Medchem and packaging Flashcards
What is the skin anatomy?
Epidermins: Thin sheet outer layer
Dermis: collagen + elastic tissue + reticular fibers
Subcutaneous tissue
What is the route of drug penetrate the skin?
Surface: drug dissolves + diffuses + releases from vehicle
Partition/diffusion - all the way to the systemic circulation
What are the different type of bases for hydrophobic ointments?
Hydrocarbon bases:
Hard paraffin BP + Yellow and white soft paraffin BP
Immiscible with water and low water absorbing capactiy
Form an occlusive barrier - hydrate and encourage absorption
Not prone to oxidation
Parafffin can be sterilised by dry heat - i.e. eye ointment and many antibiotics
Messy and stain clothing
Absorption base:
absorb water
Water in oil emulsions i.e. lanolin alcohols
less occlusive - increaseing water absorptive power
What is ideal properties of a drug for rectal delivery?
Good solubility and lipophilicity + substantialy unionised at pH 7.5
Slower absorption rate - lower peak plasma conc
Lipophillic durgs best formulated in a hydrophillic suppository base and
What are the advantages of using glass as a packaging material?
Clear Strong Stable + heat resistance Impermeable Resistant to acid Canb e treated to modify the surfaces Hygienic Sterilisable Economic
What are the disadvantages of using glass as a packaging material?
Not maleable or ductile Breakable Difficult to work Attached by alkali Sensitive to mechanical handling Heavy Limited range of colours Transparent to visible light + some UV
What are the properties of glass?
super cooled liquid
Prmary constituesnt of silica and mineral quartz
Pure silica forms glass when heated
Silicon dioxide polymerise with strong covalent bonds - matrix
Great tensile strength
Fragile and not ductile
Thermal resistant - high softening point (1600dec)
Transparaent to visible and some UV
Very resistant to acid but attached by alkali - forms soluble sodium silicates at pH >8
Why is soda (sodium carbonate) added to the glass?
reduces softening point of glass to approx 600 dec
Soda alone reduces chemical resistance - susceptible to degradation
Why is lime added to glass?
Replace some of the sodium ions with calcium and closing up the matrix in the glass
Hence improves chemical resistance
Soda lime glass - sodium ions in the matrix can diffuse out of the glas into aqueous solutions - leaching
Problem for alkali sensitive compounds i.e. alkaloids
Microfractures and separation of flakes of glass
Sodium salts can cause flaking i.e. sodium chloride, bicarbonate, citrate, lactate and gluconate
What are the Pharmacopoeial glass types?
PhEur/USP Type I: Neutral glass (Borosilicate) - parenteral use
PhEur/USP Type II: Soda lime Silica glass - Aq parenteral use where pH is lower than 7 (Surface treated: sulphated or silicon coated)
PhEur/USP Type III: Soda lime Silica - Aq oral, not for parenteral
USP-NP: Soda lime silica - low hydrolytic resistance - non-aq solids for oral use
Special considerations in glass bottles manufacturing.
Glass formation and quality in the furnace
Lubricants for parison graphite based - burned off in Lehr
Quality of tools
Spray outside of bottles “conveyor” lubricants - contamination inside?
Temperature control
Final handling of containers - clean when come out from Lehr
What is vulcanisation?
General term involves compounding of rubber with a variety of additives i.e. curing agent and compressing it in metal moulds at elevated temp
Invovles corss-linking between polyisoprene chains
Improves heat stability of the rubber and its resistance to organic solvents
What are the disadvantages of natural rubber?
High permeability to gas and water Ages rapidly/cracking of surface Poor thermal stability Susceptible to microbial attack Leaches additives - form haze in stored solutions Sorbs some compounds i.e. preservatives
What are the main types of rubber?
Natural Rubber
Tapping the tree Hevea brasiliensis
Highly elastic at room temp
Soluble in a variety of organic solvents
Soft plastic rubers formed by vulcanisation
Synthetic Rubber
Generally more resistant to chemcia nd less permeale to air/water
less inclided to leach
Poor elastic properties
i.e. butyl, halobutul and silicone rubbers
What are the typical ingredients of a rubber formulation?
