Formulation and Processing Flashcards

Question

What are CPP and how are they used?

Answer 1

Critical Process Parameter (CPP) – A process parameter whose variability has an impact on a CQA

Answer 2

ICH Q11 DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES - Describes approaches to developing and understanding the manufacturing process of the drug substance Also refers to ICH Q8, 9 & 10.

Answer 3

ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle - IN DRAFT Works with ICH Q8 to Q11 to facilitate the management of post-approval changes

Answer 4

Ref Annex 9: Controls relating to: - Facility & Equipment design (high quality stainless steel) - Maintenance & Cleaning - Gowning - Training / Education

Answer 5

Potential for contamination (microbiological or chemical or foreign matter or TSE)

Answer 6

Depends on type and usage: Sterile Products: (WFI: Parenteral, Irrigation) or (Purified water: Opthalmic , Nasal or Ear) Non Sterile: Purified Water

Answer 7

Eudralex vol 4. Annex 1: Sterile Medicinal Products: Depends on - Type (sterile/ non sterile?)and usage (route of admin) of product. - Closed or open handling? Terminal sterilisation or aseptic processing? Also depends on the risk profile and specific requirements for each given processing step: Some examples are given in Annex 1. i.e. Operations for terminally sterilised products: A Filling of products, when unusually at risk C Preparation of solutions, when unusually at risk. Filling of products D Preparation of solutions and components for subsequent filling Examples of operations for aseptic preparations: A Aseptic preparation and filling. C Preparation of solutions to be filtered. D Handling of components after washing.

Answer 8

Use requirements in EU GMP Volume 4 Annex 15: 'Qualification & Validation' as a guide.and EMA HBEL guidance. Also other documentation - e.g. ICH Q9, FDA and ISPE. - Multiproduct? - Product(s): Health based exposure limits: PDE assessment, potency, cleanability (solubility etc.) - Equipment: Design, Non product contact v's product contact, hard to clean hot spots, effect of processing (e.g. temperature/ mixing) on cleanability, manual clean v's automated, CIP cycles, Identify sampling points - Processes: procedures, documentation (instructions & records), personnel training & education, Max dirty and clean hold times, clean expiry. - VMP - Crossfunctional team “Walk the plant”. Identify potential contaminants. Understand what can affect your cleaning results and to either engineer out those areas of concern or include them in your cleaning procedure. - Worst case, risk Assessment, matrix/ bracketing approach? - Design and control of cleaning methods - Address issues with sampling and testing - Issues with sampling and testing - Swabbing & Routine methods - Acceptance criteria (for chemical and microbiological residues, as applicable) Y Y - Validation of analytical method. - Cleaning Validation protocol/report - Campaign length validation Y Y (if campaign production approach is applied by the company) - Cleaning verification?

Answer 9

Dispensing & Sieving-> Blending -> Granulation & Milling -> (Drying) -> Compression -> (Film Coating) Key finished product testing: Uniformity of dosage units (Content uniformity- individual assay of 10 tablets, Mass variation -- weigh individually and use single assay value) disintegration (6 tablets in wire basket, dip repeatedly in water at 37oC. must disintegrate within specified time e.g. 15 min). Dissolution (measures amount of active dissolved in a certain time). Hardness testing (sustained load until tablet breaks). Thickness (if coated/ blister packed would be done as IPC). Friability (resistance to abrasion. subject tablet to repeated tumbling/ dropping for specified time then measure loss in weight).

Answer 10

'-Active substance- pharmacological action. -Diluent/ filler- used to increase the bulk content of the dosage form (e.g. lactose, microcrystalline cellulose). -Binder- dry powders or liquid added during wet granulation to promote granules or to promote cohesive compact during direct compression. Also provide mechanical strength to the tablet (e.g. PEG, microcrystalline cellulose). -Disintegrant- added to the formulation as it breaks the dosage form into smaller particles which have greater surface area and will increase the dissolution of the drug. (E.g.. Starch, clay). -Lubricants- used to reduce the friction between the tablet and die cavity when the tablet die cavity is getting ejected (e.g. Stearic acid, PEG). - Glidants -used to improve the flow property of the formulation, it reduces the friction between the particles and between the hopper and particles and die cavity (e.g. Talc, colloidal silicon dioxide). - Flavourants- to improve the flavour or give a pleasant taste to the formulation, mostly for chewable/dissolving tablets. (E.g. food flavourings). - Colorants- added to increase the patent compliance or for identification of the formulation (e.g food dyes)

