Formulation and Processing

Question 1

What are the Key Quality Requirements for Sterile Products?

Answer 1

1. Sterility (complete absence of viable organisms)
2. Apyrogenic
3. Low in particulates
4. Container Integrity Maintained

Question 2

What are the Critical Processing Parameters for Sterile Products?

Answer 2

People: (source of ~80% particulate contamination in cleanroom & most micro contamination) <aseptic>
Equipment: for Sterilisation <e.g. steam/ air quality/ time/ pressure/filter>
Materials: (e.g. bioburden/ endotoxin controls) <temperature>
method: of sterilisation and filling, for Pack Integrity <e.g. filling/ stopping etc.>
Filling Environment: <temperature/ humidity></temperature></aseptic>

Question 3

What is a Sterility Assurance Level (SAL)?

Answer 3

SAL= the probablity of a viable org being present in a load. 10-6 accepted as sterile by regulatory bodies

Question 4

How can you assure quality in sterile manufacture?

Answer 4

• Minimise Challenge
• Prevent Recontamination

Question 5

What are the principle sterilisation approaches used in manufacture of sterile pharma products?

Answer 5

1. Terminal Sterilisation - prefered option
   Achieved by: Steam sterilisation (autoclave), Dry Heat, radiation < or Ethylene oxide fumigation for containers>
   Typical Process: Bulk, remove particles and reduce bioburden, fill in grade C into depyrogenated containers, sterilise, seal, check integrity
2. Aseptic Processing
   Achieved by: Control of PEMME
   Typical Process: Bulk, Sterile Filter to remove particles and sterilise, fill in grade A into depyrogenated containers, seal, check integrity

Question 6

What environmental standards are there for cleanrooms?

Answer 6

Go look at: * ISO 14644
* EU: Eudralex Vol 4. Annex 1
- Viable and Particulates

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products :
  Grade A: filling zone, A uni-directional air flow
  Grade B: background environment for the grade A zone.
  Grade C: Filling of terminally sterilised product. Preparation of solutions to be filtered for aseptic
  Grade D: Preparation of solutions for terminally sterilised products. Handeling components post clean

Question 7

What are the facility requirements for manufacture of sterile products?

Answer 7

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products :
• Smooth surfaces, airlocks with interlocking doors, changing room should in the at-rest state be the same grade as the area into which it leads, washing facilities in the first stage of the changing rooms
  -A filtered air supply maintaining a pressure differential of 10 - 15 pascals (except where unsafe)
• Air-flow patterns

Question 8

What would you expect for an Environmental Monitoring (EM) programme in a sterile product facility?

Answer 8

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products : EM is maintaining a controlled environment re: Micro, particles, temperature, humidity.
• Grade A : Airborne particulate (particle counting) for the full duration of critical processing. similar system for Grade B zones, lower frequency.
• Non Viable sites per ISO 14644, Viables based on a risk.
• Grade C and D monitoring based on QRM.

Question 9

Describe the EU cleanroom classifications

Answer 9

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products :
  Grade A: filling zone, A uni-directional air flow
  Grade B: background environment for the grade A zone.
  Grade C: Filling of terminally sterilised product. Preparation of solutions to be filtered for aseptic
  Grade D: Preparation of solutions for terminally sterilised products. Handeling components post clean

Question 10

What are the media fills, when are they required and what are the limits?

Answer 10

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products :
  Validation of aseptic processing.
• Imitate the routine aseptic manufacturing process and various interventions and worst-case situations.
• Initial validation,repeated approx every 6 months for lines, and annually for operators.
• The number of containers / volume / hold times sufficient to represent batch size.

Question 11

What types of operation can be carried out in the various cleanroom grades/ classifications?

Answer 11

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products :
  Grade Examples of 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

Grade Examples of operations for aseptic preparations.
A Aseptic preparation and filling.
C Preparation of solutions to be filtered.
D Handling of components after washing

Question 12

What should be considered when using isolator technology in the manufacture of sterile products?

