API Flashcards
What tests are on an API certificate?
Testing required: Section 11.2 of the EU GMP Guide Part II :
For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications. Specifications typically listed in monographs- Ph Eur, USP, JP etc. and would include, e.g.:
- Identification tests
- Tests for Quality (e.g. pH, Loss on Drying, Content Assay, particle size, density, identification)
- Impurity tests (e.g. related substances, residual solvents)
- Appropriate microbiological tests should be conducted where microbial quality is specified.
- (see ICH Guideline Q5A & B for specific requirements relating to Biotechnological Products:)
COA should contain the following information:
- Name of the intermediate or API
- Batch number
- Release date
- Expiry date
- List of the tests performed including acceptance limits
- Numerical results
- Dated signature by authorised personnel
- Name of the company or Name of the laboratory.
Name countries on the white list
UK List of Approved Countries for API
- Brazil
- Israel
- Switzerland
- Korea
- Japan
- Australia
- USA
How would you validate a stability indicating method?
Raise VMP, Look at preformulation studies around hydrolysis, oxidation and photostability. Follow ICH Q2 R1.
(Stress testing should help you to know where to look out for peaks)
What is the structure of an API monograph?
- Analytical Methods
- Mandatory if referred to in a monograph
- Approved specifications
- Validated analytical procedures and acceptance criteria
What I.D tests would you carry out on an API, why?
Typically 2 identity tests performed, one of which is a definitive fundamental test. This fundamental test is most frequently an infra-red spectroscopy technique (FTIR or nIR), because of the ease of collecting the spectra (with a number of different sampling techniques) and the ability to perform a quantitative comparison to a library of IR spectra. in order to provide a positive confirmation of the material in question. Ultraviolet (UV) spectroscopy or HPLC retention time are frequently used for the secondary identification technique.
For an Active Pharmaceutical Ingredient (API), FTIR and HPLC retention time are very frequently used. The acceptance criteria for these tests will often be a short list of specific peaks in the FTIR spectrum that must match the reference spectrum within a few (to be specified) wave-numbers (cm-1). From a qualitative perspective, it is also advisable to inspect the entire spectrum in comparison to the reference. HPLC retention times are usually specified within 5% difference from the reference peak in the chromatogram of a reference standard.
What would you be concerned about if an API solvent for crystallisation step was being changed
API produced by crystallisation - changes can lead to potential polymorphism, whereby an organic molecule can adopt more than one crystalline forms. This is of considerable importance when trying to achieve consistent product quality- although morphology and particle size-distribution are important solid-state characteristics, the uncontrolled occurrence of multiple physical forms (polymorphs, solvates, salts, co-crystals or amorphous) of an API can have significant effects on the performance of the material during processing, manufacture, storage and administration. For example, the solubility difference between some polymorphs has been shown to be over four times that of the least soluble form and can vary by significantly more for amorphous forms. Such differences may have a potentially significant impact on the bioavailability of solid dosage forms or the physical stability of liquid formulations or suspensions.
Potential for residual sovents, polymorphism and impact on bioavailability and product therapeutic index.
Need to demonstrate bioequivalence. Variation (type II unless proved otherwise)
Would you include disintegration as IPC? Why not?
In-process controls during hard capsule production typically include the moisture content of the mixture and/or granulate (as well as of the shells), the size of granules, the flow of the final mixture, and the uniformity of mass, capsule size, integrity of the seals, and disintegration or dissolution rate (e.g. for modified-release capsules) of the finished dosage form.
In-process controls during tablet production typically include the moisture content of the mixture and/or granulate, the size of granules, the flow of the final mixture and, where relevant, the uniformity of mass of tablet cores before coating. In-process controls during tablet production
should also include the dimensions (thickness, diameter), uniformity of mass, hardness and/or crushing force, friability, disintegration, or dissolution rate (for example, for modified-release tablets) of the finished dosage form.
What tests would you carry out on capsules and where might you find these referenced?
Pharmacopoeial Standards: 4 tests generally applicable to pharmaceutical capsules and other drug products:
1. Description (appearance)-
Qualitative description of the pharmaceutical capsules e.g. white cap, red body, imprinted with ‘‘Rx’’ on cap
2. Identification-
To verify identity of the API in the capsule. Should discriminate between compounds of closely related structure, likely to be present.
3. Assay-
Determines strength or content of the API in the capsule (content test)
4.Impurities-
Determines presence of any component not the API or an excipient. Most common impurities are related substances (process impurities from drug substance synthesis, degradation products of the API, or both)
Physical parameters controlled by IPC tests: temperature, pressure, relative humidity, particle size, color, fill weight, shell weight, softgel ribbon thickness, softgel seal thickness, softgel shell moisture level, softgel hardness, disintegration time etc. and Finished product tests: assay, fill weight, uniformity of content, uniformity of mass, mass variation, microbiological test, disintegration test, dissolution test, stability test etc.
Pharmacopoeial Tests: Appearance, Size & Shape, Unique identification markings, Assay, Content of Active Ingredients, Content Uniformity, Uniformity of Mass, Mass Variation, Disintegration, Dissolution, Moisture Permeation, Stability
During API manufacture what methods are there for purification?
Crystallization:
Distillation:
Extraction:
Filtration:
Drying:
Recrystallization:
An audit is required to be performed on a critical API supplier
a. Does the QP have to do this audit? If it can be delegated, who can it be delegated
to?
b. What are the key things that you would focus on during the audit?
During an audit of an API supplier, you are auditing the labs and you notice on the HPLC records there are chromatograms that look like your product that are unaccounted for in the log and these show failed results
a. What do you do?
b. They tell you that this information is confidential but you know this is your product?
You have an API manufactured in South Korea, the bulk is manufactured in Switzerland, the product is packed and QP released by you in the UK. What documentation and controls would you need for each stage to enable release?
a. Relevant Guidance?
b. API Stage?
c. Bulk Stage?
d. importation into UK
e. Release?
a. Relevant Guidance?
FMD, I’s, Chapter 5, Annex 15, Annex 16, also mentioned upcoming Annex 21
(Importation of product)
b. API Stage?
Audit, TA, GMP Cert, Written Confirmation as per FMD (I was asked to explain this)
c. Bulk Stage?
Audit, TA, GMP Certificate
d. Importation into UK?
No testing (other than ID) required as there is an MRA with Switzerland. If no MRA? Then full qualitative and quantitative testing on at least all APIs and any other tests which are quality critical
e. Release?
MIA covers release and Importation of this product; API and Bulk site named on MA; other duties as per Annex 16
As part of the investigation it comes to light that your API manufacturer accidentally discharged recovered solvent from a different API manufacturing process into the vessel containing the solvent for purification of your API. They calculated the potential carry over and did not perceive any issues, so they did not tell you, it has since been identified that there were errors in the calculation. What do you do now?
You manufacture ibuprofen tablets. Your API supplier informs you that they have changed the final recrystallisation step from methanol to toluene. How do you manage the introduction of this change?
1) manufacturing impact - impact on isomerisms, shape and crystal size, impact in final product and release
2) QC - can isomerism be detected in the testing, particle size distribution
3) regulatory and legal impact - what is registered, what’s in the DMF/monograph, what’s register by same Holder, contact regulatory authority if not as per registered info, could result in recall!
Silicon oil had leaked into a clinical API batch due to a crack in the distiller. The oil is in a separate layer. Can you use the batch?
oTested the API layer and some silicon oil is still mixed with it
o Level of detail registered is low due to being a clinical product
