Castilho Leda R., Moraes Angela Maria (Ed.) Animal Cell Technology: From Biopharmaceuticals to Gene Therapy

Подождите немного. Документ загружается.

Studies of chronic toxicity require daily or intermittent administration

of the drug, mimicking the clinical use. The doses are chosen within a

deﬁned range, ensuring that the higher dose can induce an adverse effect of

moderate amplitude and the lower dose does not induce any adverse effect

at all. Two species are chosen, usually rats and dogs of both genders,

submitted to clinical evaluation with blood and urine analysis. At the end

of the study the animals are evaluated by pathological tests. The duration

of the study depends on whether the biopharmaceutical is intended for a

short or prolonged usage.

Reproductive and teratogenic toxicity

The evaluation of reproductive and teratogenic toxicity, when required,

depends on the biopharmaceutical itself and on the end users. Therefore

product characteristics should be taken into consideration when designing

the study. In cases with potential immunotoxicity for fetal development,

the study must include monitoring of newborn immune functions. Gen-

erally the reproductive toxicity study veriﬁes the drug effect on the

reproductive functionality of males and females. Male spermatogenesis

and female follicular maturation are speciﬁcally monitored as well as post-

mating surveillance to verify possible effects on the fertilization, implanta-

tion, and fetal development stages. At least two species are used in the

study, generally rodents, mainly rats and rabbits, sacriﬁced when the

gestation period reaches near term, allowing the examination of mother

and fetus.

Mutagenic activity

The routine studies for potential mutagenic activity normally performed

on chemical drugs do not apply to biopharmaceuticals, as the administra-

tion of large amounts of peptides or proteins makes the results difﬁcult to

analyze. There is no evidence that these substances interact with DNA or

other chromosomal material. In some instances the tests verify the effect

of new excipients added to the formulated product.

Carcinogenicity

Conventional tests to verify the carcinogenicity are generally not adequate

for biopharmaceuticals. Even so, the tests should be performed depending

on the duration of treatment, the target population, and the biological

activity of the product, for example, growth factors and immunosuppres-

sion agents. The study plan should be adapted to any suspected activity

and may depend on speciﬁc product characteristics, starting with in vitro

studies and, if needed, complemented with in vivo tests.

14.9.2 Clinical studies

Any new medicine needs to be submitted to clinical trials to determine its

safety and efﬁcacy. Clinical research with humans must meet the ethical

and scientiﬁc criteria deﬁned in ‘‘Good Clinical Practices’’ (GCP) (ICH,

1996c). Adherence to the GCP guarantees a trial design of high quality, its

implementation, and appropriate divulgence of the results, thus assuring

364 Animal Cell Technology

the rights, safety, and care of the participants. The ICH norm (1996c)

contains the requirements of the European Union, Japan, and the USA.

Clinical trials phases

Usually clinical studies follow three consecutive phases, I, II, and III. An

additional post-registration study may be required, designated Phase IV

(Acceturi et al., 1997; CNS, 1997). In some instances, intermediate phases

are carried out, I/II, Ia/Ib, etc.

Phase I

The drug is administered to a small group of healthy volunteers with the

objective of determining the processes of absorption, distribution, meta-

bolism, and excretion (ADME) and the pharmacokinetic effects. Escalat-

ing doses are compared to choose one suitable for both safety and efﬁcacy.

Phase II

This consists of a pilot therapeutic study, following acceptable results in

Phase I. This phase aims to evaluate the medicinal effect on patients

suffering from the disease or pathological condition for which the

biopharmaceutical was developed. It has the objectives of establishing the

beneﬁts and efﬁcacy of the drug, the dose-response ratios and the short-

term safety. Usually the double-blind technique is used, dividing the

patients into two groups, one receiving the biopharmaceutical and the

other the placebo, in such a way that neither the physicians nor the

patients know to which group they belong. In some instances the placebo

is substituted by a previously approved drug for comparison.

Phase III

If Phase II is concluded with safety and efﬁcacy, the therapeutic study is

enlarged to include different groups of patients suffering from the disease.

Conﬁrmation of safety and demonstration of efﬁcacy are the primary

endpoints of Phase III. As it involves a large number of participants, the

data analysis should be conclusive on the most frequent adverse reactions,

interactions with other medicines, effective doses, advantages over pre-

existing drugs, and main factors that affect the results (e.g. age). Phase III

is usually an ‘‘open study’’ in which the patients are aware of which

medication they are receiving. The competent authorities evaluate the

clinical data of the Phase III study to decide whether to grant a license for

commercialization or not.