Answer 12

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products :
• The transfer of materials into and out of the unit
• The background air classification is dependant on isolator design and its application. but should be at least grade D.
• Validation should take into account all critical factors eg quality of the air inside and outside (background) the isolator, sanitisation of the isolator, the transfer process and isolator integrity.
• Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system.

Question 13

What should be considered when using blow-fill seal technology in the manufacture of sterile products?

Answer 13

• EU: Eudralex Vol 4. Annex 1 (current and revised): Manufacture of Sterile Products :
• Blow/fill/seal equipment for aseptic has grade A air shower, installed in at least a grade C environment, provided that grade A/B clothing is used.
• Blow/fill/seal equipment for terminally sterilised should be installed in at least a grade D environment.
• equipment design and qualification, cleaning val critical

Question 14

What are the gowning requirements for cleanrooms?

Answer 14

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products
• Grade D: Hair incluiding beard should be covered. protective suit shoes or overshoes should be worn.
• Grade C: Hair incluiding beard should be covered. protective suit shoes or overshoes should be worn (high neck, gathered at wrist, non shedding)
• Grade A/B: Headgear totally enclosed, a face mask non-powdered rubber gloves, sterilised or disinfected footwear . Trouser-legs tucked in and sleves in gloves. non shedding, outdoor clothing should not enter areas leading to B or C.

Revised annex 1: Goggles to cover all skin in A&B. Dedicated Socks before entry into B&C

Question 15

What are the requirements for Sterilisation?

Answer 15

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products
• Where possible, terminal heat sterilisation used. Load pattern Validated - (B.I.’s used for validation, next to physical monitoring)
• Load to be processed should be demonstrated and verified at scheduled intervals, at least annually.

Question 16

What are the requirements for Sterilisation by dry heat?

Answer 16

Dry heat
- Air circulation under positive pressure to prevent “dirty” air reentering, air entering should be hepa filtered..
- Challenge tests using endotoxins should be used as part of the validation if intended for pyrogen reduction. - e.g. 250oC for 30 minutes to show a 3 log endotoxin reduction

Question 17

What are the specific requirements for Sterilisation by moist heat?

Answer 17

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products
  Annex 1 & EN 285 Moist heat
• Temperature, Pressure, air removal, steam quality.
• Tests: Leak rate and air removal.
• packaging allows removal of air and penetration of steam but which prevents recontamination when dry.
• EU regs accept F0 ≥ 8 minutes is required for all steam sterilisation processes. (Ph. Eur. 5.1.1 ≥121 °C, ≥15 min otherwise need to validate to demo >SAL 10-6)
• Load mapping distribution (cold spots)

Question 18

What are the specific requirements for Sterilisation by methods other than dry/ moist heat?

Answer 18

• EU: Eudralex Vol 4. Annex 1: Manufacture of Sterile Products
  Sterilisation by radiation
• Used mainly for heat sensitive materials and products.
• GAMMA radiation to get vials into filling line.

Sterilisation with ethylene oxide
- Method only used when no other method is practicable.

Question 19

How do you qualify a water system? Any guidelines/standards?

Answer 19

A PW installation must meet the following requirements regarding water quality:
* Pharmacopoeias (e.g., Ph. Eur, USP, JP),
* GMP guidelines, including Eudralex volume 4 Annex 15: Qualification & Validation

VMP-> URS «<Quality>>>-> FAT -> SAT -> IQ -> OQ -> PQ (3 phases) <1 year seasonal data> : Ongoing monitoring & periodic review of equipment/ process review</Quality>

Question 20

What types/grade of water are there?

Answer 20

• Potable water per competent authority
• Purified water: for non sterile and/or non pyrogenic.
• Highly Purified: high quality water is needed, but not WFI - double pass RO, meets same quality standards as WFI but production methods may be different.
• Water for injection (WFI): for parenteral products or for diluting parenteral substances. Distillation is most widely used method, however PhEur now permits other methods such as RO with ultra filtration

Question 21

Where can you use potable water in manufacture?

