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.