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The first part of this article covered the selection of materials for the manufacture of packaging components and the regulatory requirements that have to be considered. Now, in part II the focus will be on Extractables and Leachables, Container- Closure Integrity and requirements for sterile packaging as well as defect evaluation lists.

New USP Chapter on the Integrity of Pharmaceutical Packaging

So far there existed only the general USP chapter <1207> on the integrity evaluation of sterile product packaging. The original content of the chapter has been revised comprehensively and divided into four related chapters.

With USP39-NF34, first Supplement, the following USP chapters came into effect on 1 August 2016:

  • Sterile product packaging - integrity evaluation <1207> (revision)
  • Package integrity and test method selection <1207.1> (new)
  • Package Integrity leak test technologies <1207.2> (new)
  • Package seal quality test technologies <1207.3> (new)

Chapter <1207> is supposed to provide an overview of the different leak test methods as well as of the suitability or quality of closures that have to be used for the integrity evaluation of primary packaging for sterile products. The three sub-chapters on specific topics give detailed recommendations for the selection, qualification and use of leak test methods.

Live Online Training: Design Controls for Drug - Device Combination Products


9/10 November 2021

Live Online Training: Design Controls for Drug - Device Combination Products

Extractables & Leachables Three new USP General Chapters on extractables and leachables have officially come into effect on 1 August 2015 (USP 38-NF33, first supplement):

  • <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems,
  • <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery systems,
  • <1664.1> Orally Inhaled and Nasal Drug Products.

One further chapter is in the planning stage:

  • <1664.2> Parenteral and ophthalmic drug products.

These chapters are for informational purposes and give an overview of design, justification, and execution of an extractables/leachables assessment for pharmaceutical packaging. They do not contain specific experimental conditions, specific tests, analytical procedures or limits of acceptance for packaging materials.

Furthermore, the preparation of a new General Chapter <1665> Toxicological Safety Assessment of Extractables and Leachables has been planned (announced in PF 39(6) in the stimuli article: USP Plastic General Chapters: An Overview). It will contain the key points for the performance of toxicological safety assessments. It will not contain specific protocols or specifications.

The USP chapters mentioned in the area of the numbers around 1000 have "only" informational character. But they could as well get a more official character if a reference is included in individual USP monographs or in General Chapters on dosage forms. In the issue PF 41(5) of September - October 2015 reference to the two new chapters <1663> and <1664> has been integrated into the drafts for the General Chapters Ophthalmic products <771> and Injections <1>. This means that it might be necessary to discuss the scientific bases and good practices for the test of extractables/ leachables in the future.

Furthermore, the assessment of possible leachables/extractables and the establishment of acceptance criteria for these substances might be based on a risk assessment for a specific combination of product, indication, type of use and packaging system.

Safety by Design

The FDA published a guidance with the title "Safety Considerations for Product Design to Minimize Medication Errors" in April 2016. This guidance provides a set of principles for using a systems approach to minimize medication errors relating to product design and container closure design beforehand and thus enhance patient safety. The recommendations are intended to provide best practices on how to improve the medicinal product and container closure design. The guidance also provides examples of product designs that have resulted in postmarketing medication errors. Many medication errors can be avoided at the design stage by drawing on lessons learned from past medication errors and by conducting proactive risk assessments before marketing.

The selection of the packaging system should for instance be based not only on stability and manufacturing considerations, but also on the ability of the design to protect against improper use and errors.

Defect Evaluation Lists

The question how to define the quality of packaging materials in the incoming goods inspection arises again and again. Defect evaluation lists are good and generally recognised tools for the decision whether to accept or to reject batches of packaging material. These can be supported by limitboards or photos that clearly show types of errors (including the relevant AQL):

For aluminium tubes the DIN-Normenausschuss Verpackungswesen (NAVp) (DIN-Packaging Standards Committee) published the draft DIN SPEC 55513 "Packmittel - Aluminiumtuben - Fehlerbewertungsliste" (Packaging - Flexible Aluminium Tubes - Defect Evaluation List) with the publication date May 2016.

Until now the standard reference in this field is the "Defect Evaluation List for Tubes Made of Aluminium", written in German and English from the year 2007, series "Quality Assurance of Pharmaceutical and Cosmetic Packaging" of the publisher Editio Cantor Verlag (ECV).

The actual DIN document in German has been compiled by the working committee NA 115-02-08 AA "Tuben" (tubes) at DIN-Normenausschuss Verpackungswesen (NAVp) in collaboration with representatives from the cosmetic, pharmaceutical and food industry. The draft can be read section  by section after a free registration in the Norm-Entwurfs-Portal of DIN (commenting was open until 22 August 2016).

