BSE/TSE Compliance for Pharmaceutical Packaging

BSE/TSE compliance means demonstrating that a material carries no meaningful risk of transmitting transmissible spongiform encephalopathy agents. For pharmaceutical packaging, the governing text in Europe is the Note for Guidance EMA/410/01 rev. 3, reproduced identically as European Pharmacopoeia general chapter 5.2.8. Packaging is almost never made of animal tissue, so the risk sits in processing aids: stearates, tallow-derived fatty acids, slip agents, lubricants and adhesives. A packaging supplier discharges the obligation with a traceable declaration covering every material and additive in the component, not with a single blanket statement.

This guide explains what the guidance requires, where animal-derived material realistically enters a vial seal or a closure, what a usable supplier declaration contains, when a TSE Certificate of Suitability is involved, and how the whole thing feeds a customer’s regulatory dossier.

Key takeaways

TSE covers the family of prion diseases; BSE is the bovine form. The regulatory concern is transmission to humans through a medicinal product or its packaging.
The controlling European text is EMA/410/01 rev. 3, published in the Official Journal C 73 of 5 March 2011 and applicable from 1 July 2011.
Ph. Eur. general chapter 5.2.8 is identical in text to the Note for Guidance, and Ph. Eur. general monograph 1483 covers products with a risk of transmitting TSE agents.
Revision 3 moved country risk classification onto the World Organisation for Animal Health (WOAH, formerly OIE) BSE risk categories and added criteria for gelatin, bovine blood derivatives and peptones.
In packaging, the exposure is in processing aids and additives: stearic acid and metal stearates, tallow-derived fatty acid esters, slip and release agents, forming lubricants, adhesives and some ink and coating components.
A usable supplier declaration is material by material and additive by additive, states the governing reference, and is covered by change control so a masterbatch substitution does not silently invalidate it.
The declaration flows into the customer’s dossier and, for packaging, typically into a Type III Drug Master File as well.

What BSE and TSE actually are

Transmissible spongiform encephalopathies are progressive, fatal neurodegenerative diseases caused by prions, misfolded forms of a normal cellular protein that induce the same misfolding in others. Bovine spongiform encephalopathy is the cattle form; scrapie is the sheep and goat form; the human forms include Creutzfeldt-Jakob disease and the variant form associated with exposure to the BSE agent.

Two properties make prions a packaging problem rather than a purely clinical one. They are extraordinarily resistant to the physical and chemical treatments that inactivate bacteria and viruses, including standard autoclaving, dry heat, most disinfectants and ionising radiation at sterilizing doses. And infectivity is unevenly distributed across tissues, concentrated in the central nervous system and lymphoid tissue, which is why regulators classify by tissue and by country of origin rather than by species alone. Current country risk classifications are maintained by WOAH.

The regulatory answer is prevention by sourcing and processing rather than removal by treatment. Establish that the material either contains nothing of ruminant origin, or that what it contains came from a low-risk country, a low-risk tissue and a process that reduces infectivity.

The governing guidance: EMA/410/01 rev. 3 and Ph. Eur. 5.2.8

The Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products, reference EMA/410/01 rev. 3, is the operative European document. It was published in the Official Journal C 73 of 5 March 2011) and applied from 1 July 2011. The same text appears as European Pharmacopoeia general chapter 5.2.8, so a supplier that cites either reference is citing the same requirements. The title is deliberate: it covers human and veterinary medicinal products alike, so a veterinary injectable attracts the same declaration as a human one.

The guidance applies across the product, not only to the active substance. Its scope reaches active substances, excipients, adjuvants, processing aids and materials that come into contact with the product, which is where primary packaging enters. It builds its assessment on three factors:

The source animals, meaning species, the BSE risk status of the country of origin, and the age of the animals.
The tissue used, ranked by infectivity, with central nervous system and lymphoid tissue at the top.
The manufacturing process, and whether it includes steps that inactivate or remove prion infectivity.

