details of ICH guideline

1. Presented By
Prashik s shimPi
m.Pharm
rCPiPer

2. What Is ICH?What Is ICH?
International
Conference on
Harmonization
Of Technical Requirements
for the Registration of
Pharmaceuticals
for Human Use

3. Established in 1990 between the European Union,
Japan, and United States
Committed to reducing duplication during
research and development of new drugs while
safeguarding quality, safety and efficacy
Developed over 40 guidance documents mostly
addressing technical/regulatory requirements for
registering new human drug products

4. ICH MEMBERS
Regulatory agencies
EMEA - European Union
MHLW - Japan
FDA - US
Trade associations
EFPIA - Europe
JPMA - Japan
PhRMA - US

5. ICH Technical TopicsQuality (chemical and pharmaceutical QA)
Q1, Stability Testing
Safety (in vitro and in-vivo pre-clinical studies)
S1, Carcinogenicity Testing
Efficacy (clinical studies in human subject)
E6, Good Clinical Practices
Multidisciplinary (cross-cutting topics)
M1, Medical Terminology

6. 21 CFR 211 does not apply
to manufacture of APIs
PhRMA Guidelines for
Production, Packing,
Repacking or Holding of
Drug Substances is
insufficient
FDA’s Guide to
Inspection of BPCs
is obsolete
FDA’s Draft Guidance for
Industry: Manufacturing,
Processing or Holding
APIs will not be finalized
Q7 isQ7 is thethe
definitivedefinitive
GMPGMP
guidanceguidance
for APIs!for APIs!

8. What Is an Active
Pharmaceutical Ingredient (API)?
 Any substance or mixture of substances
intended to be used in the manufacture of a
drug (medicinal) product and that, when used
in the production of a drug, becomes an active
ingredient of the drug product.

9. Process Characteristics
API
APIAPI
BasicBasic
ChemicalsChemicals
BasicBasic
ChemicalsChemicals
Different Raw MaterialsDifferent Raw Materials
APIAPIAPIAPI
DrugDrug
ProductProduct
DrugDrug
ProductProduct

10. Process Characteristics
API Vs. Drug Product
APIAPI DrugDrug
ProductProduct
DrugDrug
ProductProduct
Chemical & BiologicalChemical & Biological
ProcessingProcessing
(synthesis, fermentation,(synthesis, fermentation,
extraction, purification)extraction, purification)
Different Facilities, Equipment and ProcessesDifferent Facilities, Equipment and Processes
Physical ProcessingPhysical Processing
(granulating, dissolving,(granulating, dissolving,
mixing, compressing)mixing, compressing)

12. QUALITY MANAGEMENT
There should be a quality unit which is
- independent of production
- fulfils both Q.A. & Q.C. responsibilities
1) Q.C. Unit :-
- Releasing or rejecting all API
- Releasing or rejecting raw materials,
packing & labeling materials

13. 2) Q.A Unit :-
- Review & approve all quality related
documents.
- Review of batch production & quality
control records.
- Reviewing & Approving validation
protocols.
- Internal audits.

14. PERSONNELQualification
Responsibilities
Personnel hygiene
- Personnel suffering from infectious
disease or having open lesions on the
exposed surface of the body should not
engage in activities.
- smoking, eating, drinking, chewing should
be restricted.

15. BUILDING & FACILITIES1) Design & Construction :-
 Buildings & facilities should have adequate space for
the orderly placement of equipment & material to
prevent mix ups & contamination.
 Design of building should be such that there is a
minimum flow of material or personnel through
manufacturing area to prevent contamination.

16.  Defined areas for following activities.
- Receipt, identification,sampling &
quarantine of incoming materials.
- Quarantine area before release or
rejection of API.
- Retain sample area.
- Production operation.
- Packing & Labeling operations.
- Laboratory operation.
Laboratory area should be separated from
production area.

17. Separate production area should be employed for
-Production of highly sensitizing materials such
as penicillin or cephalosporin.
-Materials having high pharmacological activity
or toxicity.

18. 2) Process water quality
Potable water acceptable for preparation of USP drug
substances
Purified water used in later isolation and purification
steps

19. Water used in final isolation and purification steps
of a non-sterile API intended for producing a sterile
drug product should be monitored and controlled
for :-
Total microbial counts
Objectionable organisms
Endotoxins

20. 3) Sanitation
- Written procedure should be established
for the use of rodenticide, insecticide,
fungicide, & sanitizing agent to prevent
the contamination of equipment,
raw materials & packing materials.

21. PROCESS EQUIPMENTEquipment should be of appropriate design,
adequate size & suitably located for it’s intended
use.
Equipment should be constructed so that surfaces
that contact raw materials, intermediates, do not
alter the quality of raw materials.
Any substances associated with operation of
equipment, should not contact intermediates or
API.
Weighing, monitoring & test equipment that is
critical for assuring the quality of intermediates or
API should be calibrated & the records of calibration
should be maintained.

22. DOCUMENTATIONAll documents related to the manufacture of
intermediates or API should be prepared, reviewed,
approved, & distributed according to written
procedure.
All production, control, & distribution records
should be retained for at lest 1 year after the expiry
date of the batch.
For API with retest dates, records should be
retained for at least 3 years after the batch is
completely distributed.

23. A) Equipment Cleaning & Use records :-
- Records of major equipment use, cleaning & sterilization
should show the date, time, product, batch number,
& the person who performed the cleaning.
B) Master Production Record :-
- To ensure uniformity from batch to batch ,
master production instruction for each intermediates &
API should be prepared, dated,& signed by the Q.A.
unit.
 Master production instructions should include,
1) The name of the intermediates or API being
manufactured & document reference code.
2) List of raw material & it’s quality characteristics.
3) Accurate quantity of each raw material with unit of
measures.
4) List of major production equipment to be used.

24. 5) Detailed production instructions like
- Sequence to be followed.
- Sampling instructions & in process controls.
- Time limit for completion of individual
processing
steps.
6) Labeling & packing materials.
7) Instruction for storage of intermediates or API.

25. C) Batch Production Record :-
Batch production record should include,
1) Name of API
2) Batch No.
3) Date
4) Identity of major equipment.
5) Specific identification of each batch
including weight, measures, &
batch no. of raw materials.
6) Signature of the person performing &
directly supervising the each critical
steps in the operation.

26. 7) In process & laboratory test results
8) Description of packaging & label for API
D) Laboratory Control Records :-
1) Description of samples received for testing
which includes,
- Material name
- Batch No.
- Date of Sampling
- Quantity
- Date – the sample was received
for testing.
2) Reference to each test method.

27. 3) Weight of sample used for each test.
4) A complete record of all raw data
generated during each test with graphs,
charts & spectra from laboratory
instrumentation.
5) Signature of the person who performed
each test & the date on which the tests
were performed.
6) Date & Signature of a second person
showing that the original records have
been reviewed for accuracy, & completeness.

28. PACKAGING AND IDENTIFICATION LABELLING OF APIs
There should be written procedures describing
the receipt, identification, quarantine, sampling,
examination and/or testing and release, and
handling of packaging and labeling materials.
Packaging and labeling materials should conform
to established specifications. Those that do not
comply with such specifications should be
rejected to prevent their use in operations for
which they are unsuitable.

29. Containers should provide adequate protection
against deterioration or contamination of the
intermediate or API that may occur during
transportation and recommended storage.
Containers should not be reactive, additive, or
absorptive so as to alter the quality of the
intermediate or API beyond the specified limits.
All excess labels bearing batch numbers or other
batch-related printing should be destroyed. Returned
labels should be maintained and stored in a manner
that prevents mix-ups and provides proper
identification.

30. Labels used on containers of intermediates or APIs
should indicate the name or identifying code, the
batch number of the product, and storage conditions

31. VALIDATION What Is Validation ?
Establishing documented evidence which provides
a high degree of assurance that a specific process will
consistently produce a product meeting it’s pre-
determined specifications & quality attributes.

32.  QUALIFICATION :-
1) Design Qualification (DQ) :-
The purpose of design qualification is to make
ensure that the design of the facilities,
Equipment, or System is suitable for the
intended purpose.
2) Installation Qualification (IQ) :-
The purpose of installation qualification is to make
ensure that the system is correctly installed & the
installation requirements are fulfilled.

33. 3) Operational Qualification (OQ) :-
The purpose of operational qualification is to
make sure that the system has the functions
specified and that it works properly as
specified in the functional specification.
4) Performance Qualification (PQ):-
The purpose of performance qualification is to
qualify that the process can perform as specified in
the user requirement specification.

34. Process Validation
Process Validation (PV) is the documented evidence
that the process, operated within established
parameters, can perform effectively and reproducibly
to produce an intermediate or API meeting its
predetermined specifications and quality attributes.

35. Types of Process Validation
1) Prospective validation :-
 Prospective validation should normally be
performed for all API processes.
 Prospective validation performed on an API process
should be completed before the commercial
distribution of the final drug product manufactured
from that API.

36. 2) Concurrent Validation :-
Concurrent validation is a subset of prospective
validation and is conducted with the intention of
ultimately distributing product manufactured during
the validation study.
3) 2) Concurrent Validation :-
Concurrent validation is a subset of prospective
validation and is conducted with the intention of
ultimately distributing product manufactured during
the validation study

37. Stability Monitoring of APIs
The test procedures used in stability testing should be
validated.
Stability samples should be stored in containers that
simulate the market container.
Normally the first three commercial production
batches should be placed on the stability monitoring
program to confirm the retest or expiry date.