Phase IV

This is a post-marketing study, to establish the long-term safety of a drug,

especially when a biopharmaceutical is intended for prolonged use. If

unexpected adverse effects are observed the product can be withdrawn

from the market. Some Phase III licenses are granted with the condition

that an additional study phase should follow according to a predeﬁned

plan.

Regulatory aspects 365

14.10 Biogenerics or biosimilars

A biogeneric or biosimilar medicine is deﬁned as a substance produced

after an original patent has expired and with the demonstration of

similarity or equivalence to the original product. It is expected to be

approved through an abbreviated and simpliﬁed regulatory process, re-

quiring lower costs, and to be sold with a generic name at a lower selling

price than the branded product. FDA has adopted the name ‘‘follow-on

protein product,’’ deﬁning it as a product that intends to be a similar

version of a protein product already approved.

Patent protection for the ﬁrst group of biotechnological innovative

products has expired or will expire shortly, including interferons, human

insulin, erythropoietin, granulocyte-colony stimulating factor, and hepati-

tis B vaccine. Annual biopharmaceutical sales exceeded 30 billion dollars

in 2003 (Dimond, 2003), and this large market has stimulated companies to

invest in the development of biogeneric versions of products that have a

good market size, a high aggregated cost, and a well-characterized active

principle. However, the hurdles for obtaining biogeneric approval are

associated with their complexity. Biologics are large proteins, structurally

complex, heterogeneous, cell-derived products, attributes that are very

dependent on the manufacturing process used to meet the required

speciﬁcations. Any change in the upstream or downstream steps might

lead to protein alterations and the biogeneric manufacturer is posed with

the difﬁcult task of proving that the new product is as safe and effective as

the original one, that the immunogenicity is not altered, and that there is

no detectable difference that could impact safety or efﬁcacy. The require-

ment for an extension of the clinical and preclinical studies will depend on

the nature of the active substance, the formulation, and the molecular

complexity, as well as on possible differences from the reference product,

including impurities and stability.

The principle that ‘‘the process makes the product’’ is mitigated in cases

where the product is considered ‘‘well characterized’’ and can be easily

characterized by well-reﬁned analytical tools. A biogeneric is not identical

but comparable. As an example, human growth hormone is being pro-

duced by ﬁve different companies in Europe through different processes

and expression systems; even so, all the processes seem to result in

products presenting the same amino acids sequence proﬁle, potency,

safety, and efﬁcacy (Polastro and Little, 2001).

The approval of biogenerics for commercialization depends not only on

technical and scientiﬁc criteria, but also on the balance of political and

economic interests. Generic medicines will allow a greater number of

patients to beneﬁt from high cost medicines, as biogenerics are expected to

be more affordable. Nonetheless the innovative pharmaceutical companies

try to postpone the marketing of biogenerics, intending to strategically

protect their investments, extending the patents through some modiﬁca-

tion, reducing prices and innovating by launching a second generation of

the original product or a modiﬁed formulation intending to present a safer

product or a more practical delivery route.

Both the EMEA and FDA are discussing the procedures that should be

required for registration of biogenerics. In 2004, EMEA was the pioneer

366 Animal Cell Technology

agency to adopt new rules to authorize the generic version of biopharma-

ceuticals (Dorey, 2004), directed to the comparability of biological pro-

ducts similar to those approved (EMEA, 2003, 2004, 2005a). The trend is

to intensify the post-marketing requirements, especially regarding immu-

nogenicity. A pharmaco-vigilance plan must be considered in the registra-

tion application to the European Union for given biopharmaceuticals such

as erythropoietin (EMEA, 2005b), granulocyte-colony stimulating factor

(EMEA, 2005c), and human growth hormone (EMEA, 2005d). The FDA

considers that some biogenerics should follow the same pathway already

established for chemically synthesized pharmaceuticals, with the original

approval designated as NDA (new drug application) instead of BLA

(biologics license application) (Bouchie, 2002a; Evans, 2003). The only

consensus is that the biogeneric ﬁeld is controversial involving many legal

considerations. Given this, the FDA has given the opportunity for differ-

ent interested groups to argue their positions. Workshops (FDA, 2004,

2005a) have been organized to examine the technological and scientiﬁc

aspects related to the development and marketing of biogenerics. When

innovative companies make changes in their processes after the ﬁrst

approval, aiming at optimization, they need to submit comparability

protocols (FDA, 2005b) that could be used for the biogenerics companies

as well.

