Packing knowledge checks

Question 1

How important is line clearance in manufacturing and packing?

Answer 1

Extremely, it is our assurance that everything from the previous batch has been removed from the line before material and components are brought to line for the next batch - assures traceability of batch materials and no cross contamination

Question 2

What level of reconciliation would you expect of printed components?

Answer 2

100%

Question 3

What are the differences between manual and high speed packaging lines?

Answer 3

High speed is automated and has various controls on line. Manual is packed by people with manual checks

Question 4

How do you ensure print is correct on the printed packaging?

Answer 4

Validation vision systems / scanners. Variable data checks and vision system challenge tests

Question 5

What is the requirement for Braille?

Answer 5

Article 56(a) of Directive 2001/83/EC, as amended, requires that the name of a medicinal product must be expressed in Braille format on the outer packaging.

Question 6

What are the requirements on the packaging for a Prescription only Medicinal product in the UK?

Answer 6

The MHRA Best Practice Guidance on Labelling and Packaging of Medicines advises that the pack must include the name of the medicinal product (brand name, followed by its strength and pharmaceutical form) and the generic name(s) of the active ingredients where the product contains up to three active substances.

Question 7

What are the legal requirements for PL no and address on packaging

Answer 7

These must be present on the packaging. The information may be present on the PIL but if these get separated then the traceability is lost.
The licence states which illness the medicine can be used for how much can be used how to give the medicine which group of patients it can be given to.

Question 8

What are the common packaging security systems in place on a packaging line?

How would you validation them?

Answer 8

Vision systems,
barcode readers,
checkweigher,
presence sensors.

Challenge tests

Question 9

What are the advantages and disadvantages of these security systems?

Answer 9

Advantages - increase production speed, safety and security of product, Disadvantages - Reliance, breakdown impact, high speed lines if found something not working as it should it can scope a lot of product

Question 10

What materials are suitable for packaging tablets?

Answer 10

Plastic or foil blisters, plastic or glass bottles

Question 11

General controls around generation of printed components.

Answer 11

Artwork updates / Version Control
Waste Disposal of Artwork – Falsified Medicines
Braille requirements
Language
Batch Specific Data
Earliest implementation date and latest implementation date

Question 12

Concerns and controls associated with rework?

Answer 12

Raise a deviation
Rework protocol has to be approved and appropriate controls in place to ensure the following:-
Reconciliation of blister packs
No Damage to blisters
Appropriate segregation from routine processes / no risk of cross contamination
Manual / Automatic
Waste Management
Batch traceability – Original batch number / re-work batch number

Question 13

You are auditing a packaging supplier, what are the key items you would focus on?

Answer 13

What kind? Primary? Printed?
PICs Aide Memoire – Packing
Inspection History
Supplier Management
Storage Areas – Suitable, Secure
Packaging operation
Quality Control / Sampling
Material Specifications AQL’s
Pest control

Question 14

How do you ensure print is correct on the printed packaging?

Answer 14

Compare with approved artwork

Question 15

What is the requirement for braille? -

Answer 15

As per the requirements of 2001/83/ec and 2012/1916 stipulates that all products should contain braille on label.

Question 16

Is braille required on all types of medication?

Answer 16

Not required for hospital given products

Question 17

What systems would you have in place to ensure suitability of the packaged
product?

Answer 17

IPCs:
Blister leak test
Vision (camera) for tablets in pockets
Pharmacode (leaflets/cartons/foil) detection
Pin hole detection
Line clearance before and after operations (start/end)
Reconciliation
Materials issuance checks (against provision list)
Check weigher (leaflet/blister)
Appearance checks (manual) BVD

CPPs:
Machine speed
Tablet feed rate
Temperature of forming and sealing
Pressure and dwell time
Machine set-up
Challenge tests
One batch at a time

Question 18

Can you talk through an FMD compliant high speed blister packaging line?

Answer 18

Line:
Line clearance before and after operations (start/end)
Receipt to line checks
Dedicated order footprint stations
Machine set up and challenge testing
Packaging material such as plastic, foil, cartons etc fed to line
splice detectors
Pharmacode (leaflets/cartons/foil) detection
Pin hole detection
Line speed and temperature of pocket forming
leaflet stackers
Pharmacode (leaflets/cartons/foil) detection
labels threaded, Variable data entered onto line
Vision system for correct labels , size, variable
data
Tablet hopper and in feed
Tablet fee rate
Vision (camera) for tablets in pockets, upright, size, shape, colour
Packet sealer
Pressure temperature and dwell time
Check weigher (leaflet/blister)
Appearance checks (manual)
Blister leak test
Reconciliation
Tamper evident checks (and challenge)
Serialisation (if required)
How codes are issued to the line
Reconciliation of codes (have more)
Start-end and IPCs
Sample packs are recorded as such and not returned to the line

Question 19

Change in Primary container of your Oral Liquid Product – the bottle is changing from Glass to Plastic.

