Packaging Flashcards
Describe a high speed packaging line. What security features would you expect to find on this line and what checks would be performed during packaging?
E.g. IMA High speed Integrated blister and cartoner-600 to 1300 blisters per minute.
Typical process:
1. Forming
2. Product loading
3. Sealing
4. Coding
5. Perforation
6. Cut
Forming materials
Thermoforming:- Single layer: PVC. Multilayer: PVC + PVdC, PVC + PCTFE (Aclar)
Coldforming: Multilayer: Cold Forming Foil
Security Features (FMD):
- Tamper evident seals
- 2d barcode
Control Systems :
- Heat sealing
- Capsule in pocket/ Correct capsule in pocket
- Checkweighing
- Pinhole detection
- product/leaflet presence controls,
- variable print check,
- presence/ no presence of label/ leaflet
- barcode reading on blister, leaflet and carton
material forming, feeding or sealing. It is then carried through the whole cartoning, labelling and overwrapping processes until the palletizing stages.
Start up checks
1. Ensure readiness of the area and equipment
2. Ensure materials are available
3. Carry out pre start-up checks, check ‘first offs’, vision challenge tests (e.g. defective pharmacode on any printed packaging component, incorrect variable data etc).
IPC Checks
- examples: sealing/ leak detection, print quality….
What is the impact of serialisation (to Manufacturer/MAH and the QP)?
Impact to Manufacturer/ MAH:
Highly challenging and far reaching- requirements stated in delegated regulation 2016/161
- Meet all relevant (potentially different) EU and any national authority requirements and timelines.
- No transition period in EU: required for all product release from 09 Feb 2019
- Updates to registered packaging information.
- Selecting the most suitable and appropriate equipment and software systems.
- Only one 2D barcode permitted per pack (incorporate datails of any existing)
- Management of indivdual pack/ aggregations systems
- Significant cost and CAPEX investment.
- Challenging supplier/ service provider lead times and implementation projects given demand and enforcement date.
- Potential for complex logistics and higher shipping costs due to ‘dead air’ with increased carton sizes to accomodate label/direct print.
- Handling of damaged/ unsold/ sample stock and decommisioning from verification system
- Record keeping of every operation on or with the unique identifier (longest of wither: 1 yr past expiry or 5 years after release for sale).
Impact to QP:
Included in changes to legal duties (2001/83/EU) “ensure that the safety features have been affixed on the packaging”, and- operational resonsibilities of QP (Eudralex Vol 4 Annex 16) “safety features referred to in Article 54(o) of Directive 2001/83/EC, as amended, have been affixed to the packaging, where appropriate.”
- QP must understand the specific requirements for products and markets they are certifying for.
-Ensure QMS incorporates appropriate checks of serialisation information during setup, IPC and example packs are checked as part of packaging operations and batch record review.
-Require appropriate process flow for loading details onto verification system and checking prior to QP certification.
What information is required on the outer packaging of medicinal products or, where there is no outer packaging, on the immediate packaging
2001/83/EC Article 54:
- Name (And in Braile), expiry
- Strength, Number of doses of the product;
- dosage form, method of admin
- if intended for babies, children or adults
- Storage conditions
- Name of the active substances
- excipients known to have a recognized action or effect (if the product is injectable, or a topical or eye preparation, all excipients must be stated)
- “Store out of the reach and sight of children”
- the name and address of the marketing authorisation holder and, where applicable, name of representative to represent him;
- the MA number
- Safety features
What should be contained on a Patient Information Leaflet (PIL)?
All patient information leaflets are required to follow the order and include the content specified in article 59(1) of Council Directive 2001/83/EC.
(a) for the Identification of the medicinal product (name, strength, pharmaceutical form, and, if appropriate, whether intended for babies, children or adults.
(b) the therapeutic indications;
(c) Information necessary before product is taken (contra-indications; appropriate precautions for use; forms of interaction with other medicinal products and other substances, special warnings)
(d) Necessary and usual instructions for proper use (dosage, method and, if necessary, route of administration, frequency, time, duration of treatment, action to be taken in case of an overdose, what to do when one or more doses have not been taken, indication, if necessary, of the risk of withdrawal effects; recommendation to consult the doctor or the pharmacist for any clarification on use.
