Analysis and Testing

Question 1

What is an OOS (Out of Specification) Result?

Answer 1

Test result that does not comply with the pre-determined acceptance criteria (e.g, filed applications, drug master files, approved marketing submissions, or official compendia or internal acceptance criteria).
– Test results that fall outside of established acceptance criteria which have been established in official compendia and/or by company documentation (i.e., Raw Material Specifications, In-Process/Final Product Testing, etc.).

Question 2

What is an Out of Trend (OOT) result?

Answer 2

– The result is not necessarily OOS but does not look like a typical data point.

• Generally a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study
• However trends of starting materials and in-process samples may also yield out of trend data.
• Should be considered for environmental trend analysis such as for viable and non viable data (action limit or warning limit trends)

Question 3

Whay is an Atypical / Aberrant / Anomalous Result?

Answer 3

Results that are still within specification but are unexpected, questionable, irregular, deviant or abnormal. Examples would be unexpected result for stability test point, etc.

Question 4

When do “Out of Specification (OOS) / Out of Trend (OOT)/ Atypical -results” need to be investigated?

Answer 4

in cases of:
– Batch release testing and testing of starting materials.
– In-Process Control testing: if data is used for batch calculations/decisions and if in a dossier and on Certificates of Analysis.
– Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on-going / follow up stability (no stress tests)
– Previous released batch used as reference sample in an OOS investigation showing OOS or suspect results.
– Batches for clinical trials

Question 5

When are additional analyses permitted without OOS/OOT/Atypical investiation?

Answer 5

Pharmacopoeia have specific criteria for additional analyses of specific tests (i.e. dissolution level specification for S1, S2 & S3 testing; Uniformity of dosage units specification for testing of 20 additional units; Sterility Testing).
However if the sample test criteria is usually the first level of testing and a sample has to be tested to the next level this should be investigated as it is not following the normal trend
Also for In-process testing while trying to achieve a manufacturing process end-point i.e. adjustment of the manufacturing process. (e.g. pH, viscosity), and for studies conducted at variable parameters to check the impact of drift (e.g. process validation at variable parameters).

Question 6

What is a Phase 1a Investigation?

Answer 6

To determine if there is clear obvious error(s) due to external circumstances affecting the analysis.
Examples:
* Calculation error
* Power outage
* Equipment failure
* Spilling of sample
* Incorrect Instrument Parameters

Question 7

What is a Phase 1b Investigation?

Answer 7

Initial Investigation conducted by the analyst and supervisor using the Laboratory Investigation Checklist

Question 8

What is a Phase II Investigation?

Answer 8

Conducted when the phase Ia+Ib investigations did not reveal an assignable laboratory error.
Phase II investigations are driven by written and approved instructions against hypothesis to determine whether there is a laboratory testing issue or there is a possible manufacturing root cause.

Question 9

What is a Phase III Investigation?

Answer 9

(typically done as part of manufacturing deviation). The batch is rejected, there still needs to be an investigation to determine:
– if other batches or products are affected.
– identification and implementation of corrective and preventative action.

Question 10

What is a Specification?

Answer 10

From MHRA guidance on OOS & ICH Q6A:
A list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance, drug product or materials at other stages of its manufacture should conform to be considered acceptable for its intended use. “Conformance to specification” means that the drug substance and drug product, when tested according to the listed analytical procedures, will meet the acceptance criteria.
Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.

Question 11

What is an Acceptance Criteria?

Answer 11

Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures which the drug substance or drug product or materials at other stages of their manufacture should meet.

Question 12

What can an OOS result be invalidated?

Answer 12

A test is considered invalid when the investigation has determined a sample/ laboratory assignable cause.

Question 13

What is a Reportable Result?

Answer 13

The final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from the original sample.

Question 14

What is Hypothesis testing?

Answer 14

Documented and approved testing performed (phase 1b or phase II) to help confirm or discount a possible root cause.
For example: it may include further testing regarding sample filtration, sonication /extraction; and potential equipment failures etc. Multiple hypothesis can be explored.

Question 15

What is a Retest?

