GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009

GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING

MATERIALS OF ANIMAL ORIGIN
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 11 - Page 1 of 7

APPENDIX 11 GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL
PRODUCTS CONTAINING MATERIALS OF ANIMAL ORIGIN

Medicinal products containing animal-derived components animals carry the potential risk
of Transmissible Spongiform Encephalophathy (TSE). The safety of these products is
assured through the requirements as described in this appendix along with the main
guidance document.

This guideline
1
is applicable to all medicinal products containing an ingredient, whether
active or inactive, that is derived from animals. It applies to all materials of animal origin
that are used in the preparation of both active (e.g. insulin) and inactive ingredients (e.g.
gelatin, cell culture medium), and any other reagent that may come into contact with a
pharmaceutical product during its manufacturing process (e.g. cell culture serum and
enzymes).

Transmissible Spongiform Encephalopathy (TSE)

Transmissible Spongiform Encephalopathy (TSE) is a group of degenerative brain
diseases that includes scrapie in sheep and goats, Chronic Wasting Disease (CWD) in
deer and elk, Bovine Spongiform Encephalopathy (BSE) in cattle and Kuru and
Creutzfeldt-J akob Disease (CJ D) in humans. Agents causing these diseases replicate in
infected individuals generally without evidence of infection detectable by currently
available diagnostic tests. There is evidence to show that these agents may have
incubation periods of up to several years before causing observable disease (usually
neurological disorder) and eventually death. There is currently no treatment or vaccine for
the disease.

BSE is a food borne infection characterised by the presence of prion proteins, abnormal
infectious proteins in nervous tissue. The subsequent spongy degeneration of the brain
results in severe and fatal neurological signs and symptoms. There is evidence
suggesting that the new variant of human Creutzfeldt-J akob Disease (vCJ D) may be
caused by the same agent that is responsible for BSE in cattle.

The discovery of vCJ D has raised concerns that the BSE agent can be transmitted to
humans. Therefore caution is warranted if biological materials from animals known to be
affected by TSE are used in the manufacture of medicinal products.

1 DOCUMENTARY REQUIREMENTS

Applications for medicinal products containing animal-derived materials will be evaluated
on its quality, safety and efficacy prior to marketing. Documents with detailed information
must be submitted to support the registration of all the medicinal products that contain
animal-derived ingredients.

The documents listed below are to be submitted as part of Adventitious Agents Safety
Evaluation in section 3.2.A.2 of the ICH CTD or in section Q A.2 in the ACTD. The
checklist in Annex 1 may serve as a guide to the documentary requirements.





1
Adapted from CPMP-CVMP NfG on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Human and Veterinary Medicinal Products (EMEA/410/01 Rev. 2)
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING
MATERIALS OF ANIMAL ORIGIN
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 11 - Page 2 of 7

1.1 Products Containing Animal-Derived Materials WITH a valid TSE risk
evaluation Certificate of Suitability (CEP)

Preference is accorded to animal-derived materials that have been awarded Certificates
of Suitability by the European Directorate for the Quality of Medicines & Healthcare
(EDQM). Applicant may refer to the European Pharmacopoeia and the EDQM website
2

for more information on TSE and the Certificate of Suitability.

Supporting documents to be submitted include:

a) A valid TSE Risk Evaluation Certificate of Suitability (CEP)

b) A brief description of the following:

i. Rationale for using animal-derived materials

When manufacturers choose to use animal-derived materials, the rationale for
using these materials instead of that from the non-animal origin should be given.

ii. Source of animals

A compulsory notification of BSE cases in the country of origin and a compulsory
clinical and laboratory verification of suspected cases are required for product
application.

The most satisfactory source of materials is from countries without any reported
case of BSE. The assessment of a countrys BSE status is based on the following:

Office International Des Episooties (OIE) classification
3

Opinions of the Scientific Steering Committee of the European Commission
4


As far as possible, animal-derived materials should be sourced from countries with
a negligible BSE risk in accordance to Terrestrial Animal Health Code (Chapter
2.3.13) of the World Organisation for Animal Health (OIE).

iii. Nature of animal tissue used and measures taken to minimise BSE risk

A declaration of the nature of the animal tissue used should be submitted.