Answer 11

1.Enteric coated tablet: intended to be insoluble in the stomach ph and get solublized in the intestinal ph. (polymers like cellulose acetate phthalate, polyvinyl acetyl phthalate, HPMC phthalate are used- these acid esters remain insoluble in the acidic ph below 4 and they get hydrated in the ph range of 4 to 6 i.e. in duodenum, when the drug molecule enters into the intestines where the ph is in the range of 7 to 8 where these polymers get ionized, and the ester bonds between them is broken by the esterase present in the intestinal fluid.) 2.Film coated :give a smooth finish to the tablets and to protect the tablet from the external atmospheric conditions, plasticizer and a surfactant (for even spreading) is used. coating are hydroxyl propyl cellulose, HPMC. 3.Effervescent tablets: intended to produce effervescence when they come in contact with the water or liquid. formulation of these tablets includes organic acid and bicarbonates. prepared by the direct compression or by compaction of the granules; wet granulation method is very seldom used.

Answer 12

* Protect tablet from handling, light/ moisture * Conceal unpalatable taste and aid swallowing * Colour and aid identification, improve appearance * Improve mechanical handling in packaging and dispensing * To provide enteric or controlled release properties

Answer 13

Granulation has many advantages including dust free formulation, improved flowability, stability, eliminates poor content uniformity, improved bioavailability of API etc. During dry granulation, the particle size is enhanced by aggregating the particles by roller compaction and then milling to the desired size, resulting in improved content uniformity, dissolution times, and stability. Slugging: Compress powder -> large rough tablet->mill-> screen/sieve-> uniform granule -> compress <>> Roller Compaction: Pass powder through roller -> thin sheets/ribbons->mill-> screen/sieve-> uniform granule -> compress During wet granulation, liquid binders or adhesives are added to the lactose and active mixture, usually by blending. The mixture is then dried and sized, and compressed into tablets. There by producing a dust free formula plus improving flowability, eliminating poor content uniformity and the ability to encapsulate a poorly soluble API.

Answer 14

*Capping (upper/ lower separates) *Lamination (separate into ≥ 2 horizontal layers) * Chipping (break at edges) * Cracking (small fine cracks) * Sticking (to die) * Picking (rubbed offby punch face) * Mottling (uneven colour)

Answer 15

1) Solution: Single phase- Solvent + Solute 2) Suspension: Liquid continuous phase + 2nd solid phase suspended as particles 3) Emulsion: Liquid continuous phase + 2nd phase consisting of globules in immiscible liquid emulsified

Answer 16

Very product dependant! Example oral product: Dispense ingredients -> Mixing -> Add solvent -> Filling Control: Order of ingredients, mixing (no dead legs/ accumulation, time and temp important, continuous mixing avoids separation), homogeneity (especially in long filling lines/ start/stop), Cleaning (difficult for viscous products, accumulation in nozzles etc.), Deposition (if allowed to deposit or mixing is inadequate= problem)

Answer 17

* Solvent: Aqueous (e.g. relevant pharma grade water), Non aqueous (alcohol, flycol, Dimethyl Sulphoxide, Oils) * Solubility Enhancer * pH Adjustment * Co solvent (to alter polarity) * Surfactant (to lower surface tension between liquids. E.g. Tween/ Polysorbate * Buffers (to control pH, maintain solubility and stability e.g. citrates, gluconates, lactates, phosphates, acetates) * Isotonic (for non oral, especially mucous admin- to reduce irritation) * Viscosity enhancer (assist use of spoon/ device e.g.povidone, cellulose systems) * Taste Mask (for oral products e.g. food flavourings) * Sweetening agent (for oral products, increase viscosity, flavour & soothing properties e.g. saccharin, aspartame) * Flavouring (for oral products e.g. food flavourings) * Colours (for oral products e.g. identification, consumer trend). * Wetting agent (for suspension products, reduce surface tension) * Suspending agent (for suspension products, control flocculation of particles) * Emulsifying agent (for emulsion products, e.g. surfactants to reduce surface tension and promote mixing) (preservatives- e.g. antioxidants etc. must be included for non sterile and multi use sterile products. “Inclusion of antimicrobial preservatives or antioxidants in a finished product needs special justification. Avoid wherever possible ))

