Skip to main content

Autofits

Autofits logo
Menu

Vial Closure Regulatory FAQs: Standards, DMFs, CDSCO and Certification

Sealed injection vials on a quality control bench, representing vial closure regulatory requirements

Three layers of requirement apply to a vial closure. Product standards define the parts: ISO 8362-6 for aluminium-plastic caps, ISO 8362-3 for all-aluminium caps, and USP <381>, USP <382> and Ph. Eur. 3.2.9 for the rubber stopper. Quality-system standards define how they are made, chiefly ISO 15378 for primary packaging. And the drug manufacturer’s regulator sets what must be qualified and filed, through FDA Drug Master Files, India’s revised Schedule M, or EU guidance. Autofits holds ISO 9001:2015, ISO 14001:2015 and ISO 15378:2017 certification and Drug Master File 18100. The answers below take each question in turn and link to the primary source.

Standards that apply to seals and stoppers

Each standard below has its own explainer in the standards library, and the whole set is gathered in the regulatory compliance pack.

What ISO and USP standards apply to vial flip-off caps?

The cap itself is covered by ISO 8362-6, caps made of aluminium-plastics combinations for injection vials, and the vial neck it fits by ISO 8362-1 or ISO 8362-4. The stopper under the cap is covered by ISO 8362-2 and by the compendial chapters USP <381>, USP <382> and Ph. Eur. 3.2.9. Integrity of the closed vial is assessed under USP <1207>. The manufacturer’s quality system for primary packaging is certified to ISO 15378.

What is the difference between ISO 8362-3, ISO 8362-6 and ISO 8362-7?

All three are parts of the ISO 8362 series on injection containers. ISO 8362-3 covers aluminium caps for injection vials, the all-aluminium tear-off and tear-down family. ISO 8362-6 covers caps made of aluminium-plastics combinations, where the plastic part overlaps the aluminium, as on a flip-off seal. ISO 8362-7 covers aluminium-plastics combination caps without an overlapping plastics part.

Does a flip-off seal count as primary or secondary packaging under FDA definitions?

It depends on the definition in use. FDA’s 1999 guidance on container closure systems defines a primary packaging component as one that is or may be in direct contact with the dosage form, and a secondary component as one that is not and will not be. A seal does not touch the drug, but the same guidance lists stopper overseals as packaging components and counts secondary components in the container closure system when they protect the product. In practice the seal is qualified as part of that system.

Is FDA’s 1999 container closure guidance still the reference?

It remains the published guidance, and in August 2026 FDA issued a draft guidance titled Container Closure Systems for Human Drugs and Biological Products, open for public comment and marked not for implementation. A draft guidance does not replace the final one until FDA finalises it, so check the FDA guidance database for its status before relying on either text in a submission.

Which USP chapters apply to rubber stoppers?

USP <381>, Elastomeric Components in Injectable Pharmaceutical Product Packaging/Delivery Systems, covers biological reactivity and physicochemical properties of the elastomer, including extractable elements. USP <382>, Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery Systems, covers how the component performs in the packaging system, such as penetrability and self-sealing. The aluminium seal is not the subject of either chapter.

What does Ph. Eur. 3.2.9 test on rubber closures?

Ph. Eur. 3.2.9 covers rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders. It sets identification tests, tests on an aqueous extract of the closure such as appearance of solution, acidity or alkalinity, absorbance, reducing substances, ammonium, extractable zinc and heavy metals, residue on evaporation and volatile sulfides, and functional tests for penetrability, fragmentation and self-sealing.

Does Ph. Eur. 3.2.9 set a tensile strength requirement for rubber closures?

Tensile strength is not among the tests the chapter lists, which are identification, extract tests and functional tests on the closure. Mechanical properties such as hardness and tensile behaviour are normally fixed in the compound specification agreed with the stopper supplier. Confirm against the edition of the European Pharmacopoeia in force for your submission, since chapters are revised.

Drug Master Files

A Drug Master File lets a packaging supplier give confidential information to a regulator without sharing it with each customer. The background is on Type III DMF.

What is a Type III Drug Master File?

A Type III DMF is the FDA category for packaging materials. FDA describes it as holding information on the intended use, components, composition and controls of packaging materials such as vials, bottles and stoppers, with supporting data. FDA does not require packaging information to be filed in a DMF: an applicant can put it directly in its application, and a DMF is used when the manufacturer wants to keep that information proprietary.

Does the FDA approve a Type III DMF?

No. FDA states that DMFs are neither approved nor disapproved and are not required by statute or regulation. FDA reviews the technical contents of a DMF when it reviews an application that references it, such as an NDA, ANDA, BLA or IND. A supplier holding a DMF number has filed information with FDA; it does not hold an approval.

What is a letter of authorization for a DMF?

It is the DMF holder’s letter permitting FDA to refer to the DMF in support of a named customer’s application. The customer includes it in the submission, which lets FDA read the confidential packaging information during review without the supplier disclosing it to the customer. Without that letter, the application cannot rely on the DMF.

Can a customer reference the Autofits Drug Master File in a submission?

Autofits holds Drug Master File 18100, and a customer who needs to reference it should raise that at enquiry, naming the application and the regulator, so the filing details and the authorisation to reference it can be arranged for that submission. Autofits also holds a CFDA registration, and its quality system is certified to ISO 15378:2017, ISO 9001:2015 and ISO 14001:2015.

India: Schedule M and CDSCO

India’s manufacturing requirements sit in the Drugs Rules, 1945, and CDSCO is the national regulator. The Autofits summary is on CDSCO guidelines.