Answer 21

• Potable water may be used in chemical synthesis and early stages of cleaning of equipment

Question 22

• Describe how you would set up an environmental monitoring programme for a sterile site
  o Tell me more about how you would use a risk-based approach

Answer 22

Follow requirements within : Eudralex volume 4: Annex 1- Manufacture of Sterile Medicinal Products and ISO 14644 ‘Cleanrooms and associated controlled environments’
Purpose of EM:
– The state of control in the manufacturing facility re: Viable, non viable, temperature, humidity
- Consider PEMME
EM program should include scheduled monitoring of:
1. Viable (Surface and Air)
2. Nonviable (Surface and Air)
3. Pressure differentials
4. Direction of air flow
5. Temperature and humidity

Risk based approach:
- product/process specific considerations, measures needed to manage or reduce those risks are determined.
- identify ‘worst case’ locations and alert limits.
- Periodically review, reassess and update as necessary.

Question 23

• Describe the raw materials used to manufacture a cream.

Answer 23

Products can be either a water in oil (w/o) or oil in water (o/w) emulsion, consisting of waxes, emollients and lubricants dispersed in an oil phase, and a water phase containing emulsifying, stabilizing and thickening agents, preservatives and in some cases, colorant. Active ingredients are dispersed in either phase or added when the emulsion has been formed and allowed to cool.

CREAM (w/o or o/w) =

Oil Phase (waxes, emollients, lubricants)
+
Water Phase (water, emulsifier, solubiliser, thickening agent, Preservative, colourant)

<API>
</API>

Question 24

What is a CQA and how are they identified?

Answer 24

Critical Quality Attributes (CQA)
– CQA Types: Physical, Chemical, Biological, Microbiological to ensure quality

Question 25

What are CPP and how are they used?

Answer 25

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

Question 26

What is ICH Q11?

Answer 26

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.

Question 27

What can you tell me about ICH Q12?

Answer 27

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

Question 28

What controls, high level, would you expect to see for a liquid product?

Answer 28

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

Question 29

Why is source of raw materials important for for liquid products?

Answer 29

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

Question 30

What facility grade would you expect for manufacture of a liquid product?

Answer 30

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

Question 31

What EM specifications would you have for a liquid product manufacturing facility?

Answer 31

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.

Question 32

Talk through how you would design a cleaning validation strategy for a product

Answer 32

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?

Question 33

What are key processes in tablet manufacture and finished product tests?

Answer 33

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).

Question 34

What are typical ingredients (and purpose of each) within a tablet formulation?

Answer 34

‘-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)

Question 35

Describe some tablet types

Answer 35

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.

Question 36

What would possible reasons be for film coating a tablet?

Answer 36

• 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

Question 37

What is the purpose of granulation and discuss the possible types

Answer 37

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 «common»>
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.

Question 38

What are common tablet defects?

Answer 38

*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)

Question 39

What are key types of liquid formulation?

Answer 39

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

Question 40

What are key processes in oral liquid product manufacture?

Answer 40

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)

Question 41

What are typical ingredients (and purpose of each) within an oral liquid product formulation?

Answer 41

• 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 ))

Question 42

What are key processes in cream &, ointment manufacture and finished product tests?

Answer 42

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)

Question 43

What are key quality requirements for liquid, cream &, ointment manufacture?

Answer 43

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.

Question 44

What is PUPSIT?

Answer 44

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.

Question 45

Discuss RABS compared to Isolators

Answer 45

Closed Isolator:
- Sealed unit
- Positive pressure & Turbulent airflow (typical)
- Pressure differential is critrical <gloves/ sleeves>
- 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. <avoid>
- Challenge via smoke studies and routine monitoring.
- Mostly process line, complex lines including washing , depyro, filling & stropping</avoid>

Question 46

Describe a lyophilisation process

Answer 46

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 <concertina> , Balancing chamber pressure <allow>, Removing load <grade>, Defrost condenser < regularly clean>, Clean & sterilise lyophiliser <sterilise>.</sterilise></grade></allow></concertina>

proteins are very vulnerable to freezing therefore need good controls during freezing. Water removed =>

Question 47

When are dedicated facilities required?

Answer 47

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.

Question 48

How would you validate a wet massing process?