Elastomer i.e. natural rubber + Rutyl Rubber + EPDM
Curing agent/vulcanising agent: i.e. Sulpur + organic peroxide + high energy radiation (cross link)
Accelerators i.e. complex organic compounds (control curing process)
Activators: i.e. ZnO + Stearic Acid (Activate the accelerator)
Plasticisers i.e. Di-octyl Phthalate + LMW polythene (soften the rubber)
Protecting agents i.e. Waxes + Phenolic compounds (prevent ageing)
Colorants i.e. Inert materials - FeO2 + TiO2 + carbon black
Extender/fillers i.e. Oils + china clay (obtain corect physical properties
What are the typical pharmacopoeial testing for closures?
There are 12 typical tests: Appearance/characters Acidity/alkalinity or pH Change Absorbance Reducing substances Extractable heavy metals Extractable zinc Ammonium Residue on evaporation Volatile sulphides Penetrability Fragmentation Self sealing test dimension i.e. min dia internal seal of stopper vs max neck dia of bottle
What are the typical pharmacopoeial testing for glass?
See Ph Eur: 3.2.1. Glass containers for pharmaceutical use
Type I & II: test A; hydrolytic resistance of the inner surfaces of glass containers
(surface test)
Type I glass containers (to distinguish from type II and type III glass containers) Test B (glass grains test) or test C (etching test)
Type I and type II glass containers where it is necessary to determine whether the high hydrolytic resistance is due to the chemical composition or to the surface treatment Tests A and B, or tests A and C
test B. hydrolytic resistance of glass grains (glass grains test)
test C. to determine whether the containers have been surface-treated (etching test)
What are the major types of plastics?
Thermosets
i.e. bakelite
Freq used for caps and other items - not in direct contact
produced by a condensation reaction
Thermoplastics
consists of linear polymers - addition polymerisation of identical compounds
Do not cross link but aggregates with VDW bonds
What are the main types of polyethylene plastics?
High, medium and low density
Most verstile and useful of all plastics i.e. films, closures and containers
What are the advantages of polyethylene?
Free from additives, impermeable to water, resistance to chem and solvents, translucent and flexible
Increase in density decrease felxibility but increase barrier properties and more heat resistant
What are the disadvantages of polyethylene?
LDP: substantial permeability to atmospheric gases i.e O2
permeability to essential oils - cause swelling
Permeability of organic solvents - labels !!
Tendancy to sorb certain compoudns i.e. preservatives
Liable to stress cracking
What are the advantages of Polypropylene?
Similar to polyethylene
Tertiary carbon - 0.05% antioxidant prevent degradation during MFG
Lightest plastic
Softens at 150deg c - autoclave
better physical strenght than LDP
less inclined to stress cracking and sorption of preservatives
Translucency and permeability to water and atm gases - slightly worse than HDP
What are the properties of Polyvinyl Chloride (PVC)?
UPVC - blister packs and plasticised grades - infusion bags
Good clearity and chmical resistance
High permeability to water vapour
Low metling point - need stabiliser
Poosible leaching of additives i.e. DEHP
More chemically resistant than polyethylene and equivalent sorption
Rigid PVC is less permeabler to gasses than HDP
Plasticised PVC siomilar to polypropylene
What are the disadvantages of PVC?
Much more permeable to water vapour
dissolved by some organic solvents i.e. acetone
poor native thermal stability - soften at 80 dec
stabilisers can increase heat resistance
Leaching hazard posed by the presence of DEHP - extracted by lipophilic materials - blood and alcohol
What is PTFE?
Polychlorotrifluoroethylene (Alcar)
Better barrier prorperties than PVC - more expensive
Blister packs for moisture sensitive products
What is PET?