Answer 18

Example product: Dispense -> Mix,,,,, heat (40-70Oc) Add solvent e.g. water/oil via vacuum-> Cool-> Add sensitive materials -> Filling -> defined storage (order of addition and mixing is important for stability and homogeneity) Key Finished Product Testing: Physical (appearance, pH, viscosity, water content, wt/ml), Analytical (Active assay, preservative), Micro (Bacteria <200cfu/gm, Yest & Mould <20 cfu/ gm, Specified organisms)

Answer 19

Eudralex volume 4 Annex 9: MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTS Premises and equipment 1. Closed systems for processing and transfer. Areas where the products or open clean containers are exposed should normally be effectively ventilated with filtered air. 2. Tanks, containers, pipework and pumps designed and installed so that they may be readily cleaned and if necessary sanitised. Minimise dead-legs or sites where residues can accumulate and promote micro 3. Avoid glass apparatus wherever possible. High quality stainless steel is material of choice for product contact. Production 4. Chemical and microbiological quality of water used in production should be specified and monitored. After any chemical sanitisation of the water systems, a validated flushing procedure should be followed to ensure sanitising agent has been effectively removed. 5. Quality of materials received in bulk tankers should be checked before transfer to bulk storage tanks. 6. Care should be taken when transferring via pipelines to ensure delivered to their correct destination. 7. Materials likely to shed fibres or other contaminants (e.g. cardboard or wood pallet)s, should not enter areas where products or clean containers are exposed. 8. Maintain homogeneity of mixtures, suspensions, etc. during filling. Mixing and filling processes validated. Special care taken at the beginning of a filling process, after stoppages and at the end. 9. Maximum bulk storage time and storage conditions specified and adhered to.

Answer 20

Pre-use Post Sterilisation Integrity Testing. - common industry practice but difficult to perform without breaching systm sterility. Mehtods: flush bag, catch-can or filter arrangement. Alternatives - test prior to use on site or risk assessment to justify. More detail expected in revised Annex 1.

Answer 21

Closed Isolator: - Sealed unit - Positive pressure & Turbulent airflow (typical) - Pressure differential is critrical - Mostly small unit operations, slow lines, IMPs or potent materials. RABS (Restricted Access Barrier Systems) - Permanently open portals to surrounding envirionment - Pressure differential (often up to 50Pa) - Design is critical. FDA expect min grade B for RABS - Unidirectional air flow. Flow over critical zone sweeps contamination away. - Challenge via smoke studies and routine monitoring. - Mostly process line, complex lines including washing , depyro, filling & stropping

Answer 22

Freeze material in solution -> cause ice to 'sublime' directly -> vapour at low pressure (while supplying heat) -> Primary then secondary drying. Praactical concernsL Backfill chamber with inert gas (sterile filtered), Stoppering vials , Balancing chamber pressure , Removing load , Defrost condenser < regularly clean>, Clean & sterilise lyophiliser . proteins are very vulnerable to freezing therefore need good controls during freezing. Water removed =>

Answer 23

Eudralex volume 4: Part 1 : Chapter 3: Premises & Equioment Dedicated facilities are required for manufacturing when a medicinal product presents a risk because: i. the risk cannot be adequately controlled by operational and/ or technical measures, ii. scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta lactams) or iii. relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method. Further guidance can be found in Chapter 5 and in Annexes 2, 3, 4, 5 & 6.

Answer 24

Much the same as to implement & qualify any new process: * Guidance; Eudralex volume 4 Chapter 3 :Premise & Equipment, Annex 15: Qualification & Validation, Annex 11: Computerised Systems. ICH Q8-11 as relevant. 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 <<>>-> 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.

Answer 25

Raise a deviation, stop packing with the current line and isolate batches that have been packed using this line. Any currently in warehouse to be blocked until investigation is concluded. 1) Where are the pink tablets coming from? What are they and what is the white product mfr? Review of batch records to assess reconciliation of product. Assessment of line clearance and personnel that carried it out. Is video footage available of the packing line? Review of packaging line risk assessment. RCA on how the product could have got stuck there. 2) Patient safety - impact of patient not getting white tablet, and the impact of if they received the pink tablet. Need to engage medical team/PVQP to carry out assessment. 3) Regulatory impact - There is a risk of recall, consulting with the DMRC on most appropriate action however full investigation carried out prior.

Answer 26

- Raise Change control, went through the key areas – regulatory impact, facility, utilities, types of product, environment, equipment, people and ensuring we have sufficient knowledge to cover this new dosage form. Raise change control - engage all stake holders and carry out an impact assessment considering the following: 1) Manufacturing - impact assessment on current product, where is the manufacturing facility for new creams and ointments, facility set up - material flow vs personnel flow, grades of each room, air flow patterns and air changes and pressure differentials, utilities into the rooms, 2) Validation of AHU and facility as well as product based validations and qualification of newly purchased equipment 3) Regulatory impact - acquiring of licences, assessment of facility and approval by MHRA prior to any production. 4) Safety, Quality and Efficacy impact - how will it fit into the QMS, new procedures and documentation will have to be drawn up, personnel - enough SME's or external contractors required - qualifying them, personnel recruitment and training

Answer 27

a. Pirfenidone tablets - dispensing, sifted API, MCC and croscarmellose through 24 mesh sieve, mixed at set speed and chopper off, dry granulation using providone (set mixing speed and chopper on), drying based on LOD and set inlet temp, dry screening - until pass through set screen size, if not milled and rescreened, sift extragranulaor materials, blended, compressed, coated and packed b. sifting - mesh size defined dry mix - mixing speed and chopper off granulation - mixing speed and chopper on drying - LOD 1.5 - 3% Dry screening - screen size and milling until pass through 24 mesh blending - speed and time compression - IPC's at set time points looking at physical appearance, weight, thickness, hardness, disintegration time and friability coating - average weight gain of tablets packaging - leak test

Answer 28

Raise change control - engage all stake holders and carry out an impact assessment considering the following: 1) Manufacturing - impact assessment on current product, where is the manufacturing facility for cough syrup mfr, cross-contamination risk, facility set up - material flow vs personnel flow, grades of each room, air flow patterns and air changes and pressure differentials, utilities into the rooms, 2) Validation of AHU and facility as well as product based validations and qualification of newly purchased equipment 3) Regulatory impact - acquiring of licences, assessment of facility and approval by MHRA prior to any production. 4) Safety, Quality and Efficacy impact - how will it fit into the QMS, new procedures and documentation will have to be drawn up, personnel - enough SME's or external contractors required - qualifying them, personnel recruitment and training

Answer 29

Pediatric Tablets: Dosage Strength Taste and Flavor Size and Shape Pediatric Syrups: Dosage Accuracy Palatability Viscosity Preservative-Free Options Stability

Answer 30

active substance, bulking agent, binder, disintegrate, lubricant, glidant. colour, sweetener and film coating a. if the product is indicated in children and at what strengths - helps to decide strength of liquid formulation. Depends on type of product on the type of liquid e.g. syrup, solution or suspension. b. solution - solute e.g. api and excipients such as solubility enhancer, buffer, flavour, preservative. solvent -dissolve solute c. suspension - addition to solution, suspending agent, viscosity enhancer, wetting agent. flocculated or deflocculated

Answer 31

Quality Target Product Profile

Answer 32

Key changes focus on the following: - Use of quality risk management (QRM) approach. - Developing a holistic, facility-wide contamination - control strategy (CCS). - Deploying a continuous monitoring approach for grade A environmental monitoring. CCS - A planned set of controls for microorganisms, endotoxin/pyrogen and particles, derived from current product and process understanding that assures process performance and product quality. Covers: - active substance, - excipient - drug product materials and components, - facility and equipment operating conditions, - in-process controls, - finished product specifications, - associated methods and frequency of monitoring and control.

