3. Introduction
Quality management
Personnel
Buildings and facilities
Process equipment
Documentation and records
Materials management
Production and in-process controls
Packaging and identification labelling of API
and intermediates
Storage and distribution
January 25, 2013 3
5. Regulatory Applicability
Within the world community, materials may vary as
to the legal classification as an API.
When a material is classified as an API in the region
or country in which it is manufactured or used in a
drug product, it should be manufactured according to
this Guide.
January 25, 2013 5
6. Objective
1. Provide guidance regarding good
manufacturing practice (GMP) for the
manufacturing of active pharmaceutical
ingredients (APIs) under an appropriate system
for managing quality.
2. Help ensure that APIs meet the requirements
for quality and purity that they purport or are
represented to possess.
January 25, 2013 6
7. Scope
This Guide applies to the manufacture of
APIs.
Sterile APIs only up to the point immediately prior
to the APIs being rendered sterile.
January 25, 2013 7
8. This Guide covers APIs that are manufactured by
chemical synthesis, extraction, by recovery from
natural sources, or by any combination of these
processes.
Excludes all vaccines, whole cells, whole blood and
plasma, blood and plasma derivatives (plasma
fractionation), and gene therapy APIs.
January 25, 2013 8
9. QUALITY MANAGEMENT
Principle
Responsibility of all persons involved in
manufacturing.
Each manufacturer should establish, document, and
implement an effective system for managing quality
January 25, 2013 9
10. CONTI....
Should provide the organisational structure,
procedures, processes and resources, as well as
activities necessary to ensure confidence that the
API will meet its intended specifications for
quality and purity
Allquality related activities should be defined
and documented.
January 25, 2013 10
11. CONTI...
There should be a quality unit(s) that fulfils both
quality assurance (QA) and quality control (QC)
responsibilities.
Regular internal audits should be performed.
Allquality related activities should be recorded at the
time they are performed.
deviation should be documented and explained.
January 25, 2013 11
12. PERSONNEL
Adequate number
Qualified
Responsibilities of all personnel should be specified in
writing.
Adequate training.
Personnel Hygiene should be maintained.
January 25, 2013 12
13. BUILDINGS AND FACILITIES
Following points should be considered:
Design and Construction
Utilities
Water
Lighting
Sewage and Refuse
Sanitation and Maintenance
January 25, 2013 13
14. PROCESS EQUIPMENT
Following points should be considered
Design and Construction
Equipment Maintenance and Cleaning
Calibration
Computerized Systems
January 25, 2013 14
15. DOCUMENTATION AND RECORDS
1. Equipment Cleaning and Use Record
2.Records of Raw Materials, Intermediates, API
Labelling and Packaging Materials
3. Master Production and Control Records
4. Batch Production and Control Records
5. Laboratory Control Records
6. Batch Production Record Review
January 25, 2013 15
16. 1. Equipment Cleaning and Use Record
Major equipment use, cleaning, sanitization and/or
sterilization and maintenance
Date, time (if appropriate), product, and batch
number of each batch processed
The person who performed the cleaning and
maintenance.
January 25, 2013 16
17. 2. Records of Raw Materials, Intermediates, API
Labelling and Packaging Materials
Name of the manufacturer, identity and quantity of each
shipment of each batch
Name of the supplier; the supplier's control number(s),
if known, or other identification number;
The number allocated on receipt; and the date of
receipt;
January 25, 2013 17
18. The results of any test or examination performed and
the conclusions derived from this;
Records tracing the use of materials;
The final decision regarding rejected raw materials,
intermediates or API labelling and packaging materials.
Master(approved) labels should be maintained for
comparison to issued labels.
January 25, 2013 18
19. 3. Master Production and Control Records
To ensure uniformity from batch to batch
Dated,and signed by one person and independently
checked, dated, and signed by a person in the quality
unit.
January 25, 2013 19
20. should include:
The name of the intermediate or API being
manufactured
A complete list of raw materials and intermediates
designated by names or codes
The production location and major production
equipment to be used;
The instructions for storage
Special storage conditions with time limits
January 25, 2013 20
21. 4. Batch Production and Control Records
Should include complete information relating to the
production and control of each batch.