Polyethylene Terephthalate
high tensile sterngth
Commonly used in soft drinks industry for carbonated drinks
Recyclable
Resistant to dilute acids, alkalis and oils/solvents
What are the common additives used in plastics MFG?
Antioxidants - phenolic compounds (BHT)- leaching
Heat Stabilisers: metallic stearates (PVC)
Lubricants: internal and external - Zn Stearates and silicones
Plasticisers: reduce brittleness - extractables
Fillers: reduce flexibility - improve resistance + heat stability
Colourants: dyes bleed out - pigments do not
What are the purposes of adding additives to plastics?
7 reasons Assist processing Modify bulk mechanical properties Reduce formulation costs Modify surface properties Modify optical properties Improve ageing
What are the properties of aluminum as a packaging material?
impermeable to light, liquids, water vapour, gases
does not support bacterial growth
can be sterilised all widley used methods
25 micron - below this thickness - pin holes
What are the risk control measures in a packaging line?
Avoidance of composite gang printing Adequate control of printing media Celarance of previous work, set up, or extraneous materials from the line Use of code reading devices Avoidance of Splices
Pressurised Metered Dose Inhalers
Micronised powder suspended in propellant
Pulmonary secretion are pH 7.4
Surfactants used in the formulation (oleic aicd or lecithin)
Design of platic mouthpiece/valve are very important - correct droplet size and velocity
MDI filling
Orginal CFC - now HFA (Hydrofluoroalkane)
EU GMP Annex 10
EM at filling: Class D + propellant filtered 0.2micron
Check weight (100%)
Cleanliness of valves, cans
Care needed for leak testing - water bath method not used - store and check weigh
Summary of Annex 8: sampling of starting materials
Packaging materials:
Quantity received
Quality requried
Nature of the material
Production method - knowledge of supplier
Knowledge fo the QA system of the packaging material supplier based on audit
Number of samples - stats + sampling plan
Sampling environment:
Specifications: appropriately authorised +dated
Description + Direction for sampling and testing + Qualitative and quantitative req/limit + Storage conditions and precautions + Max period of storage
Testing: Visual appearance + ID/purity + Biologcial tests + Physical/dimention + proof/copy checking+colour
Testing record: kept 2 years 2003.94.EC
Status label
Why do we carry out stability testing?
Evaluate: Content of active Purity: impurites and degradation Organoleptic properties Physico-chem properties Micro status
What are the considerations of toxic degradation products?
Clinical use Max daily dose Duration of treatment Age group Women of child bearing potential Adverse effect from the degradation product?
What are the different types of stability testing?
3 main types:
Stress testing: force degradation to take place
Accelerated testing: incerase the rate of chem degradation or physical change of a drug substance - exaggerated storage condition
Long term: cover expected duration of the shelf life and retest period
What are the requirements on stability testing on drug products in terms of batch size?
3 representative batches
2 batches pilot scale - 1 may be smaller
Oral pilot: min 10% or 100k units
Drug substances: 3 batches where possible
12 month long term + 6 month accelerated at the time of submission
Storage condition for stability testing
Long term: 25 deg / 60 RH or 30 deg / 65 RH
Accelerated: 40 deg / 75 RH
How would you extraolate shelf life based on data?
Little/no change at accelerated + long term: x 2, max 12/12
Some change/variability: with stats analysis (x2, max 12/12); no stats (x1.5, Max 6/12)
Significant change at accelerated only: wikth stats (x1.5. Max 6/12); no stats (3/12)
Significant change at accelerated and long term: no extrapolation
What are the requirements of post approval stability commitment based on ICH guidance?
Commitment batches: MFG batches for which the stability studies are initiated or completed post approval through a commitment made in the reg application
Looking for 3 batches on long term and 6 months accelerated
What are the differences in matrix and bracketing?
Matrixing: design of a stability schedule - rotate through time points
Bracketing: rotate through strengths/pack size
What are the main changes to labelling as a result of 2004.27.EC?