What does India’s revised Schedule M require of packaging material suppliers?

Revised Schedule M, notified as G.S.R. 922(E) on 28 December 2023, places the duty on the licensed drug manufacturer. It requires suppliers of starting and packaging materials to be evaluated before approval, taking account of the supplier’s history and the material, with an audit where required to confirm the supplier’s ability to meet GMP. Changes to packaging materials fall under change control, and each delivery or batch of primary packaging material is given a specific reference number or identification mark.

Must containers and closures used in India meet pharmacopoeial requirements?

Yes. Revised Schedule M states that all containers and closures intended for use shall comply with pharmacopoeial requirements, and that packaging material for pharmaceutical products shall be in accordance with the Indian Pharmacopoeia. It also requires validated test methods, specifications and cleaning and sterilisation procedures, where indicated, so that containers and closures are not reactive, additive or absorptive and do not leach to an extent that affects the drug.

Can a primary packaging manufacturer leave design and development out of its certification scope?

That depends on which standard is certified. ISO 13485, the medical device standard, allows design and development controls to be excluded only where applicable regulatory requirements permit it. ISO 15378 describes itself as an application standard for the design, manufacture and supply of primary packaging for medicinal products, and the ISO 9001:2015 text it contains requires any requirement treated as not applicable to be justified. Autofits carries out design and development in-house.

Certification, declarations and stability

The certificate set, with numbers, is on the quality page. How ISO 15378 differs from ISO 9001 clause by clause is in ISO 9001 vs ISO 15378.

What are the certificate numbers for Autofits’ ISO certifications?

Autofits Packaging Pvt. Ltd. holds ISO 9001:2015 (certificate 21.GGCS.IN.091174), ISO 14001:2015 (21.GGCS.IN.140169) and ISO 15378:2017 (21.GGCS.IN.151175), with Drug Master File 18100 and a CFDA registration. Its seals follow ISO 8362-6 for aluminium-plastic caps and ISO 8362-3 for all-aluminium caps, with vial necks to ISO 8362-1. Certificate copies are supplied on request.

What is a TSE/BSE statement for a packaging component?

It is a supplier’s declaration on whether a material involves substances of animal origin that could carry transmissible spongiform encephalopathy agents. The European reference is EMA’s Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products, EMA/410/01 rev.3. Autofits seal components are declared BSE/TSE-free against that guidance.

Does ICH Q3D apply to elemental impurities from container closures?

ICH Q3D applies to the finished drug product, and its risk assessment considers every potential source of elemental impurities, including the container closure system. The drug manufacturer carries out that assessment. Closure suppliers contribute data: USP <381> covers extractable elements for elastomers, and Autofits declares heavy metals in its seal materials at a maximum of 100 ppm total.

Do stability studies have to use the marketed container closure system?

Yes. ICH Q1A(R2), the stability testing guideline, expects stability studies on the drug product packaged in the container closure system proposed for marketing. That is why a seal, stopper and vial are normally fixed before registration stability batches are made, and why a later change to any of them is assessed for its effect on those data.

What happens when a stopper or seal supplier changes a component?

The drug manufacturer has to assess it. Ph. Eur. 3.2.9 expects the manufacturer of the preparation to obtain assurance from the closure supplier that the composition does not vary, and to repeat compatibility testing, fully or partly, when the supplier reports a change. Revised Schedule M brings changes to packaging materials under change control. ISO 15378 defines change control as documented control of changes with appropriate risk management.

Related reading

Sources

  • ISO: ISO 8362-6, Caps made of aluminium-plastics combinations for injection vials (https://www.iso.org/standard/52806.html)
  • ISO: ISO 8362-3, Aluminium caps for injection vials (https://www.iso.org/standard/33804.html)
  • ISO: ISO 8362-7, Injection caps made of aluminium-plastics combinations without overlapping plastics part (https://www.iso.org/standard/43551.html)
  • ISO: ISO 15378:2017, Primary packaging materials for medicinal products (https://www.iso.org/standard/70729.html)
  • ISO: ISO 13485:2016, Medical devices, Quality management systems (https://www.iso.org/standard/59752.html)
  • FDA: Container Closure Systems for Packaging Human Drugs and Biologics, May 1999 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-packaging-human-drugs-and-biologics)
  • FDA: Container Closure Systems for Human Drugs and Biological Products, draft guidance (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-human-drugs-and-biological-products)
  • FDA: Types of Drug Master Files (https://www.fda.gov/drugs/drug-master-files-dmfs/types-drug-master-files-dmfs) and Drug Master Files (https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs)
  • USP: General Chapters <381> (https://doi.usp.org/USPNF/USPNF_M99140_60201_01.html) and <382> (https://doi.usp.org/USPNF/USPNF_M11355_03_01.html)
  • EDQM: European Pharmacopoeia, chapter 3.2.9 (https://www.edqm.eu/en/european-pharmacopoeia)
  • Ministry of Health and Family Welfare, India: G.S.R. 922(E), 28 December 2023, revised Schedule M to the Drugs Rules, 1945, via CDSCO (https://cdsco.gov.in/)
  • EMA: Minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (https://www.ema.europa.eu/en/minimising-risk-transmitting-animal-spongiform-encephalopathy-agents-human-veterinary-medicinal-products-scientific-guideline)
  • ICH: Quality guidelines, including Q1A(R2) and Q3D (https://www.ich.org/page/quality-guidelines)

*Last updated: 2026-09-15. This page is general regulatory information, not legal or regulatory advice. Standards and guidance are revised; confirm the edition in force with the issuing body before relying on it in a submission.*

Back to top: