Cleaning validation Flashcards
What are the risks, pros and cons of swabbing.
Swab sampling of the direct surface is designed to test small sections of the equipment surface for the presence of residues. The swab test offers the advantage that sampling can be carried out directly at the critical points and even sparingly soluble residues can be collected. The disadvantages are the high demands on analytical method development and the problem of reproducibility.
Is it permissible to use the same equipment to manufacture different products for different therapeutic groups?
Yes, a risk assessment should be carried out, cleaning validation, hold time studies etc. Designated equipment may be deemed required as part of risk assessment especially for highly sensitising, strong coloured or flavoured etc
What would be the clean down arrangements/requirements when switching between different product types?
Full end of campaign clean following validation cleaning procedures, cleaning verification can be completed if required
R&D want to share manufacturing equipment used for fully marketed product, as QP what are your concerns.
I would be concerned about this for a number of reasons: patient safety and regulatory compliance being my highest concerns. We have cleaning procedures and cleaning validation that takes into account and has been risk assessed against all commercial products the equipment / facility is used for. Cleaning validation details should be listed within my site masterfile. We know permitted daily exposure and maximum allowable carry over for all our commercial products and this may not be known for products in development.
What are the carry-over limits for impurities in products.
Reference to ICHQ3 for impurities, EUGMP Chapter 3 for premises and personnel, Chapter 5 for production and Annex 15 for cleaning validation and GUGMP Part 3 for EMA Guideline on setting health based exposure limits.
Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria - See EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities should consider the potential cumulative effect of multiple items of equipment in the process equipment train.
According to ICH Q3 guidelines on impurities in new drug products, identification of impurities below 0.1% level, is not considered to be necessary, unless potential impurities are expected to be unusually potent or toxic.
An impurity which is defined solely by qualitative analytical properties (e.g., chromatographic retention time). Validated Limit of Quantitation: For impurities at a level of 0. 1 %, the validated limit of quantitation should be less than or equal to 0.05 %.
Your site acquires a new paediatric suspension. What are your considerations.
Talk me through how you would design a cleaning validation strategy for this product?
Documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in the equipment below the scientifically set maximum allowable carryover level (Annex 15)
What guidance is there regarding cleaning validation? How would you perform cleaning validation? What is PDE? What is considered for PDE?
Reference to ICHQ3 for impurities, EUGMP Chapter 3 for premises and personnel, Chapter 5 for production and Annex 15 for cleaning validation and GUGMP Part 3 for EMA Guideline on setting health based exposure limits.
Raise Change Control
Risk Assessment
Cleaning Validation Master Plan (equipment, products, cleaning processes, sampling, limits: product residues, cleaning agents, microorganisms incl. endotoxins), change control an deviation handling
Cleaning validation should always be based on worst case (or cases)– this is determined by toxicology (and therapeutic dose), solubility and cleanability and potency.
PDE – Toxicologist – based on no observed adverse effect level (NOAEL)
MACOs (based on PDE), STV (Safe Threshold Value) – maximum safe carry over of your product STV = PDE (mg/day) x Batch Size (Next Product) / Maximum Daily Dose of next product.
How would you validate your manufacturing process? Tell me about the annex 15 approach?
Raise a change control, URS, IQ, OQ, PQ, PV, Media Fill, Routine
What is product? Is it a multi product manufacturing line ? What other products are manufacture on this production line?
Annex 15 (Chapter 10) – Qualification / validations, Part III – HBEL, ICH Q2 – Method Validation, PDE – Toxicologist, Eudralex Vol. 4 Ch 3 and 5 (esp.: dedicated equipment when cannot control by tech/oper measures, cannot define limit value, e.g. allergenic products, or when PDE < limit of detection of analytical method)
Raise Change Control
Risk Assessment
Cleaning Validation Master Plan (equipment, products, cleaning processes, sampling, limits: product residues, cleaning agents, microorganisms incl. endotoxins), change control an deviation handling
Cleaning validation should always be based on worst case (or cases)– this is determined by toxicology (and therapeutic dose), solubility and cleanability and potency.
PDE – Toxicologist – based on no observed adverse effect level (NOAEL)
MACOs (based on PDE), STV (Safe Threshold Value) – maximum safe carry over of your product STV = PDE (mg/day) x Batch Size (Next Product) / Maximum Daily Dose of next product.
Analytical methods
Maximum Swab limit = STV (mcg) x Swab Surface Area cm2 / Total Equipment Surface Area
Development of Analytical Swab Method- test swab recovery on a surface
Method validation able to detect LOD + LOQ
on-going cleaning verification (life cycle concept) (effectiveness of cleaning processes, personnel training, maintenance of manufacturing and cleaning systems, monitoring of cleansing and rinsing media (esp. water).
What limits would you use for cleaning validation?
Limits based on PDE
What is PDE?
But this is an IMP so you won’t know that information?
Permitted Daily Exposure Limits - is a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime. In mg. (Also ADI: Acceptable Daily Intake)
(EMA PDE Guideline and ICH Q3C for determination of PDE, BUT NOAEL (EMA) and NOEL (ICH)).)
Pre-clinical development toxicological and pharmacological endpoints? (pharmacokinetics, chronic testing with repeat dosing, mutagenicity/carcinogenicity/reproductive toxicity testing? Other effects on organs / CNS? - Specialist (toxicologist) support?
TTC for substances with genotoxic potential?
For cleaning validation would you do any physical tests?
Assay / Impurities
Absence of Cleaning Solutions
Visual Cleanliness
Micro Testing – Swabs
You are now asked to perform a cleaning validation of the bulk vessel used to manufacture
the suspension. What are your considerations?
What tests would you perform?
What sampling method would you use?
What is the safety limit for carryover?
Single or multi use equipment?
What is considered ‘worst case’ – Highest Potency, Lowest Solubility, Resistance to cleaning materials.
PDE , HBEL – Eudralex Volume 4 Part 3, ICHQ3
Batch Size / Equipment Size / Equipment Materials
Worst case locations for cleaning
CIP or Manual?
Visual Inspection, Assay- PDE’s, Cleaning Products , Impurities,
Swabbing / Rinse Samples
It would have to be calculated by toxicologist