Introduction of article 56a: Braille format and PIL for blinded and partially sighted
Amend Art 59: new order of PIL to bring in line with SPC
Further amend Art 59 require consultation with target patient groups - user testing
What are the standard labelling requirements and where would you find it?
Art 54 2001.83.EC
14 requirements
1. Name + strength + form (Braille)
2. Qualitative and quantitative statement of the API per dose unit
3. Pharmaceutical form and contents by wt, volume or number of doses
4. List of excipients known to have a recognised effect (all excipients for injectables, topical or ocular preparations)
5. Method and route of adminstration
6. Keep out of reach and sight of children
7. Any special warning reuqired by the authorisation
8. Expiry date (mm+yy)
9. Storage conditions
10. Any special precautions for disposal of unused product or waste materials
11. Name and address of the MA holder and where applicable his representative
12. MA number
13. Batch number
14. Where the product is non-prescritpoin - instruction for use
What are the labelling requirement for blister packs?
- Name + strength + form
- Expiry date
- Name of MAH
- Batch number
What are the labelling requirement of small immediate packaging units?
- Name + strength + form
- Contents by wt, vol or unit
- Method of administration
- Expiry date
- Batch number
What are the additional labelling requirement in the UK?
GSL Paracetamol and aspirin: Do not give to children undre 16
P: Warning do not exceed the stated dose
Ephidrine: Asthmatics consult doctor before taking
Antihistamine: warning may cause drawsiness + avoid alc drink
Embrocation - for external use only
Hexachlorophane: not to be used for babies
What is format of a PIL?
- ID of the medicinal product
- Tx indications
- List of info before taking: CI + Precautions + interaction + special warnings
- Instruction for proper use: dosage + route + Freq of admin + treatment duration + OD Tx + miss dose + withdrawal + constult pharm/doc
- Description of ADR
- Ref to the expiry date:
- Where the medicinal product is authorised
- Date of revision
What are the Annex 13 label requirements?
- Name + add + tel no. of sponsor/CRO/PI (main contact)
- Pharmaceutical form + route of admin + quantity of dosage units + strength/potency
- BN / code
- Trial ref code - id trail, site, investigaotr and sponsor
- Trial subject ID or number
- Name of the investigator
- Direction of use
- For clinical trial use only
- Storage conditions
- Period of use / expiry
- Keep out of reach of children
What are the GMP considerations in a packaging operation?
Premises:
Avoid mix up or cross contamination
storage - allow orderly stroage of all materials
Special attention to be paid to printed materials
? Straight line, dedicated room
Separate exposed product from the paper cartons etc
Product protection: creams/ointment/sterile/low bioburden
Segregation: physical barriers + risk based approach (scheduling and campaign working)
Product:
Label asap
Protect product where needed i.e. creams, liquids, and ointment
Pack design to aid detection of mixups
Use item and version codes
Coding system: Pharmacode + Dot matrix + OCR + OCV
Chp 5: check code reader is working
Hand packing: Use edge codes + check new reel for splices for reel feed labels, leaflets and foils + rigorous reconciliation limits
Process:
Treat printed materials the same as RM
Start up checks:
Area clean and clear
Line clearance
Intermediate and bulk products kept under appropriate conditions
Critical process validated
display name and batch number
check on delivery - printed materials
IPC:
General appearance of the packages
Whether the packages are complete
Whether the correct products and packaging materials are used
whether any over-printing is correct
correct functioning of line monitors
Sample taken away from the packaging line should not be returned
Other process specific checks: integrity + torque + blister seal checks
What are the likely physiological effects of injecting particles IV?
Less than 3 micron: phagocytosed
More than 12 micron: trapped mechanically
Blockage of lung capillaries: stimulate inflammatory response + granulomata
Thrombophlebilits
Sepsis
What are the pharmacopoeial requirement for inspection?
Ephur: practically free - visual inspection
100% visual inspection of all injections
Visual standard = practically free
white&black background and lighting
5s against white background and 5s against black background
Sub vis: t be 100% inspected: test manually
What are the four areas considered In a Machine and System Risk Analysis?