Answer 15

If no assignable cause can be identified during the manufacturing investigation or the assay failure investigation, retesting may be considered. Performing the test over again using material from the original sample composite, provided it has not been compromised and is still available. If not, a new sample will be used (re-sampling).
The minimum number of retests should be documented within the procedure and be based upon scientifically / statistically sound principles. (e.g. 7 or 9 retests)

Question 16

When is averaging permitted as part of OOS investigation?

Answer 16

– When all test results conform to specifications
– Where averaging must be specified by the test method.
– Consideration of the 95% Confidence Limits (CL 95% ) of the mean
- When averaging is the registered reportable result.

Question 17

When is resampling permitted as part of OOS investigation?

Answer 17

Rarely….. If original sample determined to be non representative of batch or that it is compromised, or if there is insufficient quantity of the original sample to perform all further testing. Must be discussed and agreed by QA/Contract Giver and process of obtaining the resample recorded within
the laboratory investigation.

Question 18

When can Outlier tests be used in OOS investigation?

Answer 18

Statistical analysis for Outlier test results can be as part of the investigation and analysis. However for validated chemical tests with relatively small variance and that the sample was considered homogeneous it cannot be used to justify the rejection of data.

Question 19

How are confirmed OOS results for a batch handled?

Answer 19

The OOS result should be used in evaluating the quality of the batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch’s rejection and proper disposition.
Other lots should be reviewed to assess impact.

Question 20

How are inconclusive OOS investigation results for a batch handled?

Answer 20

In cases where an investigation:-
(1) does not reveal a cause for the OOS test result and
(2) does not confirm the OOS result
– the OOS result should be given full consideration (most probable cause determined) in the batch or lot disposition decision by the certifying QP and the potential for a batch specific variation also needs considering.

Question 21

What is Accuracy?

Answer 21

The closeness of the experimental to the true value (ICH Q2 R1)

Question 22

What is Precision?

Answer 22

A measure of closeness of results (ICH Q2 R1)…..Types of Precision are: Repeatability, Intermediate Precision, Reproducibility

Question 23

What is Repeatability?
Intermediate precision?
Reproducibility?

Answer 23

Repeatability - Under identical conditions….ICH Q2R1
Intermediate - within lab variation, eg on different days/analyst ….ICH Q2R1
Reproducibility - Between lab variation (use 2 labs)….Also ICH Q2R1

Question 24

What guidance is there on reference and retain samples?

Answer 24

Eudralex volume 4 Annex 19: Reference and Retention Samples
Reference sample: A sample of a batch of starting material, packaging material or finished product -stored for the purpose analysis if needed during shelf life of the batch concerned. Where stability permits, reference samples from critical intermediate stages (e.g. those requiring analytical testing and release) or intermediates transported outside of the manufacturer’s control, should be kept.
Retention sample: A sample of a fully packaged unit from a batch of finished product. Stored for identification purposes. eg, presentation, packaging, labelling, patient information leaflet, batch number, expiry date should the need arise during the shelf life of the batch. May be exceptional circumstances where this requirement can be met without retention of duplicate samples e.g. where small amounts of a batch are packaged for different markets or in the production of very expensive medicinal products.

• necessary for manufacturer, importer or site of batch release to keep reference and/or retention samples from each batch of finished product and, for manufacturer to keep reference sample from a batch of starting material.
• can be assessed in the event of quality complaint, query relating to compliance with MA, a labelling/packaging query or a pharmacovigilance report.
• Records of traceability of samples maintained and be available for review by competent authorities.
• Should be retained for at least one year after the expiry date.
• samples of starting materials (other than solvents, gases or water used in the manufacturing process) shall be
  retained for at least two years after the release of product.
• The reference sample should be representative, close to suitable laboratory with validated methods and of sufficient size to permit on, at least, twice, full analytical controls on the batch in accordance with the MA. Must be in EEA unless MRA in place.
• A set of Retention samples must always be in EEA, preferably at certifying QP site.
• all necessary analytical materials and equipment ahould available to carry out all tests in the specification until one year after expiry of the last batch manufactured.
• Ensure appropriate storage conditions and written agreements and access by the QP performing certification.

