Med Chem Flashcards
A site which manufactures HRT wants to introduce NSAID manufacture. What recent updates to legislation would impact this?
Hormone Replacement Medicinal Product facility introducing Non-steroidal anti-inflammatory drugs:
MIA needs to include NSAID
Risk assess, considering:
- EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines, Chapter 3 and 5.
- EMA guidance on: Residual Solvents, health based exposure limits, genotoxic impurities
- ICH and VICH : Residual solvents, impurities, Elemental impurities
Tell us about one of your products and its process
How can you increase the Bioavailability of a tablet?
solubility, dissolution and gastrointestinal permeability are fundamental parameters that control rate and extent of drug absorption and its bioavailability.
Reduce particle size -e.g by mechanical micronisation. Conventional methods of size reduction are simple and convenient methods to reduce the drug particle size and increase the surface area and thus enhance the solubility and dissolution of poorly soluble drugs. (limited for some drugs due to their low efficiency, sometimes leading to thermal and chemical degradation and resulting in non-uniform sized particles)
what is required for Cleaning Validation
EU GMP Volume 4 Annex 15: Qualification & Validation has a section on cleaning validation.
Also EMA HBEL guidance (volume 4) which describes PDE = (NOAEL X Weight adjustment) / f1 x f2 x f3 x f4 x f5 (things such as species, weight, toxicity, LOEL
1. Use worst case - Solubility, cleanability, toxicity, potency)
2. Visual check is also important
3. Remove: PRODUCT, CLEANING AGENT and MICRO
4. Using swabs and rinse samples.
Talk through how you would design a cleaning validation strategy for a product
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?
What limits would you use in a product cleaning validation strategy
Eudralex Vol 4 Part III - (20 November 2014) EMA Guideline : EMA/CHMP/ CVMP/ SWP/169430/2012
“Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.”
Cleaning is a risk reducing measure and carry-over limits should be derived from the PDE
ICH Q3C present the following equation:
PDE = NOAEL x Weight Adjustment
F1 x F2 x F3 x F4 x F5
- If multi-product may consider matrixing.
How would you calculate appropriate product cleaning limit for an IMP if you don’t have full information on the product?
EMA guidance on HBEL (PDE) states that it may be difficult to set PDE for some IMPs - that being the case may use specific default value categories e.g. based on low/high expected pharmacological potency, low/high toxicity, genotoxicity/carcinogenicity. With the availability of more pharmacological and toxicological data, compound-specific limits should be calculated for the derivation of health-based exposure limits.
(Can also reference ICH Q3C which provides PDE guidance for certain residual solvents):
- Class 1 (Avoid) : Actual or suspect human carcinogen/ environmental hazard
- Class 2 (Limit) : Non genotoxic animal carcinogen/ causitive agent of irreversible toxicity (e.g. neurotoxicity, tetragenicity) + other reversible tox.
- Class 3 (Low toxic potential) : No health based exposure limit needed (PDE >= 50mg per day)
What physical tests would you do to confirm successful product cleaning validation/ verification?
Sampling:
- Swab sampling (Direct Surface Sampling)
- Rinse or Wash Solvent Sampling
- Stamps
Seen to be visibly clean (annex 15)
Locations should be ‘worst case’. test using suitable validated (or compendial) analytical method (e.g. HPLC, GC, GC-MS, TLC, dry residue, TOC, UV, titration, conductivity or pH). Also consider micro testing as required.
Rinse and swab samples should be tested for:
- Product residues in accordance with analytical protocol
- Cleaning agent residues in accordance with analytical protocol
Establish Dirty Hold Times and Clean Hold Times.
After cleaning validation, the verification may be omitted or replaced by simpler analytical methods (e.g. conductivity; pH; etc.) however, visual inspection should be maintained in the dried equipment and no visible residues should be observed. (Also consider routine scheduled verification test)
What physical tests would you do to confirm successful product cleaning validation/ verification?
Sampling:
- Swab sampling (Direct Surface Sampling)
- Rinse or Wash Solvent Sampling
- Stamps
Seen to be visibly clean (annex 15)
Locations should be ‘worst case’. test using suitable validated (or compendial) analytical method (e.g. HPLC, GC, GC-MS, TLC, dry residue, TOC, UV, titration, conductivity or pH). Also consider micro testing as required.
Rinse and swab samples should be tested for:
- Product residues in accordance with analytical protocol
- Cleaning agent residues in accordance with analytical protocol
Establish Dirty Hold Times and Clean Hold Times.
After cleaning validation, the verification may be omitted or replaced by simpler analytical methods (e.g. conductivity; pH; etc.) however, visual inspection should be maintained in the dried equipment and no visible residues should be observed. (Also consider routine scheduled verification test)
What does disinfection efficacy depend on? Give sime types and ideal propeties
Temperature
Application
Concentration
Time
Types - e.g. QUATS, Alcohols, Chlorine Compounds
Ideal: no residue, soluble, quick kill, wide spectrum, low concentration, non toxic, stable, compatible with cleaning materials, low foam, not affected by water hardness, non toxic to environment/ people, easy to discard, economical, sporicidal).
Sporicides and sterilants for the removal of spores from hard surfaces. e.g. Spor-Klenz
Disinfectants for surface cleaning with broad spectrum antimicrobial efficacy e.g. Phenolic: Vesphene QUAT: HB+
Ready-to-use alcohols for the removal of process residues and routine glove decontamination
- Describe an ADME study, describe the main elimination pathways in human physiology.
(Liberation), Absorption, distribution, metabolism and excretion (response).
Impact of the body on the drug.
Kinetics of drug handling by the body.
Combination of:
- Drug’s chemical properties
- Drug’s physicochemical properties
- Formulation’s physicochemical properties
- Site of administration’s physiology
- Body physiology
- Disease pathophysiology
Main elimination pathway: metabolism by the liver, elimination via the kidney. Other routes of elimination: biliary excretion (high molecular weight drugs); salivary; exhalation; breast milk; sweat.
- What are the advantages and disadvantages of the parenteral route of administration?
Advantages:
- Exact dose
- Rapid onset
- Drug stability on injection good
- Unconscious/uncooperative patient admin
- 100% compliance
- No first pass metabolism
Disadvantages:
- Painful
- Trained personnel
- No removal of dose once administered
- Expensive
- Self administration unusual
- Possibility of infection
What are the advantages and disadvantages of the oral route of administration?
Advantages:
- Easy
- Convenient
- Acceptable
- Self-administration
- Painless
- Controlled release
Disadvantages:
- Nausea/vomiting
- Stability in GIT
- Effect of food
- Poor availability – first pass or solubility problems
- Requires conscious patient
- Slow onset of action
- What do you understand by the terms agonist and antagonist as it relates to the mechanism of action of a drug?
Agonist – a substance that has affinity and efficacy. It binds to a receptor, activates the receptor and produces a response e.g. change in heart rate, change in blood pressure, relaxation of airways.
Antagonist – a substance that has affinity but no efficacy. It binds to a receptor but does nto activate it. It prevents an agonist from activating a receptor; prevents a response.
- What does the liver do to drugs?
The liver is the main organ of drug metabolism and is involved in 2 general types of reaction:
Phase 1 reactions – the biotransformation of a drug to a more polar metabolite by introducing or unmasking a functional group. Oxidation is the most common reaction, catalysed by enzymes called the mixed function oxidases (cytochrome P450s). Substrate specificity is very low and many different drugs can be oxidised.
Phase 2 reactions – drugs or phase 1 metabolites that are not sufficiently polar to be excreted rapidly by the kidneys are made more hydrophilic by conjugation with endogenous compounds in the liver.