In a TSE-infected animal, different organs and secretions have different
levels of infectivity. In accordance with the EMEA Note for Guidance,
selected ruminant tissues and fluids are classified into the three main
categories as follows:

Category A (High Infectivity): brain, spinal cord, retina, optic nerve, spinal
ganglia, trigeminal ganglia, pituitary gland and dura mater.

Category B (Low Infectivity): peripheral nerves, enteric plexuses, lymph
nodes, nictitating membrane, thymus, oesophagus, forestomach,
stomach/abomasums, duodenum, jejunum, ileum, large intestine, lung,
liver, kidney, spleen, tonsil, placenta, cerebrospinal fluid, adrenal,

2
http://www.edqm.eu
3
http://www.oie.int/eng/info/en_esbmonde.htm
4
http://ec.europa.eu/food/fs/sc/ssc/outcome_en.html
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING
MATERIALS OF ANIMAL ORIGIN
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 11 - Page 3 of 7

pancreas, bone marrow, blood vessels, olfactory mucosa, gingival tissue,
salivary gland, cornea, blood.

Category C (No detectable Infectivity): faeces, heart/pericardium,
mammary gland/udder, milk, semen, placenta fluids, ovary, saliva,
prostate/epididymis/seminal vesicle, skeletal muscle, testis, uterus (non-
gravid), foetus, embryos, tongue, tendon, trachea, adipose tissue, thyroid
gland, colostrum, cord blood, sweat, tears, nasal mucus, bone, skin, urine.

As a general rule, ruminant-derived raw materials that have been classified
as Category A and Category B tissues or fluids must be sourced from
countries with a negligible BSE risk.

In certain situations, there could be cross-contamination of tissues from
different categories of infectivity, e.g. direct contact between different
materials, or the use of penetrative brain stunning as a method of
slaughtering the animals.

Thus, in such cases, procedures used in collecting the intended animal
tissues/organs and the measures in place to avoid cross-contamination with a
higher risk material must also be described in detail.

iv. Nature and quantity of each animal-derived material used

Detailed information must be provided on the nature and quantity of each animal-
derived material used for the preparation of:

Drug substance;
Excipients and adjuvants;
Raw and starting materials and reagents used in production e.g. bovine
serum albumin, enzymes and culture media including those used to
prepare working cell banks or new master cell banks.

Materials that come into direct contact with the equipment used in the
manufacture of the medicinal product or that come in contact with the medicinal
product and therefore have the potential for contamination should also comply
with these guidelines. Likewise, materials used in the qualification of plant and
equipment, such as culture media used in media fill experiments to validate the
aseptic filling process shall be considered in compliance with these guidelines.

As far as possible, information on the residual amount of animal-derived
materials present in the drug product should be clearly stated as follows:

For example: Foetal bovine serum (residual) 0.350 mcg/mL

1.2 Products Containing Animal-Derived Materials WITHOUT a valid TSE risk
evaluation Certificate of Suitability (CEP)

The use of animal-derived materials that have NOT been awarded Certificates of
Suitability by the European Directorate for the Quality of Medicines & Healthcare (EDQM)
may still be acceptable, subjected to the risk assessment of the TSE in the form of a
detailed assessment report.


GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING
MATERIALS OF ANIMAL ORIGIN
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 11 - Page 4 of 7

Supporting documents to be submitted includes:

a) Detailed Assessment Report for the risk of TSE

i. The scope of this report should include section 1.1 (b) as well as the risk factors
associated with the route of administration and the maximum therapeutic dosage
(daily dosage and duration of treatment) of the product.

ii. Production process steps for inactivation of TSE agents

Controlled sourcing is the most important criterion in achieving acceptable safety of
the product due to the documented resistance of TSE agents to most inactivation
procedures. The production process, wherever possible, should be designed to
take into consideration all available information on methods that are thought to
inactivate or remove TSE agents.

If claims are made that inactivation of TSE agents occurs during the manufacturing
process, then relevant information on the process should be submitted for
evaluation.

b) Certificate of analysis for each animal-derived material used.

2 RESPONSIBILITY OF PRODUCT LICENSE HOLDER

The Product Licence holder is responsible for ensuring that the product imported for local
sale and supply is identical, in all aspects, to that approved by the licensing authority. The
licence holder should notify HSA of variations and obtain approval before implementing
the variation if necessary (for example, change of source materials for manufacturing).