Biogenerics of products such as erythropoietin, human growth hor-

mone, hepatitis B vaccine, interferons, insulin, and granulocyte-colony

stimulating factor are already available in various countries and regions,

such as Korea, India, China, and South America (Bouchie, 2002b; Jayara-

man, 2003), nonetheless the entry of these to the American and European

market is much more difﬁcult. Omnitrope

, a human growth hormone

produced by Sandoz (Novartis group), was the ﬁrst biosimilar medicine to

be approved in Australia in 2004 and in Europe in April 2006 (EMEA,

2006). In May 2006, the FDA set a precedent by approval of the same

product, although this followed a court decision and may not suggest

easier approval for future biogenerics. The challenge for the biosimilar

companies is to ensure the necessary requisites of safety, efﬁcacy, and

quality, while allowing access for a greater number of patients to beneﬁt

from high cost medicines. To attain these goals, the regulatory agencies

must consider concepts like comparability and similarity, which are likely

to be dealt with on a case-by-case basis.

References

Acceturi C, Lewi DS, Lousana GB (1997), Manual de Boas Pra´ticas em Ensaios

Clı´nicos, UNIFESP/EPM, Sa

o Paulo, Brazil.

ANVISA (2003), Resoluc¸a

o RDC N8 210 de 04 de agosto de 2003. Regulamento

te´cnico das boas pra´ticas para a fabricac¸a

o de medicamentos, Dia´rio Oﬁcial da

Unia

o, Brası´lia, D.F. Available at: http://www.cff.org.br/Legisla%C3%A7%

C3%A3o/Resolu%C3%A7%C3%B5es/res_210_2003.pdf (accessed October

2006).

ANVISA (2005), Resoluc¸a

o RDC N8 315 de 26 de outubro de 2005. Regulamento

te´cnico de registro, alterac¸a

opo´ s-registro e revalidac¸a

o de registro dos produtos

biolo´ gicos terminados. Dia´rio Oﬁcial da Unia

o, Brası´lia, D.F., 31 out. 2005.

Regulatory aspects 367

Available at: http://e-legis.anvisa.gov.br/leisref/public/showAct.php?id¼19411

&word¼Farmacovigil%C3%A2ncia (accessed January 2007).

Barone D, Zaninelli P, Ferrara B (1992), Aspetti regolatori e metodologici della

validazione de linee cellulari continue per la produzione de biofarmaci, Minerva

Biotec. 4: 82–95.

Berthold W, Walter J (1994), Protein puriﬁcation: aspects of processes for pharma-

ceutical products, Biologicals 22:135–150.

Bloom A (1984), Acquired immunodeﬁciency syndrome and other possible immuno-

logical disorders in European haemophiliacs, Lancet 1:1452–1455.

Bouchie A (2002a), FDA restructures new review centers, Nat. Biotechnol. 20:960.

Available at: http://www.nature.com/nbt/journal/v20/n10/pdf/nbt1002-960a.pdf

(accessed October 2006).

Bouchie A (2002b), GeneMedix approval in China, Nat. Biotechnol. 20:213. Available

at: http://www.nature.com/nbt/journal/v20/n3/pdf/nbt0302-211.pdf (accessed

October 2006).

CFR (2003), Code of Federal Regulations 21: parts 200–299. Available at: http://www.

access.gpo.gov/nara/cfr/waisidx_03/21cfrv4_03.html (accessed October 2006).

Christiansen GD (1999), Quality control and quality assurance issues in biopharma-

ceutical processing, In: Avis KE, Wagner CM, Wu VL (Eds), Biotechnology:

Quality Assurance and Validation, vol. 4, Drug Manufacturing Technology Series,

Interpharm Press, Buffalo Grove, pp. 33–71.

CNS (1997), Resoluc¸a

o 251/97 de 7 de agosto de 1997. Normas de Pesquisa Envolven-

do Seres Humanos para a A

rea Tema´tica de Pesquisa de Novos Fa´rmacos,

Medicamentos, Vacinas e Testes Diagno´ sticos. Dia´rio Oﬁcial da Unia

o, Brası´lia,

D.F., 23 set.1997. Sec¸a

o 1, p. 21.117.