Answer 33

cream sparates into distinct phases, resulting in the appearance of visible cracks Areas to investigate: Formulation Ingredients: Ingredients are compatible. Interactions between different components, such as emulsifiers, stabilizers, and active ingredients. Emulsion Stability: Evaluate the stability of the emulsion, which is a key factor in preventing cracking. Examine the emulsification process and the choice of emulsifiers to ensure a stable and uniform distribution of oil and water phases. pH Levels Storage Conditions: Assess whether the cream is stored under appropriate conditions. Extreme temperatures affect stability Manufacturing Process: Mixing, homogenization, and cooling processes. Microbial Contamination

Answer 34

Talked about raw materials, facility and equipment design, didn’t get to gowning or cleaning A) Know level of bioburden going into your product B) Talked through the test, listed all the organisms and said the spec is a % log reduction and it’s per product type in the pharmacopeia C) Said no formal requirement although it depended on the equipment design. If it was open I would look for grade C at point of fill or grade D if closed D) Pharmacopeia and told the spec

Answer 35

It’s unusual and would want to determine root cause A) I would increase frequency of change and assess central bank of HEPAs, look at air changes, pressure differentials and products made in the room. That I’d want a change control raised B) Not for filter change but would want to ensure any rebalancing hadn’t effected other areas C) BMS D) From the time alarm points were triggered E) Particulates and environmental monitoring

Answer 36

a. all personnel are gowned to grade B expectations, environmental controls in place, interlocking doors, smooth impervious surfaces, no water taps or shelves b. Annex 15 - DQ cleanroom design

Answer 37

a. ICH Q9, Chapter 3, Chapter 5, Annex 1 (Room Classification), Annex 10 (MDIs), Annex 11 (If computer system in place), Annex 15 b. Risk Assessment based approach covering air flows, cascades, pressure differentials, product and personnel flows, talked about the facility we had just designed and how we tried to minimise product movements and closed systems etc c. Limits at rest for 0.5um - 3520000 Air sampling - 200cfu/m3 Settle plates - 100 cfu/4hrs Contact plates - 50 cfu/plate

Answer 38

Process for cream 1) White soft paraffin, Liquid paraffin heated. addition of API, water and aqueous component (e.g. preservative). Mix and homogenise, cookl sotre and pack 2) IPC - heating temoperatures appearance check 3) Risk of water therefore pseudo risk, where the open process parts are 4) if opening processing or sterile cream 5) unified dose, easy treatment, non-irritant 6) preservative efficacy test - challenge organisms in monograph, added to the formulation and sampled at set time points. No regrowth and 1-3 log reduction daily expected. 7) at the aquous phase 8) immunocompromised patients, eye ointment or reduced preservative added.

Answer 39

pre-use post sterilisation integrity test The integrity of the sterilised filter assembly should be verified by integrity testing before use to check for damage and loss of integrity caused by the filter preparation prior to use.

Answer 40

Raise a change control - considers the following topics: 1) Regulatory - new opth suite, variation to licence and inspection fro MHRA 2) Facility - build mfr suit, sterile and complies to annex 1, strict temp and humidity control, consider air flow and product flow, dedicated HVAC system, Pa differentials 3) People - training (aseptic practice), recruit, QP experience in Annex 1?, gowning 4) Packaging - dedicated area - grade A where exposed priduct. 5) Testing - AMT, vendor assurance - audit, TA Aseptic or terminal sterilisation? CQA's Sterility: pH Level: Osmolality: Clarity and Opalescence: Viscosity: Preservative Content: Droplet Size and Uniformity: Compatibility with Contact Lenses: Particulate Matter: Container-Closure System Compatibility: Microbial Limits: Content Uniformity:

Formulation and Processing Flashcards

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