Question 25

What are the requirements for Analytical validation?

Answer 25

ICH Q2 (R1) & EU GMP Chapter 6, Quality Control: Analytical method transfer & FDA Guide – Analytical Method Validation

General Trends in Method Validation and Transfer
* Use of integrated lifecycle
Design – development – validation – routine use – updates – transfer
* Quality by Design
* Understand critical parameters
* Apply structured risk assessment for selection of DoE tests
* Use multivariate DoE studies to define method operational limits
* On-going control of critical parameters during routine operation

ACCURACY
PRECISION
- Repeatability
- Intermediate Precision
- Reproducibility
SPECIFICITY
LOD
LOQ
LINEARITY
RANGE

<ROBUSTNESS>
</ROBUSTNESS>

Question 26

Is validation required for micro methods?

Answer 26

If it was an EP method you would just verify the ability to perform the method,
If a non-EP method
I was unclear if this was a recovery, so offered protocol, washes, removal of inhibitors, Assessor asked about the specification you would apply I said I would consult my micro person – felt out of depth

Question 27

How would you validate and analytical method transfer for an assay and what values would you expect to see?

Answer 27

The regulatory requirements for analytical method validation are harmonised between EU, JP + US and are found in ICH Q2(R1). In addition CPMP/ICH/281/95 compliments the ICH guidance. There is no specific requirement regarding what level of accuracy we should expect, although it should be predefined in the validation / transfer protocol based on the development/historical data.
Discuss statistical testing?

Question 28

What range would you expect for a validated assay?

Answer 28

ICH Q2(R1):
The specified range is normally derived from linearity studies and depends on the intended application of the procedure.
It is established by confirming that the analytical procedure provides an acceptable degree of linearity, accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of the specified range of the analytical procedure.

The following minimum specified ranges should be considered:
* Assay of an active substance or a finished product: normally from 80 to 120 % of the test concentration
* Content uniformity: covering a minimum of 70 to 130 % of the test concentration, unless a wider range is justified;
* Dissolution testing: +/-20 % over the specified range;
* Determination of an impurity: from the reporting level of an impurity to 120% of the specification; (adjust if potent/ toxic)
* if assay and purity are performed together as one test and only a 100% standard is used, linearity should cover the range from the reporting level of the impurities to 120% of the assay specification;

Question 29

What LOD value would you expect for a validated assay?

Answer 29

ICH Q2(R1):
The detection limit and the method used for determining the detection limit should be presented. If DL is determined based on visual evaluation or based on signal to noise ratio (usually), the presentation of the relevant chromatograms is considered acceptable for justification.

Question 30

What would a TSE certificate certify according to and for what materials would you require this?

Answer 30

EMA/410/01 Rev. 3 ‘Guidance for minimising risk of transmitting TSE’
This guideline provides guidance for minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products.
Should be available for all natural/ animal origin materials and components which are product contact.

The Certification of Suitability to the monographs of Ph Eur (issued by EDQM) is certified against the Ph Eur monograph on ‘products with risk of transmitting agents of animal spongiform encephalopathies’

Question 31

How would you validate a stability indicating method?

Answer 31

VMP, Method qualification/ validation as per ICH Q2 R1.
Look at preformulation studies around hydrolysis, oxidation and photostability.
Stress testing to identify likely degredants

Question 32

How would you know where to look for peaks when validating a stability indicating method?

Answer 32

Based on stress testing during pre-formulation studies.

Stability indicating methods accurately quantify without interference from:
–Impurities–Degradation products–Excipients–Other potential impurities–Other active ingredients

Question 33

What is ‘Robustness’?

Answer 33

The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.

Question 34

What is ‘Linearity’?

Answer 34

The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.

Question 35

What is a ‘Quantitation limit’?

Answer 35

the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.

Question 36

What is a ‘Detection limit’?

Answer 36

the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.

Question 37

What is ‘Specificity’?

Answer 37

Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.

Question 38

What is ‘Accuracy’?

Answer 38

The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found.

Question 39

What is PAT?

