Wednesday, July 26, 2017

Pharmacovigilance Interview Questions and Answers

What is Pharmacovigilance?
Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medications, biological products, herbalism and traditional medicines.

What is the minimum criterion required for a valid case?
An identifiable reporter
An identifiable patient
A suspect product
An adverse drug event

What is an Adverse Drug Event (ADE) ?
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

What is an Adverse Drug Reaction (ADR) ?
An adverse drug reaction is a “response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function.” Note that there is a causal link between a drug and an adverse drug reaction. In sum, an adverse drug reaction is harm directly caused by the drug at normal doses, during normal use.

What is the basic difference between an ADE and ADR ?
There may not be a causal relationship between a drug and an ADE, whereas, there is a causal link between a drug and an adverse drug reaction.

When do you consider an event to be serious ?
If an event is associated with any one of the following, it is considered to be serious.
Life threatening
Hospitalization or prolongation of hospitalization.
Congenital anomaly
Medically significant or Important Medical Event
Required Intervention to Prevent Permanent Impairment or Damage (Devices)

Name the regulatory authorities in USA, UK, Japan and India ?
USA : United States Food and drug administration (USFDA).
UK : Medicines & Health Care Products Regulatory Agency (MHRA)
Japan : Pharmaceuticals and Medical Device Agency (PMDA)
India : Central Drugs Standard Control Organization (CDSCO)
Australia : Therapeutic Goods Administration
Canada : Health Canada
GVP Guidelines ? Total 16 Modules present, which replaces VOL 9A.

When do you consider a case to be medically confirmed?
A case is considered to be medically confirmed if it contains at least one event confirmed or reported by an HCP (Health Care Professional)
Note: HCP can be a Physician, Nurse, Pharmacist, Coroner or psychologist (only in Germany).

What do you mean by causality ?
Causality is the relationship between a set of factors. In Pharmacovigilance, causality is the relationship between the suspect product and the adverse drug reactions, like Related, Unrelated and Possible.

Name some data elements in ICSR ?
Patient demographics : Age, gender and race.
Suspect product details : Drug, dose, dosage form, therapy dates, therapy duration and indication. Adverse event details: Event, event onset date, seriousness criterion, event end date and latency.

What should a Safety narrative consist of ?
A narrative should consist of precise and concise information about the source of report, patient demographics, patient’s medical history, concomitant medications, suspect product details and adverse event details in an orderly manner.
This vary to type of reports like Spontaneous, Clinical trial and Literature and as per the Sponsor conventions as well. In upcoming article, we would share a full article of Safety Narrative.

What do you mean by MedDRA : Medical Dictionary for Regulatory Activities.
14. Explain the hierarchy in MedDRA :
System Organ Class (SOC)
High Level Group Term (HLGT)
High Level Term (HLT)
Preferred Term (PT)
Lower Level Term (LLT)

Abbreviations : Common terminology used in day to day PV Activities
a) SUSAR : Suspected Unexpected Serious Adverse Reaction
b) SAE : Serious Adverse Event
c) CIOMS : Council for International Organizations of Medical Sciences
d) ADE : Adverse Drug Event
e) SSAR : Suspected Serious Adverse Reaction
f) ADR : Adverse Drug Reaction
g) ICSR : Individual Case Safety Report
h) PSUR : Periodic Safety Update Report
i ) ICH : The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
j) HIPAA : Health Insurance Portability and Accountability Act
h) ESTRI : Electronic Standards for the Transfer of Regulatory Information.
ICH Guidelines : ICH-Efficacy Guidelines, E2A to E2F
E2A : E2A guidelines give standard definitions and terminology for key aspects of clinical safety reporting. It also gives guidance on mechanisms for handling expedited (rapid) reporting of adverse drug reactions in the investigational phase of drug development.
E2B : E2B guidelines for the maintenance of clinical safety data management and information about the data elements for transmission of Individual Case Safety Reports.

18. E2D :This document provides a standardised procedure for post-approval safety data management including expedited reporting to relevant authority. The definitions of the terms and concept specific to post-approval phase are also provided.

19. E2E : Pharmacovigilance Planning, This Guideline is intended to aid in planning pharmacovigilance activities, especially in preparation for the early postmarketing period of a new drug (in this Guideline, the term “drug” denotes chemical entities, biotechnology-derived products, and vaccines). The main focus of this Guideline is on a Safety Specification and Pharmacovigilance Plan that might be submitted at the time of license application.

20. E2C : This document gives guidance on the format and content of safety updates, which need to be provided at intervals to regulatory authorities after products have been marketed. The Guideline is intended to ensure that the worldwide safety experience is provided to authorities at defined times after marketing with maximum efficiency and avoiding duplication of effort.

Thursday, March 30, 2017

Guidelines for Pharmaceutical Stability Study

Following are the guidelines for stability study conduction for new products:

1.  Formal stability study should consist of accelerated and long term stability testing on at least two primary production batches for stable drug products and in case of the susceptible drug products at least three primary production batches should be considered.

2.  The accelerated stability testing data at 40°C / 75% for minimum six months and long term stability testing data at 30°C / 65% for minimum 12 months should be available at the time of submission for new drug application and can be continued further..

3.  The product stable for 6 months at 40°C / 75% (Accelerated stability conditions) then it can be assigned the shelf life of 24 months.