Revision 3 made three changes worth knowing. It replaced the older Geographical BSE Risk classification with the WOAH country categories. It added criteria for the sourcing and processing of gelatin and bovine blood derivatives. And it added a subsection on peptones. It also retains the position that certain tallow derivatives, produced under the rigorous processing conditions described in the text, are considered unlikely to be infectious. That last point matters more to packaging than any other part of the document, because tallow derivatives are exactly what turns up in polymer additive packages.

Alongside the general chapter, Ph. Eur. general monograph 1483, Products with risk of transmitting agents of animal spongiform encephalopathies, is the monograph a material is assessed against. The EDQM publishes both.

Where animal-derived material enters a packaging component

A vial seal contains no animal tissue. The risk is not in the substrate, it is in the chemistry used to make and form the substrate. These are the realistic entry points for an aluminium or aluminium-plastic closure.

Component or step	Possible animal-derived input	Why it is used
Polymer additive package (polypropylene button or disc)	Calcium or zinc stearate, glycerol monostearate, oleamide	Acid scavenger, antistatic, slip agent
Masterbatch and pigment carriers	Stearate-based dispersants and waxes	Pigment dispersion, flow
Aluminium rolling and forming	Tallow-derived fatty acids and esters in rolling and drawing lubricants	Lubrication during rolling, stamping and deep drawing
Lacquers and coatings	Fatty-acid based additives, waxes, slip agents	Surface slip, scratch resistance
Printing inks and varnishes	Fatty-acid derivatives, waxes	Rub resistance, drying
Mould release agents	Stearate-based release agents	Part release in injection moulding
Adhesives, cartons and secondary packing	Gelatin or casein based adhesives	Bonding
Elastomeric stoppers (paired component, not the seal)	Stearic acid as a vulcanisation activator	Rubber cure system

Not every one of these is animal-derived in every supply chain. Stearic acid and stearates are widely available in plant-derived grades, and erucamide, a common slip agent, is derived from rapeseed. The point of the assessment is that you cannot tell by looking at the finished part; you have to ask the additive supplier. The same question is put to whoever makes the butyl rubber stopper the seal crimps over, because elastomer compounding carries its own list of processing aids.

Two practical consequences follow. First, a credible declaration has to be built bottom-up from the bill of materials, including additives present at fractions of a percent, rather than asserted top-down about the finished component. Second, the declaration has to be under change control. If a masterbatch supplier substitutes a stearate grade, or a rolling mill changes lubricant, the declaration goes stale without anyone touching the drawing. That is a supplier qualification issue as much as a documentation one, and it belongs in the same conversation as supplier selection.

What a usable BSE/TSE declaration contains

A declaration that a pharmaceutical customer can put in a dossier is specific, referenced and dated. A one-line “our products are TSE free” is not usable, because “TSE free” is not a defined regulatory status and the statement carries no scope.

A workable declaration states:

The materials it covers, identified by grade or specification, and the components they are used in.
The governing reference, normally EMA/410/01 rev. 3 and Ph. Eur. 5.2.8, with the revision cited explicitly.
The position taken: either that no materials of animal origin are used in the manufacture of the components, or, where a ruminant-derived material is used, the species, tissue, country of origin and the processing applied.
The scope of the supply chain covered, including additives, processing aids, lubricants, release agents and coatings, not just the base polymer and metal.
Change control commitments, obliging the supplier to notify the customer before any change that would affect the position.
Date, revision and an authorised signatory, so the customer can manage its currency.

Where a ruminant-derived material is genuinely present and cannot be substituted, the supporting evidence is normally a TSE Certificate of Suitability (CEP) issued by the EDQM. A TSE CEP is a pre-evaluated statement that a specific material from a specific manufacturer complies with the Ph. Eur. requirements for TSE risk; it saves each downstream user from assembling and defending the same risk assessment. EDQM assesses species, tissue, country of origin and inactivation steps as part of the certification.

