References for Pharmaceutical Development Guidelines | WHO:

1. WHO Guidelines on submission of documentation for a multi source (generic) 

finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 4 (WHO Technical Report Series, No. 970).

2. Q6A: Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1999 http://www.ich.org/fileadmin /Public Web_Site/ICH_Products/Guidelines/Quality/Q6A/Step4/Q6Astep4.pdf.

3. The International Pharmacopoeia, 4th ed., Vol. 1. General notices; monographs for

pharmaceutical substances (A–O) and Vol. 2: Monographs for pharmaceutical substances

(P–Z); monographs for dosage forms and radiopharmaceutical preparations; methods of

analysis; reagents. Geneva, World Health Organization, 2006, also available in CD-ROM 

format and online.

The International Pharmacopoeia, 4th ed., First supplement. Geneva, World Health Organization, 2008 (http://apps.who.int/phint/en/p/docf/).

The International Pharmacopoeia, 4th ed., Second supplement, 2011, available on CD-ROM.

4. Prasad B. et al. A new validated differential scanning calorimetric procedure for monitoring the less active R,S isomer of ethambutol dihydrochloride in bulk drug samples and anti-tuberculosis formulations. Pharmacopeial Forum, 2007, 33: 326-333.

5. European pharmacopoeia, 7th ed. Strasbourg, European Directorate for the Quality of Medicines, 2010.

6. Guidelines for registration of fixed-dose combination medicinal products. In: WHO Expert

Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva,

World Health Organization, 2005, Annex 5 (WHO Technical Report Series, No. 929).

7. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2006, Annex 7 (WHO Technical Report Series, No. 937).

8. M4: ICH Harmonised Tripartite Guideline – Organisation of the common technical document for the registration of pharmaceuticals for human use. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2004 (http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R3_Organisation/M4_R3_organisation.pdf).

9. M4Q: ICH Harmonised Tripartite Guideline – The common technical document for the registration of pharmaceuticals for human use: quality. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2000.

10. Q8: Pharmaceutical development. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009 (http://www.ich.org/ fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf ).

11. Q9: Quality risk management. International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human Use, 2005 (http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf).

12. Q10: Pharmaceutical quality system. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008 (http://www.ich.org /fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf).

13. Inactive ingredient guide. US Food and Drug Administration (http://www.accessdata.fda.gov/scripts /cder/iig/index.cfm).

14. Rowe RC, Sheskey PJ, Quinn ME, eds. Handbook of pharmaceutical excipients, 6th ed. London, Pharmaceutical Press, 2009.

15. Excipients in the label and package leaflet of medicinal products for human use. 

Committee for Proprietary Medicinal Products, 2003 (CPMP/463/00Final).

16. Development of paediatric medicines: points to consider in pharmaceutical development. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization, 2012, Annex 5 (WHO Technical Report Series, No. 970).

17. Containers – glass. In: United States Pharmacopeia, 2nd suppl. Rockville, MD, 2007.

18. Glass containers for pharmaceutical use. In: European Pharmacopoeia. Strasbourg, European

Directorate for the Quality of Medicines, 2010: 303–307

19. Plastic containers and closures for pharmaceutical use. In: European Pharmacopoeia. Strasbourg, European Directorate for the Quality of Medicines, 2010: 308–309.

20. Containers – plastic. In: United States Pharmacopeia, 2nd suppl. Rockville, MD, 2007.

21 Elastomeric closures for injections, In: United States Pharmacopeia, 2nd suppl. Rockville, MD, 2007: 144–145.

22. Rubber closures for containers. In: European Pharmacopoeia. Strasbourg, European Directorate for the Quality of Medicines, 2010: 316–317.

Appendix 1

Examples of presenting quality attributes of active pharmaceutical ingredients:

Physicochemical characteristics of the active pharmaceutical ingredient (API) that can influence manufacturing capability and the performance of the finished pharmaceutical product (FPP) should be tabulated and discussed, for example, as in the following tables.

pH (of the buffer)	Solubility (mg/ml)
1.2 4.5 6.8 pKa of API

 

Method (compendial):

Particle size of API used in relevant laboratory and pilot-scale batches
Measured   data (μm)	Batch number (and use)				Proposed acceptance range (μm)
	<API batch no.> <FPP batch no.>(design)	<API batch no.>  <FPP batch no.> (final laboratory)	<API batch no.> <FPP batch no.>(stability)	<API batch no.><FPP batch no.>(bioequivalence)
D 10  D 50 D 90
Add rows as needed. Change data range as relevant

 Method (compendial):

	Apparent density of API used in relevant laboratory and pilot-scale batches
	<API batch no.> <FPP batch no.>(design)	<API batch no.>  <FPP batch no.> (final laboratory)	<API batch no.> <FPP batch no.>(stability)	<API batch no.><FPP batch no.>(bioequivalence)	Proposed acceptance range(g/ml)
Bulk Tapped

Method (compendial):

Stress Condition	Treatment	Observations
None	Initial values of the API	Assay: S1: Insert as many rows as necessary D1: Insert as many rows as necessary Total unspecified: Total impurities:
Temperature	A thin layer of the API is kept at 80 °C for 4 weeks in a Petri dish (open system) with sampling once a week	Assay: S1: D1: Total unspecified: Total impurities:

   

Method (compendial):

Stress Condition	Treatment	Observations
None	Initial values of the API	Assay: S1: Insert as many rows as necessary D1: Insert as many rows as necessary Total unspecified: Total impurities:
Temperature	A thin layer of the API is kept at 80 °C for 4 weeks in a Petri dish (open system) with sampling once a week	Assay: S1: D1: Total unspecified: Total impurities:
Humidity	A thin layer of the API is kept at 40 °C /100% relative humidity for 4 weeks in a Petri dish (open system) with sampling once a fortnight	Assay: S1: D1: Total unspecified: Total impurities:
Oxidation	Oxygen is bubbled slowly through the oxygen-saturated aqueous solution/suspension (under constant mixing) of the API for 24 hours with sampling every 8 hours	Assay: S1: D1: Total unspecified: Total impurities:

S1, S2, etc., are synthesis impurities (as in API specifications).

D1, D2, etc., are degradation products.

 Appendix 2

Information on development batches:

Table 1

Screening laboratory batches with different proportions of excipients to match comparator dissolution

Composition of formulation development experiments
Ingredients	Lab01		Lab02		Lab03		Lab04
	Grams	%	Grams	%	Grams	%	Grams	%
active  pharmaceutical ingredient (API) 1 API 2 API 3 Excipient 1 Excipient 2 Excipient 3 Excipient 4 Excipient 5 Dissolution, % at pH …

Table 2

Example table for developmental multipoint dissolution profiles (hypothetical example – Ph. Int., paddle, 75 rpm, 900 ml)

	Percentage API dissolved	Percentage API dissolved	Percentage API dissolved
Time(min)	pH 1.2 buffer	pH 4.5 buffer	pH 6.8 buffer
5 10 15 20 30 45 60 90

Repeat the table as needed, for example, for comparator product and development batch chosen for scale-up.

When comparing dissolution profiles of products, for example, comparator and test products or different strengths of the same product, the dissolution conditions and sampling intervals must be the same.

Graphical presentation and summary evaluation of the results of comparative dissolution studies of the test (samples taken from the bioequivalence batch no. …) and comparator products:

Pharmaceutical Development of Multi source (generic) Finished Pharmaceutical Products – points to consider, (Annex 3, WHO Technical Report Series 970, 2012)