Answer 39

PAT = Process Analytical Testing
Numerous tools and techniques utilised to provide continuous measurement capability (.e.g. inline NIR or conductivity)

Question 40

What classifications of solvents are described in ICH Q3C

Answer 40

Class 1 solvents: Solvents to be avoided .
Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.

Class 2 solvents: Solvents to be limited.
Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.

Class 3 solvents: Solvents with low toxic potential
Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day.

Question 41

What are the ICH Stability storage conditions?

Answer 41

Q1A(R) STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

• Long term: 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH (12 months)
• Intermediate: 30°C ± 2°C/65% RH ± 5% RH (6 months)
• Accelerated 40°C ± 2°C/75% RH ± 5% RH (6 months )

Question 42

What is QC?

Answer 42

As defined in EU GMC Chapter 1: “that part of GMP which is concerned with sampling, specifications and testing and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use nor for sale or supply until their quality has been judged to be satisfactory”

Question 43

What is GcLP?

Answer 43

Quality Assurance of the Lab. The summation of all management/control aspects of a lab function which helps ensuring the integrity and authenticity of all data produced. A ‘mini’ production environment, key aspect: DATA INTEGRITY. It includes:
1. Quality System: organisation charts, supplier assurance, self inspection, change control, OOS/OOT and trending of results, risk management;
2. Documentation: organisation, origination and authorisation, SOPs, Methods, Change control, archiving;
3. Personnel: organisation charts, job descriptions, training programmes/records, competency assessment, allocation and rotation of duties;
4. Facilities: temp/humidity/ventilation, housekeeping, layout and process flow
5. Equipment: suitable, maintenance and calibration
6. Materials and Supplies: reagents and solutions, reference standards, SOP for labelling and use, expiry dates, storage
7. Sampling and Samples: written plan, labelling, storage, chain of custody;
8. Test Methods: defined and documentes, validated, trained analysts, system suitability.

Question 44

What is the role of the Pharmacopoeias? And the legal basis in the EU?

Answer 44

Pharmacopoeias are public standards accepted in Regulatory filings, setting legally ‘if tested must comply’. They set out the minimum legal standards. It does not mean we have to use it, but in any legal dispute the Ph standards would be used.
In the EU, the legal basis of the Ph is set out in Directive 2001/83/EC for HMP, 2001/82/EC for VMP

Question 45

What is EDQM?

Answer 45

European Dictetorate for the Quality of Medicines and Healthcare from the Council of Europe.
Part of the European Regulatory System with strong links with EMA, EC and National Agencies.
EDQM tasks:
1. Technical Secretariat and publisher of the Ph Eur
2. Coordinates the network of Official Medicines Control Lab (OMCL) - e.g. for marketed product surveillance programmes
3. Coordinates the Certification of Suitability to Ph Eur Monographs (CEP) - certificate that indicates that application of Ph Eur monographs assures the ‘quality’ of the material (any supplementary tests for impurities not controlled by a monograph added as an annex).

Question 46

In summary, what does the QP need to be aware in relation to the role and intent of Pharmacopoeias?

Answer 46

1. Materials must comply with Ph Eur monographs where they exist;
2. Pharmaceutical preparations must comply throughout shelf life;
3. Specific and mandatory general notices/general chapters/test methods must be considered. For dosage form monographs, all products must comply!
4. For a material to be considered Ph grade, it must meet all criteria in the monograph
5. Alternative control methods can be used for routine testing however, in case of dispute, the Ph standards are authoritative
6. Ph compliance only means that the sample tested satisfies the monograph, it does not substitute GMP quality assurance
7. The monographs are a minimum standard - additional testing/methods/techniques may be appropriate in certain circumstances
8. Regulatory Agencies may request more than the monograph standard when reviewing MAA
9. Secondary reference standards may be used for routine analysis if calibrated against Ph standards
10. QP must ensure there is a system in place to evaluate the impact of Ph updates
11. Awareness that new monographs may be issues in response to public health issues
12. Remain aware that OMCLs undertake risk based marketed products surveillance programmes that may include our products
13. Ph methods do not need validation but they require verification, demonstration of equivalence that the set of routine tests performed meet Ph requirements.

Question 47

Describe HPLC, what it looks like, describe each component and talk through a typical assay

Answer 47

(HPLC) High Performance Liquid Chromatography

Components (see diagram)
- Reservoir holds solvent [mobile phase, because it moves].
- High-pressure pump [solvent delivery system] generates and meters a
specified flow rate of mobile phase <ml>
- Injector [e.g. autosampler] injects the sample into continuously
flowing mobile phase stream; carries sample into HPLC column.
- Column contains chromatographic packing material for separation.
= stationary phase.
- Detector needed to see separated compound bands as they elute.
Mobile phase exits detector and is sent to waste, or collected.
High-pressure tubing & fittings interconnect pump, injector, column, &
detector to form conduit for mobile phase, sample, and separated bands.</ml>

Question 48

What actions/investigations would you initiate if you found an additional peak on a chromatogram?

Answer 48

An extra peak can arise from:
* Laboratory sample contamination
* Instrument related peaks (e.g. carryover from prior injection (residues in the injector, non-specific irreversible adsorption on column, Accumulation on system surfaces)
* Method resolution (e.g. a vendor modification HPLC column packing altering column performance revealing a previously undetected entity)
* Raw material impurities or contamination
* Product or aliquot degradation (a material stability issue or reaction with another excipient)
* Leachables/extractables (from manufacturing step or container closure system)
* Manufacturing process cross-contamination
* Some other unknown source

Actions:
a) Laboratory OOS/OOT investigation. (MHRA OOS guidance-> phase 1a, 1b, II).
b) If no laboratory error/ root cause found, determine if genuine confirmed result.
c) If confirmed result: Deviation Investigation. Try to identify peak(LC-UV & LC-MS)
d) Use NMR if LC-MS is inconclusive)
e) Determine if is it a related substance or external contaminant
f) Safety/ Efficacy/ Quality assessment risk assessment
g) Rlease/ Recall Decision (consider previous batches also)
h) CAPA

Work quickly if already released/ stability!

Question 49

Describe GC, what it looks like, describe each component and talk through a typical assay

Answer 49

(GC) Gas Chromatography

Components (see diagram)
- Sample solution injected into the instrument enters a gas stream
which transports the sample into a separation tube “column.”
- (Helium or nitrogen used as the carrier gas.)
- Various components are separated inside the column.
- Detector measures the quantity of the components that exit the column.
- To measure a sample with unknown concentration, a standard sample
with known concentration is injected into the instrument.
The standard sample peak retention time (appearance time)
and area are compared to the test sample to calculate the concentration.

Question 50

Compare a titration assay to a HPLC assay

Answer 50

HPLC-
+: Speed, Efficiency and Accuracy,

Question 51

Describe MS, what it looks like, describe each component and talk through a typical assay

Answer 51

(MS) Mass Spectrometry
Components (see diagram)
- MS accurately measures the mass of different molecules within
a sample.
1. Ionization.
Molecules in sample are vaporized (converted to gas phase by heating).
Electron beam bombards the vapors, converting vapors to ions.
MS measures the mass of charged particles, therefore ions only detected.
Ions created by giving electrons to a molecule or taking electrons away
Sample can only be analyzed by mass spectroscopy if can vaporise without decomposing.

2. Acceleration & Deflection.
   Next, the ions are sorted according to mass -2 stages: acceleration & deflection.
   Acceleration: Positive ions accelerate toward negative plates.
   Lighter molecules move quicker than heavier ones.
   Deflection: Ions are deflected by a magnetic field, extent of deflection also dependent
   on mass.
3. Detection.
   Ions of increasing mass eventually reach detector one after another.
   Computer provides a spectrum.

Question 52

What system suitability tests would you carry out for a HPLC assay?

Answer 52

Resolution- measure of the separation between two chromatographic peaks.
Well resolved peaks are basic requirement. Separation between closely spaced peaks
is governed by affinity for the stationary phase.

Asymmetry or Tailing factor-
Ideal chromatographic peak should be symmetrical Gaussian shape. Peak tailing is
commonly observed -mainly due to analyte retention. Tailing can be reduced by
changing mobile phase pH or end-capping of stationary phase.

Precision
Replicate injections of a standard preparation used to ascertain precision. Data from five replicate injections are used if requirement of relative
standard deviation is less than 2%. Data from six replicate injections are used if the requirement of relative standard deviation is more than 2%.

Theoretical plates
Assumes the column comprises a large number of imaginary separation layers called theoretical plates. Equilibrium of the sample takes place between the stationary and the mobile phase in these imaginary plates. The analyte moves down the column by transfer of equilibriated mobile phase from one plate to the next. Column efficiency is expressed in terms of theoretical plates.High resolution means greater number of plates in a given length of column

Retention factor
Retention factor or partition ratio or capacity factor is the relation of time spent by a compound in stationary phase to the time it spends in the mobile phase. Higher the value, greater the retention of a compound on a column

Question 53

List the tests you would do to release a solid dosage form

Answer 53

Pharmacopoeial Standards: 4 tests generally applicable:
1. Description (appearance)-
Qualitative description of the pharmaceutical drug product
2. Identification-
To verify identity of the API in the drug product. Should discriminate between compounds of closely related structure, likely to be present.
3. Assay-
Determines strength or content of the API in the drug product (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)

Finished product tests: assay, capsule fill weight, tablet friability, tablet hardness/thickness, 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 (capsules), Stability

Question 54

What is dissolution apparatus like?

Answer 54

The principle function of the dissolution test may be summarised as:
- Optimise therapeutic effectiveness during development & stability assessment.
- Routine assessment of production quality between production lots.
- Assessment of ‘bioequivalence’, (same biological availability)
- Predict in-vivo availability, i.e. bioavailability (where applicable).

2 types of apparatus; 1) Basket or 2) Paddle

Vessels of the dissolution method are usually either partially immersed
in a water bath solution or heated by a jacket. An apparatus is used on
olution within the vessels for a predetermined amount of time which
depends on the method for the particular drug. The dissolution medium
within the vessels are heated to 37°C with an acceptable difference of ± 0.5°C
Sample solutions collected from dissolution testing are commonly analyzed
by HPLC or Ultraviolet–visible spectroscopy at specified timepoints.

Question 55

What would you do if the API manufacturer changed final recrystallisation solvent? Dissolution comparison otherwise called (bioequiv)?

Answer 55

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)

Question 56

Comment on the uses of the Pharmacopoeia, relevance of the specifications for raw materials and products contained in them.

Answer 56

Ph. Eur: - one common compulsory standard. The official pharmacopoeia in Europe – complemented by national pharmacopoeias for texts of interest to only one Member State. Mandatory at the same date in 37 Member States (CoE) and the EU.
* Legally binding quality standards for ALL medicinal products in its member states, i.e. raw material, preparations, dosage forms, containers must comply with the Ph. Eur. requirements when they exist. Ph. Eur. tests are reference methods, essential in cases of dispute.
* Compliance is required, but alternative methods may be used as long as they lead to the same pass/fail result. It is the responsibility of the user to demonstrate their suitability. Approval of the competent authority is necessary in many cases.
* European Pharmacopoeia Monographs Today: Active substances (organic, inorganic), Excipients, Substances of biological origin and biotechnology (e.g insulin), Herbal drugs, Essential oils and fats, Radiopharmaceuticals, Vaccines, sera & blood derivatives, General monographs on dosage forms, General texts on quality issues and standard analytical methods ⇒ More than 2200 monographs

What does compliance mean? Compliance with all mandatory parts of a monograph.
* Compliance until time of use for raw materials, ingredients.
* Compliance throughout period of validity for preparations.
* In-use compliance decided by licensing authority for each preparation.
* Mandatory compliance for all substances for pharmaceutical use
* Ingredients (incl. excipients) of final formulation
* Components of solvents, buffers etc. in or used to make up final formulation
* Reagents? Not usually needed for upstream use
Validation? - when implementing a pharmacopoeial method, the user must assess if and to what extent the suitability of the method under the actual conditions of use needs to be demonstrated

Structure:
00. Introduction 01. General Notices 02. Methods of Analysis 03. Materials & Contsiners 04. Reagents 05. General Texts 06. General Monographs 07. Dosage forms 08. Vaccines 09. Immunosera 10. Radiopharmaceutical 11. Sutures 12. Herbal 13. Homeopathic 14. Monographs

Question 57

How would you validate an analytical method transfer for an assay and what values would you expect to see?