How US and other markets treat it

The United States regulates prohibited cattle materials by rule rather than by a single TSE guidance, and the practical documentation expectation is the same. FDA designates specified risk materials and other prohibited cattle materials in 21 CFR 189.5 for human food and 21 CFR 700.27 for cosmetics, and reviews animal-sourced material risk within drug and biologic applications. In practice a US applicant asks its packaging supplier for the same statement of animal-origin status, and files it in the adventitious agents section of the dossier.

For manufacturers outside Europe and the US, the requirement travels with the marketing authorisation rather than with the country of manufacture. An Indian seal manufacturer exporting into the EU is asked for the EMA/410/01 rev. 3 position because its customer’s European authorisation requires it, and the same declaration is normally reused for submissions handled under CDSCO and for other export markets. Maintaining one declaration set to the strictest reference is simpler than maintaining several.

How it fits the quality system and the dossier

BSE/TSE status is a supplier-controlled attribute, so it lives inside the packaging manufacturer’s quality management system, not in a one-off letter. Under ISO 15378, the GMP standard for primary packaging materials, the relevant machinery already exists: supplier evaluation, purchasing information, traceability, change control and document control. A BSE/TSE position is maintained by pointing those existing processes at the additive and processing-aid layer of the bill of materials.

On the customer’s side, the declaration is used twice. It supports the adventitious agents safety evaluation in the marketing authorisation dossier, and it supports the packaging component’s own regulatory file. For primary packaging supplied into the US, that file is often a Type III Drug Master File, which lets the component manufacturer hold confidential composition and process detail while authorising customers to reference it.

BSE/TSE assessment also sits next to, but is distinct from, the chemical safety work on the same components. Extractables and leachables studies ask what migrates from a material into the drug; the TSE assessment asks where the material came from. Both are answered from the same bill of materials, which is why they are usually requested together, along with the particulate matter controls that govern what a component sheds.

How this works in practice at Autofits

Autofits states its components as BSE/TSE-free in line with EMEA/410/01 rev. 3 across the seal and cap range. The position is straightforward to hold because of what the components are made of: an AA8011 aluminium shell conforming to EN 15088:2005, an epoxy lacquer coating conforming to 21 CFR 175.300, and, on aluminium-plastic seals, a polypropylene disc or button conforming to IS 10910 and IS 10909 and to FDA 21 CFR 177.1520. Heavy metals across chrome-VI, cadmium, mercury and lead are held to a maximum 100 ppm total per EN 602 and EC 94/62, and the aluminium is REACH and RoHS compliant.

Manufacturing runs under ISO 9001:2015, ISO 14001:2015 and ISO 15378:2017 with a Drug Master File, in a 75,000 sq ft facility at Nashik in India, with in-house polypropylene moulding, an automated washing line, ISO Class 8 cleanroom assembly and 100% camera inspection. Keeping the moulding in house shortens the additive supply chain that a TSE declaration has to cover. The certification set is on the quality page; the component ranges, including FlipTop aluminium-plastic seals and aluminium pilfer-proof caps, are on the products page.

Frequently asked questions

What does BSE/TSE compliant mean for packaging?

It means the packaging manufacturer has assessed every material and processing aid in the component against the applicable TSE guidance, normally EMA/410/01 rev. 3 and Ph. Eur. 5.2.8, and can state either that no material of animal origin is used or, where one is, that its species, tissue, country of origin and processing meet the guidance. It is a documented sourcing position, not a test result, because there is no practical release test for prion contamination in a plastic or metal component.

Which guidance applies to BSE/TSE in pharmaceutical packaging?