CTNBio (1997), Instruc¸a

o normativa CTNBio N8 7, de 06.06.97. Normas para o

trabalho em contenc¸a

o com organismos geneticamente modiﬁcados – OGMs.

Dia´rio Oﬁcial da Unia

o, Brası´lia, D.F., 09 jun.1997, Sec¸a

o I, p. 11.827.

Dimond PF (2003), Manufacturers of Biogenerics Press Forward: But Demand for

Bioequivalence Standards May Yet Limit Market, Gen. Eng. News, 23:10–11.

Doblhoff-Dier O, Bliem R (1999), Quality control and assurance from the develop-

ment to the production of biopharmaceuticals, Trends Biotechnol. 17:266–270.

Dorey E (2004), EU rules on biogenerics, Nat. Biotechnol. 22:141. Available at: http://

www.nature.com/nbt/journal/v22/n2/pdf/nbt0204-141.pdf (accessed October

2006).

Duxbury M, Jezuit M, Letwin B, Wright J (1995), DNA in plasma of human blood for

transfusion, Biologicals 23:229–231.

EC (1998a), The Rules Governing Medicinal Products in the European Union, Good

Manufacturing Practice: Medicinal Products for Human and Veterinary Use, vol.

4, Eudralex. Available at: http://pharmacos.eudra.org/F2/eudralex/vol-4/home.

htm (accessed October 2006).

EC (1998b), Quality management, In: The Rules Governing Medicinal Products in the

European Union, Good Manufacturing Practice: Medicinal Products for Human

and Veterinary Use, vol. 4, Eudralex. Available at: http://pharmacos.eudra.org/

F2/eudralex/vol-4/pdfs-en/cap1en.pdf (accessed October 2006).

EC (2001), Guide to Good Manufacturing Practice: Qualiﬁcation and Validation,

Annex 15, Brussels. Available at: http://europs.eu.int/comm/enterprise/

pharmaceuticals/eudralex/vol-4/pdfs-en/v4an15.pdf (accessed October 2006).

EC (2003), Guide to Good Manufacturing Practice: Manufacture of Sterile Medicinal

Products, Revision to Annex 1, Brussels. Available at: http://europa.eu.int/comm/

enterprise/pharmaceuticals/eudralex/vol-4/pdfs-en/revan1vol4_3.pdf (accessed

October 2006).

EC (2004), Guide to Good Manufacturing Practice: On going Stability, Addition to

Chapter 6, Brussels. Available at: http://europa.eu.int/comm/enterprise/

368 Animal Cell Technology

pharmaceuticals/eudralex/vol-4/pdfs-en/2005_10_chapter_6.pdf (accessed Octo-

ber 2006).

EC (2007), EudraLex – The Rules Governing Medicinal Products in the European

Union, Available at: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/

index.htm (accessed September 2007).

EMEA (2003), CPMP. Guideline on comparability of medicinal products containing

biotechnology-derived proteins as active substances: quality issues, London.

Available at: http://www.emea.eu.int/pdfs/human/bwp/320700en.pdf (accessed

October 2006).

EMEA (2004), CPMP. Guideline on comparability of medicinal products containing

biotechnology-derived proteins as active substances: non-clinical and clinical

issues, London. Available at: http://www.emea.eu.int/pdfs/human/ewp/309702

en.pdf (accessed October 2006).

EMEA (2005a), CHMP. Guideline on similar biological medicinal products containing

biotechnology-derived proteins as active substance: quality issues, London. Avail-

able at: http://www.emea.eu.int/pdfs/human/biosimilar/4934805en.pdf (accessed

October 2006).

EMEA (2005b), CHMP. Guideline on similar biological medicinal products containing

biotechnology-derived proteins as active substance: non-clinical and clinical

issues. Guidance on biosimilar medicinal products containing recombinant

erythropoietins, Annex, London. Available at: http://www.emea.eu.int/pdfs/

human/biosimilar/9452605en.pdf (accessed October 2006).

EMEA (2005c), CHMP. Guideline on similar biological medicinal products containing

biotechnology-derived proteins as active substance: non-clinical and clinical

issues. Guidance on biosimilar medicinal products containing recombinant granu-

locyte-colony stimulating factor, Annex, London. Available at: http://www.

emea.eu.int/pdfs/human/biosimilar/3132905en.pdf (accessed October 2006).