In section 6 "Fehlerbewertung" (defect evaluation) in table 2 the draft includes an evaluation of defect types with the corresponding test methods and the respective acceptable quality levels or rather acceptance quality limits (AQLs, in percent, "quality level that is the worst tolerable" according to ISO 2859-1). The defect evaluation list in table 2 is essentially based on the process flow of the tube manufacturer. A consecutive letter is assigned to each process step:

A) Raw materials;
B) Manufacture of the raw tube;
C) Internal coating;
D) Decoration;
E) Closures;
F) Final sealing;
G) Conification;
H) Packaging, labelling and documentation;
I) Transport and shipping;
J) Hygiene;
K) General defects.

Under the letter J (Hygiene) the defect number J.4 "Partikuläre Verunreinigung, kann in Augensalbe gelangen" (particulate impurities, can get into the ophthalmic ointment) ) can be found. The test is carried out according to Annex A of the draft (defect class 1, AQL 0,01).

Annex A (normative) includes a test for particulate matter in ophthalmic ointments with a table for the assessment of the particles according to size. 10 random samples of the delivery (empty tubes) are filled with vaseline for the test. After filtration the particles present on the filter, if applicable, are evaluated by microscope.

In section 6 there are the following defect numbers: J.10 is about "Mikrobiologische Verunreinigungen: (microbiological contamination) Vereinbarte Grenzwerte für koloniebildende Einheiten (KBE) überschritten" (agreed limit values exceeded for colony-forming units (CFU) (defect class 1, AQL 0,01). Compliance with the limit values is defined according to a test procedure the supplier and the customer have agreed upon. Defect number J.11 is "vereinbarte Sterilisationsbedingungen bei steril angelieferten Behältnissen nicht nachgewiesen" (agreed sterilisation conditions not proven in containers delivered sterile (defect class 1, AQL 0,01). Test basis are the specifications in the certificate.

Just recently (keyword Bisphenol A, BPA), a difference is made between "varnish" and "wax" concerning the internal coating (C).

New editions of ECV's "Defect Evaluation List for Containers Made of Tubular Glass" (last edition 2009) and "General Principles" (last edition 2004) (out of stock) from the already mentioned series containing several volumes were announced for 2016 and 2017. ECV's defect evaluation lists contain sampling tables, defect types with defect classes and allocated AQL (if not agreed on a bilateral basis between manufacturer and customer) and, where appropriate, drawings but usually no images/photos. As a novelty the new edition of the defect evaluation lists for tubular glass will comprise photo examples of containers with defects.

PDA's (Parenteral Drug Association) technical report TR-43 (Revised 2013) "Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing" presents a further defect evaluation list for containers made of molded glass and tubular glass. The standardised quality criteria in this document are intended as guidance for component manufacturers and for incoming inspection at pharmaceutical companies. The close cooperation between glass manufacturer and pharmaceutical entrepreneur who uses the glass containers as packaging for his products is of particular importance for the definition of specifications for containers made of glass. The report includes inter alia:

  • Sampling (according to ANSI/ASQ Z1.4 in the USA , and ISO 2859-1 in Europe);
  • Classification of nonconformities (Critical, Major A, Major B, Minor, and N/A = acceptable),
  • Description of the nonconformity and its classification including photos/ drawings.

The annexes contain very good and clearly illustrated images/photos (and sometimes also drawings) with the defect types occurring in bottles, ampoules, vials and syringes. At the same time the respective defect classes (minor, major, critical) are assigned, but without the AQLs. These must (supposedly) be agreed on a bilateral basis between manufacturer and user of the packaging, for instance in a quality assurance agreement or a technical agreement.

A re-inspection according to section "Re-inspection of Glass Containers" can be taken into consideration, for example in the case of anomalies occurring during manufacture or during the 100% (visual) control of the filled containers or when defined rejection rates are exceeded.