4.  If the shelf life period exceeding the 24 months is to be assigned for the product the real time stability data should be available.

5.  Though not accepted internationally, as internal policy decision we can give the shelf life of 36 months if product is found stable at accelerated stability conditions of 40°C / 75% for 12 months.

6.  The shelf life of 36 months or more can be assigned to the drug formulation after completion of long term stability study for 36 months or more.

7.  If there is change in the primary packing material the product should be treated as new product for conduction of stability studies.

8.  The stability studies should be performed on each individual strength of the drug product unless bracketing is applied.

9.  If the same product is having the different doses (different strengths) and identical production formulation, and but different production process then each should be treated as new product the stability study should be carried out separately for each of the strengths.

10.  The frequency of the testing for long term stability testing should be initial and after every 3 months over the first year, every 6 months over second year and annually thereafter through out the proposed shelf life.

11.  The frequency of the testing for accelerated stability testing should be initial 3 months and 6 months.

12.  While labeling the stability samples the terms ambient conditions or room temperature are not acceptable.

13.  The stability testing should cover chemical, physical, biological and microbiological attributes including preservative content and the testing of those attributes of the drug products that are susceptible to change during storage and are likely to influence quality, safety and or efficacy of the drug product.

14.  Out of three batches selected for stability study testing, the at least two batches should be pilot scale batches and third one can be smaller if justified.

15.  The photo stability testing should be carried out on at least one primary batch of the drug product.

HPLC related Interview Question

1. How the pH of mobile phase changes?

The pH of a mobile phase pH can change if u keep it for long hours due to the effect of CO2 from the atmosphere to affect pH.

Similarly, volatile reagents such as TFA may also selectively evaporate, thus changing the eluent pH.
A Buffer can help to reduce this effect to a certain extent.

2. Reagents used for modifying pH:

Mobile phase modifiers such as trifluoroacetic acid (TFA) or triethylamine (TEA) or Acetic Acid or Formic Acid or Ammonia or Triaryl methane can b used for this purpose.But the selection should help maintain pH  properly.
Therefore, we need buffers.

3. Effect of pH in HPLC:

The pH of your mobile phase can affect the
 Retention time and
Chromatographic peak shape issues like peak Tailing, Fronting, Shoulder etc.

4. Use of Buffers in HPLC:

A buffer is a solution that will resist a change in pH when small volumes of acid or alkali are added to it or when it is diluted with water.

Buffers are used in mobile phases to keep n maintain the pH constant after adjustment to the desired pH.

5. How to select a buffer:

For best results, use a buffer that has a pH at least 2 units away from the pKa for the analyte or eluant of interest in ur analysis.

6. Why is  Phosphoric Acid selected for pH adjustments of mobile phases:

Phosphoric acid is a weak acid compared to HCl, sulphuric acid etc .

But, the pka value for phosphoric acid is 2.12, 7.2 and 12.3. We can use for maximum  pH adjustments.Similarly, it has got a suitable UV cut-off value/Transparency.

Therefore, Phosphoric acid n its salts r used for pH adjustments or for the preparation of Buffers.

7. The effect of pH on stationary phase n chromatograms:

The column stationary phase is also affected by pH. At very low pH (<2) the bonded stationary phase will be stripped from the silica support. At high pH (>8) the silica itself will be damaged by dissolution.

If the pH of the mobile phase is too close to the analyte’s pKa, you might observe split peaks or shoulders.

Friday, January 27, 2017

Difference between Incidence and Deviation

 Differentiation between an incidence and deviation 

when it occurs in pharmaceutical GMP manufacturing facility. It causes a big confusion to understand the occurrence of incidence and deviation in pharmaceuticals. A huge number of pharmaceutical professionals difficulties to differentiate the incidence and deviation when they occur in real.
                                     When we have any written procedure like standard operating procedure, protocol, standard test procedure, BMR etc. and someone works against this, then it is called deviation. It means deviation from any written procedure that we have implemented. Now deviation can be of two different types:

  1.  Planned Deviation 
  2.  Unplanned Deviation

                  Planned deviations are those deviations from the procedure that are planned and we know before they occur. For example: calibration or validation is not carried out as per schedule due to delay for various reasons. In this case, we have to fill CAPA for the same. In case of unplanned deviation, the failure of procedure, utility, material, equipment or any system is occurred. We can consider it as any change from the previous or our written procedure. Unplanned deviations may be critical, major or minor.
               These can be categorised on their impact of product quality.

Critical deviations: Manufacturing instructions are not followed, wrong batch details are printed, SOPs or methods of testing not followed during analysis, etc.

Major deviations: Line clearance is not taken from QA, physician sample wrongly printed with price, etc.

Minor deviations: Raw material is received in a damaged container, manometer readings in the sampling booth are crossed the action limits, etc.

 Incidence is any event that can affect our product quality or not but that is against the cGMP. For example: Someone is found without gowning in the production area or any insect is found in granulation area.

These may have impact on product quality but not every time, sometime it will not impact. These are the deviations from GMP but difference is that these are not related to our manufacturing process. So, these will not be categorized as deviations.

Some other examples of incidence: Eating food in production area, spillage of material on floor, break down in any machine during processing, mix-up of two batches, wrong material added in batch etc.