3 CONCLUSION

The acceptability of a medicinal product containing animal-derived ingredients, or which
as a result of manufacture could contain these materials, will be influenced by a number
of factors, including:

Documented and recorded source of animals;
Nature of animal tissue used in the manufacture;
Production process;
Route of administration;
Quantity of tissue used in the medicinal products;
Maximum therapeutic dosage; and/or,
Intended use of the product.

The above guidelines only serve as guidance. Pharmaceutical manufacturers and owners
are required to observe international best practices at all times and to comply with the
requirements of the EMEA, USA, Australia, Canada, in particular, the requirements set
down in the given references and their subsequent revisions.

GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING
MATERIALS OF ANIMAL ORIGIN
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 11 - Page 5 of 7

4 REFERENCES

a) CPMP & CVMPs Note for Guidance on Minimising the Risk of Transmitting Animal
Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products,
EMEA/410/01 Rev 2)

b) Guidance for Industry The Sourcing and Processing of Gelatin to Reduce the
Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated
Products for Human Use, by US FDA

c) Ph. Eur. general monograph on Product with risk of transmitting agents of animal
spongiform encephalopathies

d) Guidelines on the Investigation of Manufacturing Processes for Plasma-Derived
Medicinal Products with regard to vCJ D risk (EMEA/BWP/5136/03)

e) CPMP/BWP/337/02/Public/Final, Risk and regulatory assessment of lactose and other
products prepared using calf rennet

f) CPMP/BWP/1793/02/Guidance on the use of Bovine Serum in the manufacture of
human biological medicinal products.

g) Terrestrial Animal Health Code, World Organisation for Animal Health (OIE)





























GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING
MATERIALS OF ANIMAL ORIGIN
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 11 - Page 6 of 7

ANNEX 1 CHECKLIST FOR THE REGISTRATION OF HUMAN MEDICINAL
PRODUCTS CONTAINING MATERIALS OF ANIMAL ORIGIN

Appendix
section
Document Yes/No
(Encl. #)
For
official
use
1.1 Products Containing Animal-Derived Materials WITH a valid TSE risk
evaluation Certificate of Suitability (CEP)
1.1 (a) TSE Risk Evaluation Certificate of suitability (CEP)
Basic information providing a brief description of the following:
1.1 (b) (i) Rationale for using animal-derived materials
1.1 (b) (ii) Source of Animals
1.1 (b) (iii) Declaration of the nature of the animal tissue used.
1.1 (b) (iii) Description of the tissue/organ-collection procedures
and measures in place to avoid cross-contamination.

Nature and quantity of each animal-derived material
used:

As a drug substance.
As an excipient or adjuvant.
As a starting material used in the manufacture of a
drug substance/excipient.

As a reagent or culture media component used in
manufacture.

As a reagent or culture media component used in
establishing master/working cell banks.

1.1 (b) (iv)
Others, give details.
1.2 Products Containing Animal-Derived Materials WITHOUT a valid TSE
risk evaluation Certificate of Suitability (CEP)
Detailed Assessment Report for the risk of TSE.
The scope of this assessment report should include the following:
1.1 (b) (i) Rationale for using animal-derived materials
1.1 (b) (ii) Source of Animals
1.1 (b) (iii) Declaration of the nature of the animal tissue used.
GUIDANCE ON MEDICINAL PRODUCT REGISTRATION IN SINGAPORE JANUARY 2009
GUIDELINE ON THE REGISTRATION OF HUMAN MEDICINAL PRODUCTS CONTAINING
MATERIALS OF ANIMAL ORIGIN
HEALTH SCIENCES AUTHORITY HEALTH PRODUCTS REGULATION GROUP Appendix 11 - Page 7 of 7

Appendix
section
Document Yes/No
(Encl. #)
For
official
use
1.1 (b) (iii) Description of the tissue/organ-collection procedures
and measures in place to avoid cross-contamination.

1.2 (a) Details of the risk factors associated with the route of
administration and maximum therapeutic dosage of
the product.

Nature and quantity of each animal-derived material
used:

As a drug substance.
As an excipient or adjuvant.
As a starting material used in the manufacture of a
drug substance/excipient.

As a reagent or culture media component used in
manufacture.

As a reagent or culture media component used in
establishing master/working cell banks.

1.1 (b) (iv)
Others, give details.
1.2 (a) (ii) Relevant information to support the claim that the
manufacturing process is capable of inactivating TSE
agents.

1.2 (b) Certificates of analysis for each animal-derived
materials used