The section "AQL" of the report deals only with the definition of the classification "none allowed" for critical defects. This is used instead of "AQL = 0". It is not possible, on principle, to realise an AQL equalling 0 by means of a sampling testing. In order to be sure that there is no defective object in the complete batch, the complete batch would have to be tested. Therefore it would be better to use the term "none allowed" relating to the sample. "None allowed" can be defects such as wrong vial size, wrong colour of the glass or wrong glass type. If packaging material with the corresponding defect is found among the sample this leads to a rejection of the batch. Alternatively, the complete batch can be tested in the case of "none allowed" in order to ensure that it contains no packaging material with a critical defect. The right to reject the packaging batch is also valid if a "non allowed" defect is found later on during the filling process. Depending on the size of the sample of the packaging tested a "none allowed" in the sample implies different percentages for the AQL with regard to the complete batch. An example: In the case of a sufficiently large size of the complete batch a sample size of 80 units corresponds to an AQL of 0.0641 or to a "maximally allowed" defect rate of 0.0641% in the batch. This means that a sample of 80 items from a batch with a defect rate of 0.0641% will contain no defective product with a probability of 95% so that this batch will be accepted. In other words, in the case of a batch with a defect rate of 0.0641% this batch will be rejected only in 5% of the cases. In the case of a sufficiently large size of the complete batch a sample size of 800 units corresponds analogously to an AQL of 0.00641 or to a "maximally allowed" defect rate of 0.00641%. In other words, among 800 tested samples from a batch with a defect rate of 0.00641% the probability to find a defect is 5%.

Sterilised Packaging Material

The European Medicines Agency (EMA) recently has published questions and answers concerning the topic "What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?". The answers stress that terminal sterilisation of the primary packaging, used subsequently during aseptic processing of the finished product, is a critical process and the sterility of the primary container is a critical quality attribute to ensure the sterility of the finished product. Both need to be assured for compliance with relevant Pharmacopoeial requirements for the finished product and product approval.

The site where sterilisation of the packaging materials takes place may not have undergone inspection by an EU authority and consequently may not hold an EU GMP certificate in relation to this activity1.

When GMP certification is not available, certification that the sterilisation has been conducted and validated in accordance with the relevant ISO standards for the sterilisation of medical devices (ISO 20857, ISO 11135, ISO 17665-1 and-2, ISO 11137-1, -2 and -3) would be considered to provide an acceptable level of sterility assurance for the empty primary container.

It is the responsibility of the manufacturer of the medicinal product (user of the packaging material) to ensure the suitable quality, including sterility assurance, of packaging materials. The site where QP certification of the finished product takes place, and other manufacturing sites which are responsible for outsourcing this sterilisation activity, should have access to the necessary information to demonstrate the ongoing qualification status of suppliers of this sterilisation service. This should be checked during inspections. The Competent Authorities may also decide, based on risk, to carry out their own inspections at the sites where such sterilisation activities take place.

The following details regarding the sterilisation of the packaging components should be included in the dossier:
1. The sterilisation method and sterilisation cycle;
2. Validation of the sterilisation cycle if the sterilisation cycle does not use the reference conditions stated in the Ph. Eur.;
3. The name and address of the site of sterilisation and, where available, details of GMP certification of the site. Where the component is a CE-marked Class Is sterile device (e.g. sterile syringe); confirmation from the manufacturer that the component is a Class Is sterile device, together with a copy of the declaration of conformity from the Notified Body will suffice.

In the absence of GMP certification or confirmation that the component is a CE-marked Class Is medical device, certification that the sterilisation process has been conducted and validated in accordance with the relevant ISO standards should be provided.

GMP for Packaging Materials - PS 9000

The Pharmaceutical Quality Group working party has developed the next version of the established PS 9000 Standards in collaboration with IPACRS: The "British" GMP document for packaging material, PS 9000:2016: Pharmaceutical packaging materials for medicinal products, with reference to Good Manufacturing Practice (GMP). The draft "Changes to PS 9000:2011" can be consulted on the Pharmaceutical Quality Group (PQG) Website. (Deadline for comments was 7 June 2016)

Goal of this new version is a revision and updating for an adaptation to the new ISO 9001:2015. Whereas here no substantial changes of the GMP requirements have been carried out the updated version of the PS 9000 Standards contains additional requirements with supporting recommendations that partly go beyond the requirements in the actual ISO 9001:2015 Standard.

These changes comprise inter alia adaptations to ICH Q8 - Q10, such as the inclusion of a chapter on PAT, on the control of the supply chain (among others definition of QTTP, CQAs), on risk assessment according to ICH Q9, the inclusion of paragraphs with requirements concerning sterile primary packaging with reference to ISO standards (also see above under Sterilised Packaging Material), on the control of extractables, on the environment and cleanrooms.


Dr Andrea Kühn-Hebecker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area pharmaceutics and cosmetics manufacturing, focussed mainly on packaging, development and life cycle management.

1 Sites located in the EU which perform sterilisation of primary packaging components only are not required to hold a Manufacturer's/Importer's Authorisation. Sites located in the EU, which carry out sterilisation of medicinal products, are required to hold a Manufacturer's/Importer's Authorisation in relation to these activities.

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