Additional EMA guidancein the ‘ Quality Review of Documents: product information templates’ to improve consistency. . In UK, refer to the: MHRA :BEST PRACTICE GUIDANCE ON PATIENT INFORMATION LEAFLETS. This guidance incorporates 6 main section of a PIL:
1) IDENTIFICATION OF THE MEDICINE
The name, the active substance(s), the pharmaceutical form, strength of the product should be stated.
2) THERAPEUTIC INDICATIONS
The conditions for which the medicine is authorised must be listed. This section should include any benefit information considered appropriate
3) INFORMATION NECESSARY BEFORE TAKING THE MEDICINE
Situations where the medicine should not be used, any precautions, warnings, interactions with other medicines or foods, information for special groups of patients (pregnant or nursing mothers), and any effects the medicine may have on the patient’s ability to drive.
4) DOSAGE
How to take or use the medicine including both the route and method of administration, how often it should be given, how long the course of treatment will last, what to do if a dose is missed and if relevant what do in the event of an overdose and the risk of withdrawal effects.
5) DESCRIPTION OF SIDE EFFECTS
All the effects which may occur under normal use of the medicine and what action the patient should take if any of these occur. These should be listed by seriousness and then by frequency.
6) ADDITIONAL INFORMATION
This covers information on excipient details, a description of the product, registered pack sizes, storage conditions, name and address of the MAH and manufacturer
Auditing a contract packing CMO. what do you look at?
Audit according to:
- Eudralex Volume 4 Part 1 Chapters/ Annexes and relevant sections therein. (work through each chapter in same way as would if auditing any CMO. Risk based priority for time: PQS, Personnel, Premises & Equipment, Documentation, Production, QC, Outsourced Activities, Complaints & Recall, Self Inspection. Annex 19 for reference/retain samples, Annex 13 if IMP, Annex 16 supply chain and spec requirements) .
- PS 9000:2016 (Pharmaceutical Packaging Materials for Medicinal Products). Specifically: focussing on areas such as; Change control, security controls for packaging, tooling and print media to prevent counterfeiting and mix up, Identification and traceability, Line clearance, Risk assessment, Segregation controls, maintenance, calibration, Validation (and Qualification).
<if IMP then controls around segregation and identification of unlabelled items, packaging specifications to maintain blonding etc>
Auditing a print packaging provider what do you look at? (include standards / guidelines)
Audit according to:
- Eudralex Volume 4 Part 1 Chapters/ Annexes and relevant sections therein. (work through each chapter in same way as would if auditing any suppler. Risk based priority for time: PQS, Personnel, Premises & Equipment, Documentation, Production, QC, Outsourced Activities, Complaints & Recall, Self Inspection. Annex 13 if IMP, Annex 16 supply chain and spec requirements) .
- PS 9000:2016 (Pharmaceutical Packaging Materials for Medicinal Products). Specifically: focussing on areas such as; Change control, security controls for packaging, tooling and print media to prevent counterfeiting and mix up, Identification and traceability, Line clearance, Risk assessment, Segregation controls, maintenance, calibration, Validation (and Qualification).
<if IMP then controls around segregation and identification of unlabelled items, packaging specifications to maintain blinding etc>
packaging differences between commercial and imp
Scale, speed, problems different, considerations for blinding, ensuring CTA compliance.
Differences in packaging between the two –
IMP requires:
- Name, address & telephone # of sponsor/ CRO/ Investigator <main contact and emergency unblinding>
- Trial Reference code <identifies trial site, investigator + sponsor>
- Name of Investigatore
- Directions for use (or reference)
- “For Clinical Trial Use only”
Does not require: safety features, braille, authorisation # or lsit of excipients
Same info IMP & Commercial;
Dosage form, Route of Admin, Qty of dosage units, Batcg/ code #, storage conditions, period of use <use by expiry / retest> Keep out of reach of children.
(Name /identifier/ strenth/ potency; of open trial)
Supply of packaging materials, how would you sample?
’- Ensure on Approved suppliers list (Audit/ QTA) - Implement appropriate specification
- Packaging and Finished product sampling should be based upon a defined sampling standard; e.g. ISO 2859 ‘Sampling by Attributes’:
- The objective is to ensure that there is a low probability of accepting material that does not comply with the predefined acceptance level.
