing processes and quality control to be demonstrated and maintained. If
a toll fractionation model were adopted in Australia, the TGA would apply the
same standards as are applied to locally manufactured products.
To ensure the continued supply of high-quality products, the Review considers
independent testing of plasma products by the TGA is appropriate.
A key policy issue in considering the feasibility of overseas toll fractionation of
Australian plasma is the ability to ensure satisfactory oversight of manufacturing. In
terms of post-market surveillance in the case of MRA countries, it would be
desirable for the TGA to have a greater scope to conduct and instigate audits of
fractionators supplying Australia from plants in these countries. Australia would
need to give strong consideration to whether the TGA’s current ability to
undertake audits of manufacturing sites within an MRA partner’s territory would
remain adequate. A reappraisal of these provisions could be warranted in order to
permit joint inspections by the TGA and counterpart organisations of
manufacturers of high-risk therapeutic goods such as fractionated plasma products.
The possibility of renegotiating relevant sections of MRAs must take into account,
however, the scale of such a task and the need for any such initiatives to be sensitive
to the element of reciprocity in MRAs.
For countries where there is no MRA in place, there may be fewer impediments to
Australian authorities conducting audits within the terms of existing formal
arrangements. However, a greater amount of work by the TGA rather than its
counterparts in inspecting overseas facilities would be [Link] costs and resources

166
 Review of Australia’s Plasma Fractionation Arrangements

associated with regulating the fractionation of Australian plasma overseas would need
to be addressed for both MRA and non-MRA countries.
In the event that Australian plasma is fractionated overseas, there must be a strong
emphasis on contractual provisions between the NBA and the product supplier to
reinforce appropriate regulatory oversight by the TGA, together with recognised
overseas regulatory agencies as may be required under any applicable international
[Link] role of the TGA in relation to oversight of GMP compliance,
including the cost and conduct of GMP audits of relevant manufacturing sites, would
need to be confirmed.

Rove McManus, from the TV show Rove Live, seen here donating blood.
The Herald & Weekly Times Photographic Collection.

167