In Europe, the Note for Guidance EMA/410/01 rev. 3, published in Official Journal C 73 of 5 March 2011 and applicable from 1 July 2011, reproduced identically as European Pharmacopoeia general chapter 5.2.8. The related Ph. Eur. general monograph is 1483, Products with risk of transmitting agents of animal spongiform encephalopathies. In the US, FDA addresses prohibited cattle materials through 21 CFR 189.5 and 21 CFR 700.27 and reviews animal-origin risk within drug and biologic applications.

Can an aluminium vial seal contain animal-derived material?

The aluminium and the polypropylene themselves are not animal-derived, but the additives and processing aids can be. Stearic acid and metal stearates used as acid scavengers, antistatics and mould release agents, tallow-derived fatty acid esters in rolling and forming lubricants, and slip agents and waxes in lacquers and inks are all available in both animal-derived and plant-derived grades. That is why the assessment has to reach the additive layer of the bill of materials rather than stopping at the substrate.

Is a TSE Certificate of Suitability needed for packaging?

Usually not, because most packaging components can be declared free of animal-derived materials. A TSE CEP, issued by the EDQM, becomes relevant when a ruminant-derived material is genuinely present and cannot be substituted. It is a pre-evaluated confirmation that a specific material from a specific manufacturer meets the European Pharmacopoeia’s TSE requirements, and it removes the need for every downstream user to build the same risk assessment from scratch.

What should I ask a vial seal supplier for?

Ask for a dated, signed declaration that names the governing reference and revision, lists the materials and components covered, extends explicitly to additives, processing aids, lubricants, release agents, coatings and inks, and commits the supplier to notify you before any change affecting the position. Ask how the position is maintained under change control, and whether the polymer moulding and metal forming are in house or subcontracted, since each additional tier lengthens the chain the declaration has to cover.

How is BSE/TSE assessment different from extractables and leachables?

They answer different questions from the same bill of materials. An extractables and leachables programme asks what chemical species can migrate out of a material into the drug product, and it is answered with analytical studies and a toxicological assessment. A BSE/TSE assessment asks where each material originated and how it was processed, and it is answered with supply chain documentation. A component can be fully characterised for E and L and still need a separate TSE position.

Does gamma sterilization remove TSE risk?

No. Prions are highly resistant to ionising radiation at sterilizing doses, and to autoclaving, dry heat and most chemical disinfectants. Sterilization of a packaging component addresses bioburden, not prion infectivity. TSE risk is controlled by sourcing and by the manufacturing processes applied to the raw material, which is the whole basis of the guidance.

Sources

EMA: Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products, EMA/410/01 rev. 3 (https://www.ema.europa.eu/en/minimising-risk-transmitting-animal-spongiform-encephalopathy-agents-human-veterinary-medicinal-products-scientific-guideline)
EUR-Lex: Official Journal C 73, 5 March 2011, publication of the Note for Guidance, CELEX 52011XC0305(04) (https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:52011XC0305(04))
EDQM: European Pharmacopoeia general chapter 5.2.8 and general monograph 1483; Certification of Suitability procedure (https://www.edqm.eu/en)
WOAH (World Organisation for Animal Health): Bovine spongiform encephalopathy, official disease status and risk categories (https://www.woah.org/en/disease/bovine-spongiform-encephalopathy/)
eCFR: 21 CFR 189.5, Prohibited cattle materials (https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-189/subpart-B/section-189.5)
eCFR: 21 CFR 700.27, Use of prohibited cattle materials in cosmetic products (https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-700/subpart-B/section-700.27)
eCFR: 21 CFR 175.300, Resinous and polymeric coatings (https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-175/subpart-C/section-175.300)
eCFR: 21 CFR 177.1520, Olefin polymers (https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-177/subpart-B/section-177.1520)
ISO: ISO 15378:2017, Primary packaging materials for medicinal products, GMP requirements (https://www.iso.org/standard/70729.html)

*Last updated: 2026-07-31. This article is general technical information, not regulatory or compliance advice; confirm the current revision of EMA/410/01, the current Ph. Eur. text and your own market’s requirements with the issuing bodies before relying on them.*