- Typical to accept a certain number of minor defects, but not critical defects.
1. Define and categorise (critical, major or minor) the potential defects of interest.
2. Define AQL ‘Acceptance Quality Limit’; i.e. max. # of defective units, beyond which lot is rejected (different AQLs for critical, major, minor defects)
3. Follow AQL Tables to prepare a sampling plan for inspection, based on the following key elements:
a. How many samples should be picked and analysed, among a lot of product or parts? b. Acceptance Criteria to reject or approve the lot
- Table 1: provides the code letter for sampling based on lot size (if you choose level II (default for most inspections), the letter is L.
- Table 2: provides the number of sample units that must be checked, and returns the maximum number of defective units which would still permit you to ‘Accept’ the lot and the number which would require you to ‘Reject’ the lot, in order to meet the specified AQL.
- (Double sampling plan may require further sampling if initial conclusive). problem -> tightened -> monitored & ok -> normal -> v.good -> reduced
Example Defects:
Critical: 0 to 1.0% (0.10% median) e.g. incorrect text for product strength
Major: 0.1-3.5% (0.65% median) e.g. text/ artwork colour, legibility issue with batch details on primary container
Minor: 0.5-5.0% (4.0% median) e.g. adhering surface spot on outer pack, minor smudge in non-text artwork
What are Extractable and Leachable studies?
- Extractables studies are an assessment performed on a material.
- Leachables studies are an assessment performed on the drug product.
Any material in direct contact with a drug solution could potentially cause contamination through leaching. This change in the product’s composition can impact its therapeutic effectiveness—E&Ls may reduce stability, alter impurity profiles, inactivate the active ingredient, alter the smell, taste or color of the product, and cause it to fail quality-control assays. Regulations in EU state that production equipment should not introduce hazards to the product. In addition, chemical compatibility (regarding E&Ls) of packaging and product must be evaluated.
The objective of an E&L study is to identify risk by conducting controlled extractable studies, which can be correlated to drug/biologic safety and quality. The first step in designing a study is to identify the various components to be evaluated and the degree of evaluation. Criticality should be assessed based on the likelihood of component interaction with the drug/biologic product during manufacture, storage, or when in contact with a patient.
«potential sources: Polymers are most common, whether plastics or rubbers. Can also arise from glass, metal, adhesives, printing inks, and cardboard packaging. (consider glass delamination)»
Can you describe how serialisation works – what products are included and excluded?
Delegated regulation 2016/161 (to apply from Feb 2019).
Safety features required for the sale, distribution and supply of products:
One of the safety features being the serial number (20 charecters alpha/numeric)
European Medicines Verification System <EMVS> allow verification by Wholesalers & distributers. verified and decommissioned before being dispensed. High risk also verified at the wholesaler.</EMVS>
Required for prescription but some exceptions (HARME)e.g. Homeopathic, ATMPs, Radiopharmaceuticals, Medicinal gases, Electrolyts
Not required for non prescription, unless in the annex (omeprazole, also national CAs can add)
Not required for IMP but tamper evidence is required anyway and the IRT (interactive Response Tech) tracks.
- Manufacturers upload valid Unique Identifier codes to the European Medicines Verification System (EMVS)
- Pharmacies may check the status of each pack via the interface with National Medicines Verification Systems (NMVS) .
- And at dispensing the status in the NMVS is changed by the dispenser from “active” to “inactive – dispensed” (decommisioned)
The system will be notified of products known to have been recalled, withdrawn, stolen or tampered with.
How would you validate serialisation….and aggregation…where does QP come in?