Answer 19

Raise CC
Advantages / Disadvantages – Glass vs Plastic
Mentioned Extractables / leachable / Impurities/ Torque / impact to packing Lines
This lead in to Supplier Assessment – how would I add the supplier to my approved supplier list
They also asked what QC Checks I would do on the bottle on incoming – dimensional / function checks

Question 20

You are a QP and the batch documentation has an incorrect batch number noted, what do you do?
You discover you have released two items with the same batch number onto the market place - what are you going to do

Answer 20

Raise a deviation
block any stock in your control
Understand the detail, what are the batches and where have they been supplied to
Is it a critical medicine
What is the supply issue, how easily can the market be replaced
Initiate a fast investigation - in response to traceability of batches on the market
Initiate product recall class 3 from brokers, warehouses and pharmacies due to compliance / traceability issue, no issue with quality of the product or patient safety

Question 21

You receive a deviation report that shows the operators did not do reconciliation and it was finally done 2 days later. The reconciliation is out and there have been other products on the line since – so now what?

Answer 21

Stop the line
Raise an investigation
Scope the deviation - initial scope to go back to batch in question - quarantine stock
Understand if the reconciliation was over or under - if over may need to scope further back
Have a look at all other batch records in scope. What was the reconciliation records like in the other batches? Check all line clearance records have been completed successfully and review all batches for other comments that may aid the investigation.
Check all return to line records
Any maintenance done on the line
Have the calculations been done correctly
Potential for rework but what it the product, can it be reworked? What about serialisation and tampers?

Question 22

You have got a new syringe supplier (previously never used syringes)
How would you set up the incoming QC department to be able to test and release
this material and what checks are important for a syringe?

How would you design the sampling plan?

How many units would you test for a 100,000 unit batch?

Answer 22

Change Control
Generate Incoming Specifications best on CQA’s
Testing will be based on Critical Dimensions, Functionality, Set AQL’s based on Quality defects (Critical, Major, Minor)

Use ISO2859 to determine samples based on batch size and sampling level

Need to see chart in ISO2859 - use the tables, follow general inspection level 2 requirements

Question 23

HMR 2012:1916 Schedule 24 -
Outer and immediate packaging

Answer 23

Outer and immediate packaging
The name of the medicinal product.
The strength and pharmaceutical form of the product.
Where appropriate, whether the product is intended for babies, children or adults.
Where the product contains up to three active substances, the common name of each active substance.
A statement of the active substances in the product, expressed qualitatively and quantitatively per dosage unit or according to the form of administration for a given volume or weight, using their common names.
The pharmaceutical form and the contents by weight, by volume or by number of doses of the product.
A list of—
(a)where the product is injectable or is a topical or eye preparation, all excipients; or
(b)in any other case, those excipients known to have a recognized action or effect and included in the guidance published pursuant to Article 65 of the 2001 Directive.
The method of administration of the product and if necessary the route of administration.
Where appropriate, space for the prescribed dose to be indicated.
A warning that the product must be stored out of the reach and sight of children.
Any special warning applicable to the product.
The product’s expiry date (month and year), in clear terms.
Any special storage precautions relating to the product.
Any special precautions relating to the disposal of an unused product or part of a product, or waste derived from the product, and reference to any appropriate collection system in place.
The name and address of the holder of the marketing authorisation, Article 126a authorisation or traditional herbal registration relating to the product and, where applicable, the name of the holder’s representative.
The number of the marketing authorisation, Article 126a authorisation or traditional herbal registration for placing the medicinal product on the market.
The manufacturer’s batch number.
In the case of a product that is not a prescription only medicine, instructions for use.

Question 24

HMR 2012:1916 Schedule 24 - Immediate packaging: blister packs

Answer 24

The name of the medicinal product.
The strength and pharmaceutical form of the product.
Where appropriate, whether the product is intended for babies, children or adults.
Where the product contains up to three active substances, the common name of each active substance.
The name of the holder of the marketing authorisation, Article 126a authorisation or traditional herbal registration relating to the product.
The product’s expiry date (month and year), in clear terms.
The manufacturer’s batch number.

Question 25

HMR 2012:1916 Schedule 24 - Immediate packaging: small packages

Answer 25

The name of the medicinal product. The strength and pharmaceutical form of the product. Where appropriate, whether the product is intended for babies, children or adults. Where the product contains up to three active substances, the common name of each active substance. The method of administration of the product and if necessary the route of administration. The product’s expiry date (month and year), in clear terms. The manufacturer’s batch number. The contents of the packaging by weight, by volume or by unit.