Ethical or GMP risk: Risk of recall
Market/business risk: Cosmetic defects and throughput of machine
Operational Risk: Functional testing of the machine
Safety or H&S risk: Risk to operator
Ethical risks - validated 100%
What are the main risks involved in artwork gerenation?
Font management - bleed out font Multiple approaval cycles & amend loops Client brief (component collation and validation) Version control Compliance with MA + variation Conversion error: between versions and software i.e. word to Quark or illustrator Cut & paste errors from base file Software compatibility Multilingual packs Proof reader validation Space allowance: truth copy vs artwork Braille application Potential ISO 9001 conflict Reliance on Text Verification Tool and other text check tools Printing plates Pharmaspecific requirement Technical agreemtns Text errors Font size and line weights Untrained personnel
How would you validate a packaging line?
Power services: confirm requirement
Compressed air + vacuum: confirm quality
Environment: achived EM conditions?
Cleaning: Materials of construction + Contact parts with drug + Ease of changeovers + dust traps + product traps
Chagne parts: Available + Compatible + meet spec
Overload, mechanical device jam: meet spec
Automated sys: PLC / MMI interface GAMP (meet spec + effective control + simulate power on/off + critical instrument + control/security in action)
Equipment interfaces: interface with other machines
Limit detectors, pressure detectors, level detetors: confirm critical instrument fitted, correct operation
Missing or damaged components and product detection
What are the common cleaning validation limits?
10ppm
1/1000 therapeutical dose
visual clean
How would you devise a cleaning validation matrix?
Evaluate overall cleaning requirements Select worst case Toxicity Acceptance limits Physical characteristics - solubility Usage: high usage needs more often cleaing Concentration of active Previous resutls, difficulties in meeting limit
What are the QC tests of pacakaging materials?
Contact:
Base materials: (PVC + PVDC + PE + Trilaminates) Description + ID by IR +thickness + width CoA
pots/bottles/lits: Description + ID + embossing + outer dia + external height + CoA
Bags: Description + ID + CoA
Contact and printed materials
Foil: Description + thickness + width + IR of heat seal lacquer + visual comparison of printed text + pentone colour ref + CoA
Printed materials
Labels/leaftlets/label leaflets/cartons: Description + visual comparison + Pantone Ref + CoA
What are the automatic monitoring system in use on a packaging line?
Missing tablets detectors:
B/W system: Detect missing tab and missing fragments of >6% + 100% inspect + only see plan of tablet
Colour system: Same as B/W + can tell different colour tablets
Electronic tablet counter: Count tablets put in container + IR beam
Pharmacode Readers: Code each component (foil + cartons + leaflets + labels + label leaflets) + made up of think thin bars (decimal code) + enter code at start
All pharmacodes are challenged periodically during the packing run
Printers/Print detection: online printing
Embossing: added to the blister with metal type tool + check orientation + pressure
Thermal/laser jet coders using dot matrix
Blob detector: look for presence of ink in a certain location
OCR: check correct coding applied + with laser coder
Missing label detector - slat lines: looks for label
Checkweigher: reject lightest component i.e. leaflet + challenge at intervals
List typical IPCs on a typical packaging line
Bulk product appearance and id Bulk product BN Quantity per container (auto) PVC/PVDC Foil ref Foil critical text Coding infomration on blister Challenge foil pharmacode (auto) Challenge missign tab detector (auto) Leaflet ref code Leaflet crtical text Challenge leaflet pharmacode (auto) Remove leaflet - challenge checkweigher (auto) Carton ref no Carton critical text Coding info on carton Challenge carton pharmacode (auto) High stack (too many blisters) (auto) Low stack (too few blisters) (auto) Quanitty per shrinkwrap Palletiser layout Record any engineering activties Ref any QERs
How would you carry out a line clearance procedure?
Finish packing operation - first operator line is free from product and packaging materials
Second operator perform second check
If rogue product / component found - photo and annotated