EMEA (2005d), CHMP. Guideline on similar biological medicinal products containing

biotechnology-derived proteins as active substance: non-clinical and clinical

issues. Guidance on similar medicinal products containing somatropin, Annex,

London. Available at: http://www.emea.eu.int/pdfs/human/biosimilar/9452805

en.pdf (accessed October 2006).

EMEA (2006), Press release: European Medicines Agency adopts ﬁrst positive opinion

for a similar biological medicinal product. Available at: www.emea.europa.eu/

pdfs/human/press/pr/3179706en.pdf (accessed October 2006).

Evans PC (2003), A coming of age for generic biologic formulations? Examining the

regulations for expedited approval of generic biological drugs, Gen. Eng. News

23:6,8,17.

FDA (1985), Center for Drugs and Biologics. Points to consider in the production and

testing of new drugs and biologicals produced by recombinant DNA technology,

Rockville. Available at: http://www.fda.gov/cber/gdlns/ptcdna.pdf (accessed

October 2006).

FDA (1993a), CBER. Points to consider in the characterization of cell lines used to

produce biologicals. Rockville. Available at: http://www.fda.gov/cber/gdlns/

ptccell.pdf (accessed October 2006).

FDA (1993b), Ofﬁce of Regulatory Affairs. Guide to inspections of validation of

cleaning processes, Rockville. Available at: http://www.fda.gov/ora/inspect_ref/

igs/valid.html (accessed October 2006).

FDA (1997), CBER. Points to consider in the manufacture and testing of monoclonal

antibody products for human use, Rockville. Available at: http://www.fda.gov/

cber/gdlns/ptc_mab.pdf (accessed October 2006).

FDA (2004), CDER Public Workshop: Scientiﬁc Considerations Related to Develop-

ing Follow-On Protein Products, September 14–15, 2004. Available at: http://

www.fda.gov/cder/regulatory/follow_on/default.htm#publicworkshops (accessed

Regulatory aspects 369

October 2006).

FDA (2005a), CDER Workshop: Scientiﬁc Considerations Related to Developing

Follow-On Protein Products, February 14–16. Available at: http://www.fda.

gov/cder/regulatory/follow_on/default.htm#publicworkshops (accessed October

2006).

FDA (2005b), CBER Guidance for Industry: Comparability of biotechnological/

biological products subject to changes in their manufacturing process, Rockville.

Available at: http://www.fda.gov/cder/guidance/6677fnl.htm (accessed October

2006).

Foulkes J, Traynor G (1999), Regulation of antibodies and recombinant proteins, In:

Rehm HJ, Reed G, Pu

hler A, Stadler P (Eds), Biotechnology, 2nd Ed., vol. 5a,

Recombinant Proteins, Monoclonal Antibodies and Therapeutic Genes, Wiley-

VCH, Weinheim, pp. 495–516.

Henry C (1996), FDA, reform, and the well-characterized biologic, Anal Chem., Nov

1. Available at: http://pubs.acs.org/hotartcl/ac/96/nov/fda.html (accessed October

2006).

ICH (1995), Steering Committee, Quality of biotechnological products: analysis of the

expression construct in cells used for production of rDNA derived protein

products, Geneva. Available at: http://www.ich.org/LOB/media/MEDIA426.pdf

(accessed October 2006).

ICH (1996a), Expert Working Group (Quality). Guidance for Industry. Validation of

Analytical Procedures: Methodology, Geneva. Available at: http://www.ich.org/

LOB/media/MEDIA417.pdf (accessed October 2006).

ICH (1996b), Guideline for Industry. Quality of Biotechnological Products: Stability

Testing of Biotechnological/Biological Products, Geneva. Available at: http://

www.ich.org/LOB/media/MEDIA427.pdf (accessed October 2006).

ICH (1996c), Steering Committee. Guideline for Good Clinical Practice, Geneva.

Available at: http://www.ich.org/LOB/media/MEDIA482.pdf (accessed October

2006).

ICH (1997), CPMP. Viral safety evaluation of biotechnology products derived from

cell lines of human or animal origin, Geneva. Available at: http://www.ich.org/

LOB/media/MEDIA425.pdf (accessed October 2006).

ICH (1998a), CPMP. Quality of biotechnological products: derivation and character-

ization of cell substrates used for production of biotechnological/biological

products, Geneva. Available at: http://www.ich.org/LOB/media/MEDIA429.pdf

(accessed October 2006).