To implement & qualify any new Equipment:
* Guidance; Eudralex volume 4 Chapter 3 :Premise & Equipment, Annex 15: Qualification & Validation, Annex 11: Computerised Systems. ICH Q8-11 as relevant. Other guidance e.g. ISPE GAMP 5
QRM approach - Document use. Review/ repeat risk assessment as required. Consider software/ DI risks
Quality and project plan - Project Definition, Scope, Milestones, Deliverables, Resources. Change Control - > Change Board Approval. Sourcing & Procurement, Vendor & System Evaluation,
Validation Master Plan (VMP) - separate validation plan - Include; Q&V policy, Org structure, Summary of facilities, equipment, systems, processes, Change control & deviation management for Q&V; Guidance on developing acceptance criteria; References; Q&V strategy
Qualification Stages: URS «<Quality>>>-> FAT -> SAT -> IQ -> OQ ->(documentation) PQ
Release & Ongoing evaluation -Complete change control actions. Notify & Release for use. Effectiveness Review. Ongoing review/ assessment/ monitoring. Periodic requalify or evaluate to confirm remains in a state of control.</Quality>
Where do the serialised numbers need to go and how do they get there?
Manufacturers will upload valid UI codes to the European Medicines Verification System (EMVS) via the European Medicines Verification Organisation (EMVO) and supply chain stakeholders / pharmacies will be able to check the status of each pack at any point along the supply chain and during the dispensing process via their interface with appropriate National Medicines Verification Systems (NMVS) . The system will be notified of products known to have been recalled, withdrawn, stolen or tampered with.
The European Medicines Verification System (EMVS) will act as a hub, linking the national systems together and allowing parallel trading of medicines to continue. Dispensing entities and in some cases wholesalers will also have to check that the ATD is still intact.
What information is contained within the 2D Data Matrix?
Each individual pack of a prescription medicine will need to carry a unique identifier (UI) encoded via a 2D data matrix (barcode). If the pack size permits it, the pack will also carry the same information in human-readable text, printed adjacent to the 2D-code where possible.
The unique identifier will consist of [Article 4]:
- Product code: the name, common name, pharmaceutical form, strength, pack size and pack type
= Serial number: randomised numeric or alphanumeric sequence of up to 20 characters - National reimbursement number: national identifying code, if required by Member State [note: not in the UK]
- Batch number & Expiry date
<pack also requires a tamper evidence device in addition to 2D data matrix
Explain the repository structure of the EVS?
The EC states which structure the repositories system should adopt: Central information and data router (the European Hub) and repositories which serve the territory of one or multiple Member States. Those repositories will all have to be technically connected to the EU-Hub.
Each EU/EEA country has to implement a National Medicines Verification System (NMVS) which will be set up and managed by a National Medicines Verification Organisation (NMVO). The main purpose of the NMVS is to serve as the verification platforms that pharmacies or other registered parties – such as wholesalers, self-dispensing doctors or hospital pharmacies – will use to check the authenticity of a product.
SecurMed UK is the UK NMVO. Arvato Systems GmbH is the Blueprint Service Provider NMVS. Aims of an NMVS:
- Holding the relevant product serialization data for the national market
- Receiving revised/new product serialization data from the EU-Hub.
- Serve as the verification platform for pharmacies or other registered parties e.g. wholesalers & hospitals to certify authenticity.
- Serve as the platform for wholesalers in the case of a product pack marked as decommissioned prior to handing it over the patient
- Serve as the platform for wholesalers to mark a product pack as “decommissioned” e.g. ‘exported out of EU’.
Where do serialised numbers need to go and how do they get there?
Explain the repository structure of the EVS?
In order to counter the threat of falsified medicines entering the legal supply chain, the European Parliament and Council have released a Directive on Falsified Medicines (2011/62/EU) (amending Directive 2001/83/EC). It aims at improving patient safety by mandating the Marketing Authorisation Holders and manufacturers to put a system in place that is preventing falsified medicines from entering the legal supply chain, the European Medicines Verification System (EMVS) should guarantee Medicines authenticity by an end-to-end verification.
Upload: European Level
Manufacturers can upload the unique identifiers via the European Hub and verification of medicines will take place in the National Medicines Verification Systems. The overall technical and quality standards, such as system interoperability, data ownership and access have been agreed by the stakeholders based on mutually endorsed principles that are compatible with the FMD requirements.
Point of dispense medicines verification
At the point of dispense the medicine will be scanned, checked and verified for authenticity against a national (or supranational) repository. If the UI on the pack matches the information in
the repository, the pack is decommissioned
and supplied to the patient. Otherwise, if
there is a warning related to this pack, then
the system will highlight this as an exceptional
event and the package will not be supplied to
the patient. An investigation needs to
determine whether the pack has been falsified
or not.