Question 26

HMR 2012:1916 Schedule 24 - Packaging requirements: information for blind and partially sighted patients

Answer 26

(1) The name of a medicinal product must also be expressed in Braille format on the outer packaging of the product (or, if there is no outer packaging, on the immediate packaging of the product). (2) The holder of a marketing authorisation, Article 126a authorisation or traditional herbal registration for a medicinal product must ensure that the package leaflet is made available on request in formats suitable for blind and partially-sighted persons. (3) Nothing in this regulation applies to a registrable homoeopathic medicinal product.

Question 27

HMR 2012:1916 Schedule 27 - patient information leaflet general requirements

Answer 27

The name of the medicinal product. The strength and pharmaceutical form of the product. Where appropriate, whether the product is intended for babies, children or adults. Where the product contains up to three active substances, the common name of each active substance. The pharmaco-therapeutic group, or type of activity, of the product, in terms easily comprehensible for the patient. The product’s therapeutic indications. A list of— (a)contra-indications; (b)appropriate precautions for use; (c)interactions with other medicinal products which may affect the action of the product; (d)interactions with other substances, including alcohol, tobacco and foodstuffs, which may affect the action of the product; and (e)special warnings, if any, relating to the product. The list mentioned in paragraph 7 must— (a)take into account the special requirements of particular categories of users (including, in particular, children, pregnant or breastfeeding women, the elderly and persons with specific pathological conditions); (b)mention, if appropriate, possible effects on the ability to drive vehicles or to operate machinery; and (c)list any excipients— (i)if knowledge of the excipients is important for the safe and effective use of the product, and (ii)the excipients are included in the guidance published pursuant to Article 65 of the 2001 Directive. Instructions for proper use of the product including in particular— (a)the dosage; (b)the method and, if necessary, route of administration; (c)the frequency of administration (including, if necessary, specifying times at which the product may or must be administered); (d)the duration of treatment if this is to be limited; (e)symptoms of an overdose and the action, if any, to be taken in case of an overdose; (f)what to do if one or more doses have not been taken; (g)an indication, if necessary, of the risk of withdrawal effects; and (h)a specific recommendation to consult a doctor or pharmacist, as appropriate, for further explanation of the use of the product. A description of the adverse reactions which may occur in normal use of the medicinal product and, if necessary, the action to be taken in such a case. A reference to the expiry date printed on the packaging of the product with— (a)a warning against using the product after that date; (b)if appropriate, details of special storage precautions to be taken; (c)if necessary, a warning concerning visible signs of deterioration; (d)the full qualitative composition (in active substances and excipients), and the quantitative composition in active substances, using common names, of each presentation of the medicinal product; (e)for each presentation of the product, the pharmaceutical form and content in weight, volume or units of dosage; (f)the name and address of the holder of the marketing authorisation, Article 126a authorisation or traditional herbal registration relating to the product and, if applicable, the name of the holder’s appointed representative; and (g)the name and address of the manufacturer of the product. Where the product is authorised under different names in different member States in accordance with Articles 28 to 39 of the 2001 Directive, a list of the names authorised in each member State. For medicinal products included in the list referred to in Article 23 of Regulation (EC) No 726/2004, the statement: “This medicinal product is subject to additional safety monitoring”. The statement: “Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side effects via the internet at www.mhra.gov.uk/yellowcard. Alternatively you can call Freephone 0808 100 3352 (available from 10 a.m. to 2 p.m. Mondays to Fridays) or fill in a paper form available from your local pharmacy.”. The date on which the package leaflet was last revised.

Question 28

HMR 2012:1916 Schedule 27 - patient information leaflet - Paracetamol

Answer 28

If a medicinal product contains paracetamol, unless the product is wholly or mainly intended for children twelve years old or younger, the words “Talk to a doctor at once if you take too much of this medicine even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage”. If a medicinal product contains paracetamol and is wholly or mainly intended for children twelve years old or younger, the words “Talk to a doctor at once if your child takes too much of this medicine even if they seem well. This is because too much paracetamol can cause delayed, serious liver damage”.

Question 29

Packing Eudralex Volume 4, Part 1 Chapter 3 – Premises

Answer 29

Packaging lines specifically designed to avoid mix-ups/cross contamination  tech & op measures Sufficient & orderly storage areas for items required during packaging Printed packaging materials must be stored in safe and secure location – critical

Question 30

Packing Chapter 5 – Production

Answer 30

Chapter 5 – Production Segregation: use barriers to minimise risk of cross- contamination, mix-ups Different products should not be packed in close proximity unless physical segregation. Material & operators flows Labelling of packaging line: Product, Batch number, status, expiry date Line clearances Start-up checks, equipment checks, IPCs, component reconciliation Samples removed from packaging line should not be returned