Answer 48

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 «<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>

Question 49

What are the controls on high speed packing line?
During engineering maintenance 6 pink rogue tablets are found struck in the hopper and the position is just above the web. The maintenance schedule is every 6 months. The first batch manufactured after maintenance is pink tablets and rest of the batches are white tablets.
What would you do? How would you investigate?

Answer 49

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.

Question 50

You currently manufacture solid oral dose and your CEO has decided to expand their portfolio into creams and ointments. Explain how you would build this new facility?

Answer 50

• 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

Question 51

What would you expect to see in a process validation of a liquid process?
a. What quality of water would you expect? (non-sterile, oral solution)
b. What are the bioburden limits for Purified water?
c. What about WFI?
d. What are the TOC limits for Purified water?
e. What about WFI?
f. What would be different if the product in question to be PV’d was a solution?

Question 52

Describe a product made by your company?
a. How is it made?
b. Tell me about the IPCs?
c. How does it work?
d. What preservatives are present?
e. What is on the specification?

Answer 52

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

Question 53

You are updating your facility. You currently manufacture steriles and will be adding a new area for cough syrup – what are your considerations for the facility?

Answer 53

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

Question 54

What are the IPC/ CPP/ CQA of a cough syrup, what would the base be? What micro testing would you perform?

Question 55

What would the key characteristics be for a paediatric tablet and syrup?

Answer 55

Pediatric Tablets:

Dosage Strength
Taste and Flavor
Size and Shape

Pediatric Syrups:

Dosage Accuracy
Palatability
Viscosity
Preservative-Free Options
Stability

Question 56

Talk through aseptic filling and lyophilisation processes. How would you ensure sterility of the product (Vancomycin)?

Question 57

Tell us about the constituents of a tablet.
a. You have a tablet formulation at your company and there is a requirement to formulate a product for 2-5years olds. Would anything be different? If so what and what are your options?
b. Describe the typical constituents for either a solution or a suspension
c. what would be different about a suspension?

Answer 57

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

Question 58

What is a QTPP?
a. Can you describe a QTPP for a capsule?

Answer 58

Quality Target Product Profile

Question 59

What are the changes to Annex 1? What is Contamination control strategy?

Answer 59

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.

Question 60

Cream question - What is cracking? What are the key areas to investigate?

Answer 60

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

Question 61

What controls, high level, would you expect to see for a liquid product?

a. Why is the source of raw materials important?

b. What is a PET test and how do you complete it?

c. What facility grade would you expect it to be?

d. Where would you find the micro spec for a liquid product and what is it?

Answer 61

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

Question 62

Your engineer tells you that they have had to change two HEPA filters in your facility as they were blocked, what are your concerns? It’s a liquid product

a. You are told that there is external work going on outside which is causing the build up

b. You would want a change control for a like for like filter change?

c. You mentioned increasing filter changes and what products been made; is there anything else you can check?

d. When would you start assessing the room from the BMS data?

e. What else would you look at – it’s a liquid product?

Answer 62

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

Question 63

In an aseptic manufacturing area for an IV product what kind of conditions would you expect?
a. What would you expect to see?
b. How would you qualify this environment?
c. What are the specifications for Grade A?
d. What are the patient risks associated with IV sterile injection products?
e. What extra measures would you expect if the products were cytotoxic?
f. How would the airflows be arranged?

Answer 63

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

Question 64

What is quality culture?
a. How do you know if a manufacturing site has a good quality culture?

Question 65

What are the critical quality attributes for a parenteral product?
a. Why is pH important?
b. Why is endotoxin important?

Question 66

You are a QP for a liquid manufacturer, you have a new product coming on line and it is a paediatric leukaemia treatment
a. What are your concerns as a QP and how would you bring this product on line?
b. What are the controls required to be in place for this product?
c. What is added during the manufacture of a suspension?
d. What additional items would you consider as this is going to be given to a child?

Question 67

You are designing a new facility, what are your concerns?
a. Relevant Guidance?

b. What would you want to consider?

c. You mentioned Grade D, what is Grade D and what are the limits?