ICH (1998b), CPMP. Note for Guidance on Preclinical Safety Evaluation of Biotech-

nology- Derived Pharmaceuticals, Geneva. Available at: http://www.ich.org/

LOB/media/MEDIA503.pdf (accessed October 2006).

IES (1992), Institute of Environmental Sciences, Federal Standard 209E, Airborne

particulate cleanliness classes in cleanrooms and clean zones, Mount Prospect.

Available at: http://www.set3.com/papers/209e.pdf (accessed October 2006).

Jayaraman KS (2003), Indian biogenerics industry emerges, Nat. Biotechnol. 21:1115–

1116. Available at: http://www.nature.com/nbt/journal/v21/n10/pdf/nbt882.pdf

(accessed October 2006).

Kurt R (1995), Risk potential of the chromosomal insertion of foreign DNA, Ann. N

Y Acad. Sci. 772:140–151.

Levine HL, Castillo FJ (1999), Validation of biopharmaceutical processes, In: Avis KE,

Wagner CM, Wu VL (Eds), Biotechnology: Quality Assurance and Validation,

Interpharm Press, Buffalo Grove, p. 115.

Lubiniecki AS, Wiebe ME, Builder SE (1990), Process validation for cell culture-

derived pharmaceutical proteins, In: Lubiniecki AS (Ed.) Large-Scale Mammalian

Cell Culture Technology, vol. 10, Bioprocess Technology, Marcel Dekker, New

York, pp. 515–541.

370 Animal Cell Technology

Lupker JH (1998), Residual host cell protein from continuous cell lines: effect on the

safety of protein pharmaceuticals, In: Brown F, Griffths E, Horaud F, Petricciani

JC (Eds) Safety of Biological Products Prepared from Mammalian Cell Culture,

vol. 93, Dev. Biol. Stand., Karger, Basel, pp. 61–64.

NIH (2002), Guidelines for research involving recombinant DNA molecules. Available

at: http://www4.od.nih.gov/oba/rac/guidelines_02/nih_guidelines_apr_02.htm

(accessed October 2006).

Novartis (2004), March to global leadership: follow-on biologics. Available at: http://

www.novartis.com/annual_reports/2004/march.shtml (accessed October 2006).

Onions D (1997), Safety evaluation of products derived from mammalian cell lines, In:

Hauser H, Wagner R (Eds), Mammalian Cell Biotechnology in Protein Produc-

tion, Walter de Gruyter, Berlin, pp. 171–190.

Petricciani JC (1988), Changing attitudes and actions governing the use of continuous

cell lines for the production of biologicals, In: Spier RE, Grifﬁths JB (Eds),

Animal Cell Biotechnology, vol. 3, Academic Press, London, pp. 14–23.

Petricciani JC, Horaud FN (1995), DNA, dragons and sanity, Biologicals 23:233–238.

Polastro E, Little A (2001), When will we see legal generics of top biopharmaceuticals?

ContractPharma Out. Available at: http://www.contractpharma.com/articles/

2001/10/the-future-of-biogenerics.php (accessed October 2006).

Rodrigues MTA, Raw I, Moro AM (1997), Residual DNA from hybridoma cultures:

decorrence of apoptosis?, In: Carrondo MJT, Grifﬁths JB, Moreira JL (Eds),

Animal Cell Technology: From Vaccines to Genetic Medicine. Kluwer Academic,

Dordrecht, pp. 467–472.

SBCC (2005), Classiﬁcac¸a

o de Salas Limpas. NBR ISO 14644-1 cancela e substitui a

NBR 13700, Revista da SBCC, 19:16.

Schiff LJ (2004), Biotechnology products derived from mammalian cell lines: impact of

manufacturing changes, Regulatory Affair Focus Oct:29–31.

Temin HM (1990), Overview of biological effects of addition of DNA molecules to

cells, J. Med. Virol. 31:13–17.

Timenetsky J, Miyaki C, Mendes IF, Rizzo E (1992), Identiﬁcac¸a

o de micoplasmas

pela inibic¸a

o de crescimento de amostras isoladas de culturas celulares, Rev. Sau´de

Pu´ bl. 26:17–20.

Tydeman MS, Kirkwood TBL (1984), Design and analysis of accelerated degradation

tests for the stability of biological standards I. Properties of maximum likelihood

estimators, J. Biol. Stand. 12:195–206.

Ugwu SO, Apte SP (2004), Efeito de tampo

es na estabilidade conformacional de

proteı´nas, Pharm. Technol. Brazil 8:56–78.