Answer 57

Talked about a VMP stating purpose, equipment, methods, tests and specifications. Listed the table in ICHQ2 for all tests but could only remember values for precision and linearity

Question 58

You have miscellaneous peaks on a stability batch – what would you do?
A) Talk me through your OOE investigation
B) You now find 2 release batches are showing the same peaks
C) You find it’s a contaminated dish washer
D) You have 2 batches on the market and 3 in the warehouse
E) Who else would you need to complete your risk assessment?
F) I didn’t say they had failed but talk me through how you would recall?
G) Who can make the decision to recall? Who would you get involved?
H) These batches haven’t failed – what would you do?

Answer 58

I would raise an OOS then changed to OOE as in spec
A) Phases of investigations from 1a, 1b and 2
B) Identifying root cause using GMR
C) Said I would assess the potential contamination and complete a risk assessment on
patient risk. What and where is the stock?
D) Said I would quarantine the batches in the warehouse and recall the product
E) Medic and PVQP
F) Talked about SOP, recall team and contacting DMRC with recommendation
G) Senior manager, COO and CEO
H) Test retains

Question 59

Dissolution scenario. You have a batch of product that has failed dissolution testing – result is low. What would you do?

a. After lab investigation what else would you do?

b. In manufacturing investigation what factors could affect dissolution?

c. An operator reports that the API looked discoloured during manufacture, what
would you think about that?

Question 60

One of your products is stored in an external warehouse, the temperature storage requirement is 20°C. You get a call from the warehouse manager that he has been made aware the temperature is fluctuating between 15 and 25°C and has been for two months. You have product in the warehouse and in the market place
a. What would you do?
b. What are the ICH stability storage conditions?

Question 61

You are carrying out a method transfer of a HPLC assay to a contract laboratory; what are your protocol expectations? What would you expect to see?

Answer 61

I talked about first auditing the site, putting a TA in place and submitting a variation to the site MIA to have the lab put on the licence before generating a method transfer protocol
I then basically talked through ICH Q2 etc. I was then asked about linearity. What is linearity and what is key number? Correlation co‐efficient 0.9998. He did ask how many nines!!

Question 62

During an analysis your laboratory contact you to tell you they have identified a new peak during the quantitative analysis of your drug product
a. What do you do?
b. Describe an OOS procedure

Question 63

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 64

Routine annual stability testing generates a low bioassay for a product
a. All other test results ok for this timepoint and other assay ok at other timepoints.
Sample tested after longer period than normal
b. Extensive lab investigation reveals no obvious error. Samples held for different timepoints following prep don’t show a decrease in assay
c. Previous timepoints all ok for the same batch
d. Retests all ok – near to target value

Answer 64

Classified as an OOT? What are the limits and what is the result? Timepoint of testing.
Understanding as to why a retest was carried out.
How much longer and why?
Routine stability batch - not due to unexpected deviation. Any other deviations noted during mfr
Type of product - impact on patient
Storage conditions of sample - when was it removed from the cabinet?
Stability cabinet data

Question 65

You have been informed of an OOS for assay on a stability study, what action do you take? As scenario developed – could not get a root cause either analytical or manufacturing

Question 66

Dissolution OOS on release‐ results of 68%
o Failed to stage 3
o Discussed lab investigation. Was confirmed as a true result
o On stating a manufacturing investigation would need to be initiated. They asked
what areas I would focus on. Discussed empty capsules storage‐ impacts dissolution
and particle size. It was due to the capsules storage
o More batches fail on stability. After 9 months with a 36 months shelf life. I discussed
recall requirements