Answer 67

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

Question 68

You receive complaints regarding particle present in sterile oncology product
a. What are your concerns and what action would you take?

Further information becomes available the issue is due to antioxidant precipitation
a. What considerations do you have now?

Question 69

You are reviewing IPC data for a bottle product and note that every 30th bottle has a low weight. Weight is in‐spec but lower than usual
a. Not related to incorrect set‐up on filler head, or empty bottle weight. No evidence of leakage
b. Not related to measurement system (balance or operator etc)
c. All bottles individually weighed. All results in‐spec. No root cause so far. Can you
release?
d. Any other considerations?

Question 70

What needs to be in place for sterile manufacture?
a. What are the media fill limits?

Question 71

At what point during manufacture should the date of manufacture be taken from?
a) If you had a semi‐solid critical intermediate that was stored for 6 months before further processing, would it be acceptable to assign the expiry date from the point this intermediate is then processed further (mixed with remaining excipients)?

Question 72

As part of the process validation of the product above on your 3rd Media fill you have a sterility failure OOS on one vial. What do you do?

a) As part of the process validation of the product above on your 3rd Media fill you have a sterility failure OOS on one vial. What do you do?

b) They tried to pressure me from a production perspective saying we have no time to lose and we need to start manufacturing ASAP. Do we really need to do another media Fill?

c) No Lab issue and it was a Bacillus

d) After I asked some questions, they told me that they found out that the disinfectant used was out of date for the clean done before that media fill batch was ran.

e) I told them we had to root cause and put CAPA in place, clean everything again and do another media fill as we were validation the Process

f) Luckily it was a validation media fill and there was no product at risk, but think about this as well, the scenarios can easily change

Question 73

Your site is currently manufacturing oral solid dosage form and they wish to introduce
creams and ointments. What are your thoughts?

• What are the main differences between each formulation and their ADME profile?
• What are the typical ingredients?
• What controls are needed around creams manufacturing and what are the key challenges– I talked about EM monitoring, cleaning validation
• What if this product is a worst case?
• How HBELs are calculated and who is responsible for calculation?
• What are preservatives and why are they used?
• How do you manufacture creams and ointments?
• What are CPPs and CQAs for creams?
• What type of change would this be and what documents need to be updated?

Question 74

• What would you have to consider if you wanted to make a paediatric cream and a normal strength cream using the same equipment?
• Take me through the general process for making a cream
• What in‐process checks would you have?
• What considerations would you have for setting up an environmental monitoring programme in your cream manufacture suite?
• Would you need to monitor the operators?
• What are the CQAs for creams?
• Describe the preservative test and where would you find it?
• Name some preservatives
• What is the limitations of the preservative test?
• Tell me at what stage you would expect to add the preservative in the manufacturing process?
• For what kind of treatment would you expect to have to use a sterile cream?

Answer 74

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.

Question 75

Canadian Tablet manufacturer notify you of deviation: Tablet machine has broken down – engineer fixed the problem but has led to an 8 hour delay – granulates held for that time.

What would you do?

What information do you need?

Question 76

What do you understand by the term PUPSIT?

Answer 76

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.

Question 77

You are a QP in a site which does manufacturing and packing of an Oral Solid Dose. Your company purchased a M.A. for an eye drop solution. What do you need?

-The product is thermo‐labile, how would that impact the process?

• What is the critical quality attribute of an eye drop solution?

Answer 77

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:

Question 78

You get a complaint from a pharmacist that your cream product was found to be discoloured and smelly when opened. Product is for treating nappy rash on babies.

• What are your concerns?
• What do you do next?
• Confirmed no previous complaints/tube sealed before opening/stored
  correctly/no changes etc but in final product testing results there was a correction made on preservative assay level. Originally written as 9.9% but crossed through and reported as 99.9%.
• On further investigation 9.9% was found to be true result. Analyst said they had been doing this regularly.
• What could be causing the discolouration in the product?
• What are you going to do with the original complaint batch?
• Who is part of a recall committee?
• What are you going to do with the information that the analyst said they have been doing this regularly?
• What IPCs would you expect to see in cream manufacturing?
• What is a typical cream formulation?