Question 31

Packing checks

Answer 31

Packaging Security Systems Line clearance: performed according to documented check list, recorded & verified Checks of material brought on line against a materials provision list Camera vision system to detect missing/wrong bulk product – not a sorting tool!! Only one batch online at 1 time Online pharma code check for every foil, carton and PIL Packaging start-up checks Line clean and clearance check Components checked against provision list Packaging set-up checks Check printed/embossed variable data inc. linear/2D barcodes for content & legibility Check machine settings correct/correct programs selected Machine speed, forming & sealing temp & pressures, dwell time, checkweigher set up correctly Packaging challenge checks (Start/End of batch, new day, after eng activity) Blister leak test to verify integrity of blister sealing Vision system check for empty blister pockets Splice checks on joins in PVC/foil reels Pin hole detection (cold form only) Pharmacode reader challenge for foil, carton and PIL Checkweigher reject challenge of ‘heavy’ & ‘light’ carton to detect missing/extra cpts Printed variable data challenged (inc. linear/2D barcodes) Label detector challenged (inc. tamper evident labels, bollini labels, vial/bottle labels)

Question 32

Packaging IPCs (Every 30min to 2hrs: QRA)

Answer 32

Samples taken at designated points Samples NOT returned to line Check sealing, variable data, print quality, right cpts Blister leak test for seal integrity

Question 33

Packing line rejects

Answer 33

Procedures must define if rejects can be reworked Reject bins locked Where they can be out back in the packaging line Must go through required camera systems Higher than normal level reject? Deviation Eqp set-up correct? In-going materials ok? Can you put packs back through the line?

Question 34

Packing line serialisation

Answer 34

How are codes issued to line Reconciliation of codes – should always have more than needed to ensure all packs have codes Start, end and IPC checks Ensure sample packs are recorded as such

Question 35

Packing End of run checks:

Answer 35

Investigate any significant or unusual issues during reconciliation. Secure return of unused material Secure transfer of packaged material End of run line clean and clearance

Question 36

Packaging supplier considerations

Answer 36

Audit Facility location & capacity Manufacturing standards Depend on cpt PS9000 (QMS) Change Control Buildings/Utilities EM Controls Mix-up avoidance controls Artwork management Product security controls QTA Material specs/samplings/COAs Ongoing review

Question 37

Auditing Packaging Supplier – PS9000 (std)

Answer 37

GMP reqs for suppliers of primary packaging materials/artwork/printed packaging materials, includes QMS

Question 38

Artwork Management

Answer 38

Artwork Preparation  Transfer to Supplier  Generate Proof  Customer Approval  Plate Preparation & Control  Printing  Component Supply Artwork management NB. High risk areas where errors can be made: Composite gang printing/Control print media/Line clearances/Code reading/Splices or joins Common artwork challenges include large numbers of artwork to manage and update, different country requirements and multi language packs. Anti-counterfeiting features on packaging – at least one overt & one covert

Question 39

Packaging Equipment Qualification

Answer 39

URS Considerations: Intended equipment use Target production rates Size and location of equipment Safety considerations Line connectivity Type of maintenance required Line product security devices (detection systems/reject mechanisms) GAMP compliance and FDA 21 CFR Part 11 compliance for e/sigs Product and packaging component specs Range of pack presentations AQLs Manning levels (operator skill sets) Training Supplier documentation packages FAT performed pre-delivery. Equipment must comply with Design Specification. Use components intended to run on equipment Training opportunity Documented Opportunity to make changes before equipment is delivered to site! SAT performed at delivery to ensure equipment received against Design Specification On site IQ/OQ Considerations Power/services Utilities (Compressed air/vacuum) Cleaning Change parts Automated systems Procedures, batch documentation, SOPs, training, posted instructions Missing/damaged component or product detection  vision systems/cameras Equipment interfaces Variable data coding Print verification Rejection systems

Question 40

Packaging Equipment PQ/Validation

Answer 40

Variation in equipment processing parameters, especially during primary packaging, may have a significant impact on the integrity and correct functioning of the pack therefore primary and secondary packaging equipment for finished and bulk products should be qualified and validated. Qualification and validation of the equipment used for primary packing should be performed at the min and max operating ranges defined for the CPPs such as: Temperature (forming and sealing) Machine speed Sealing Pressure Dwell time Tablet feed rate All individual pieces of equipment on line must be qualified before validation  PQ is everything running together (end to end) Consider impact of line stoppages (e.g. lunch breaks)  mimic real life during validation runs 100% verification of product quality Review levels and types of defects generated 3 or more run to assess upper/lower/optimum limits of process design space

Question 41

Process Development Considerations (Tablets – Blister)

Answer 41

Mechanism to feed tablets into blister pockets Tablet feed rate Line dwell time Forming temperature Sealing temperature Sealing pressure Line speed Product security verification Correct product Correct fill Blister sealed