Walsh G (2004a), The drug development process, In: Biopharmaceuticals: Biochemis-

try and Biotechnology, 2nd Ed., John Wiley & Sons, West Sussex., pp. 69–91.

Walsh G (2004b), The drug manufacturing process, In: Biopharmaceuticals: Biochem-

istry and Biotechnology, 2nd Ed., John Wiley & Sons, West Sussex, pp. 97–102.

WHO (1990), Expert Committee on Biological Standardization, Requirements for

poliomyelitis vaccine (oral), Tests for bovine viruses in serum, Geneva, Appendix

1: p. 66 [Technical Report Series no. 800].

WHO (1992), Expert Committee on Biological Standardization. Guidelines for assur-

ing the quality of monoclonal antibodies for use in humans, Geneva, pp. 47–67

[Technical Report Series no. 822].

WHO (1996), Good manufacturing practices: guidelines on the validation of manufac-

turing processes, Geneva, pp. 81–95 [Technical Report Series no. 863].

WHO (1998), Expert Committee on Biological Standardization. Requirements for the

use of animal cells as in vitro substrates for the production of biologicals, Geneva,

pp. 19–56 [Technical Report Series no. 878].

WHO (2002), Good manufacturing practices for sterile pharmaceutical products,

Geneva, pp. 76–96 [Technical Report Series, no. 902].

Regulatory aspects 371

WHO (2003), Working Group on International Reference Materials for Diagnosis and

Study of TSEs. Guidelines on Transmissible Spongiform Encephalopathies in

Relation to Biological and Pharmaceutical Products, Geneva. Available at: http://

www.who.int/bloodproducts/publications/en/WHO_TSE_2003.pdf (accessed

October 2006).

Wiebe ME, May LH (1990), Cell banking, In: Lubiniecki AS (Ed.), Large-scale

Mammalian Cell Culture Technology, vol. 10, Bioprocess Technology, Marcel

Dekker, New York, pp. 147–160.

Wierenga DE, Cogan J, Petricciani JC (1995), Administration of tumor cell chromatin

to immunosuppressed and non-immunosuppressed non-human primates, Biologi-

cals 23:221–224.

Regulatory agencies web sites

ANVISA: http://www.anvisa.gov.br

EC: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev4.htm

EMEA: http://www.emea.eu.int/

FDA: http://www.fda.gov/cber/guidelines.htm and

http://www.fda.gov/cder/biologics/default.htm

ICH: http://www.ich.org

WHO: http://www.who.int/biologicals/en/

372 Animal Cell Technology

Intellectual property

Ana Cristina Almeida Mu

ller and Leila Costa Duarte Longa

15.1 Introduction

Intellectual property covers industrial property including author’s rights

over written material, novel processes, products, computer programs, and

integrated circuits. One of the main goals of intellectual property is to

promote progress of technology and industry, by granting a temporary

monopoly for innovation through patents.

Industrial property is protected through patents covering inventions,

utility models, registration of industrial designs, and trademarks. These are

protected through rights of exclusivity. Another aspect of protection is

through the suppression of unfair competition, which is directed against

acts of industrial or commercial competitors contrary to honest practices,

including:

(i) acts that can create confusion with a competitor’s establishment,

products, industrial or commercial activities;

(ii) false claims that can discredit a competitor’s establishment, products,

industrial or commercial activities; and

(iii) indications or claims that can mislead the public as to the nature of

the manufacturing process or the characteristics, suitability or quan-

tity of products.

This chapter discusses the protection of inventions in the ﬁeld of

biotechnology, including processes based on cell cultures. The ethical and

moral aspects of patent protection of the results of research involving the

use of genetic engineering and the difference between discovery and

invention are also discussed. The requirements for patentability are cov-

ered, and examples of inventions involving antigens and antibodies are

presented. Finally, the importance of internal intellectual property and

technology transfer ofﬁces and of specialists in these areas is discussed.

15.2 The biotechnology sector

According to the deﬁnition of Bull et al. (1982), biotechnology can be

deﬁned as ‘‘the application of the principles of science and engineering for

the development of materials, through the use of biological agents, aiming

to produce services and goods.’’ Biotechnology is a recent industrial

sector, based on the knowledge acquired through research in the areas of

biochemistry and biology, particularly molecular biology. It involves some

small start-up ﬁrms that have a close relationship with university scien-

tists. Even more important, these biotech ﬁrms play a key role in