Documentation of each significant step like
• Dates and, when appropriate, times;
• Identity of major equipment
• weights, measures, and batch numbers of raw materials,
intermediates, or reprocessed materials
• Any sampling performed;
• Actual yield
January 25, 2013 21
22. Laboratory Control Records
should include
complete data derived from all tests conducted to
ensure compliance with established specifications
and standards, including examinations and assays
The quantity and date the sample was received for
testing;
A statement of or reference to each test method
used
All data generated i.e. graphs, charts, spectra
All calculations performed
Signature of the person who performed each test
Signature of a second person who reviewed
January 25, 2013 22
23. MATERIALS MANAGEMENT
General Controls
written procedures for receipt, identification, quarantine,
storage, handling, sampling, testing, and approval or
rejection of materials.
System evaluation of supplier of critical materials.
Receipt and Quarantine
Upon receipt and before acceptance container examined
visually for correct labelling
Materials should be held under quarantine until they
have been sampled, examined or tested as appropriate,
and then released for use.
January 25, 2013 23
24. Sampling and Testing of Incoming Production
Materials
At least one test to verify the identity of each batch
A supplier's Certificate of Analysis used in place for
performing other tests
Full analyses should be conducted on at least three
batches before reducing in-house testing
January 25, 2013 24
25. Storage
Such to prevent degradation, contamination, and cross-
contamination.
Materials stored in fiber drums, bags, boxes should be
stored off the floor, suitably spaced to permit cleaning
and inspection.
Usage should be such that oldest stock is used first.
Re-evaluation
To determine their suitability for use e.g., after
prolonged storage or exposure to heat or humidity.
January 25, 2013 25
26. PRODUCTION AND IN-PROCESS
CONTROLS
Production Operations
Raw materials should be weighed under appropriate
conditions that do not affect their suitability for use.
All measuring devices should be calibrated
Critical activities should be witnessed or subjected to an
equivalent control.
January 25, 2013 26
27. Actual yields should be compared with expected yields
at designated steps in the production process.
Expected yields with appropriate ranges should be
established based on previous laboratory, pilot scale, or
manufacturing data.
Deviations should be investigated documented and
explained.
Any critical deviation should be investigated.
Materials to be reprocessed or reworked should be
appropriately controlled to prevent unauthorized use.
January 25, 2013 27
28. In-process Sampling and Controls
Written procedures should be established to monitor the
progress and control the performance of processing
steps that cause variability in the quality characteristics
of intermediates and APIs.
In-process controls and their acceptance criteria should
be defined based on the information gained during the
development stage or historical data.
January 25, 2013 28
29. Critical in-process controls, the control points and
methods, should be stated in writing and approved by
the quality unit.
Sampling should be in a manner to prevent
contamination of the sampled material.
Integrity of samples maintained after collection.
January 25, 2013 29
30. Blending Batches of Intermediates or APIs
Process of combining materials within the same
specification to produce a homogeneous intermediate or
API.
Batches should be
Adequately controlled documented and tested for
conformance
If the blending could adversely affect stability, stability
testing of the final blended batches should be performed.
January 25, 2013 30
31. PACKAGING AND IDENTIFICATION
LABELLING OF APIs AND INTERMEDIATES
Packaging Materials
Provide adequate protection during transportation and
storage.
Clean, sanitized
They should not be reactive, additive or absorptive
For re-use, clean in accordance with documented
procedures
All previous labels should be removed or defaced.
January 25, 2013 31
32. Label Issuance and Control
Access to the label storage areas should be limited to
authorised personnel.
Proceduresshould be used to evaluate discrepancies
found between the number of containers labelled and
the number of labels issued.
Allexcess labels bearing batch numbers or other batch-
related printing should be destroyed.
January 25, 2013 32
33. Returned labels should be stored in a manner that
prevents mix-ups and provides proper identification.
Obsolete and out-dated labels should be destroyed.
A printed label representative of those used should be
included in the batch production record.
January 25, 2013 33
34. Packaging and Labelling Operations
Documented procedures should be followed
Prevent mix-ups.
For transport outside the management system, the name
and address of the manufacturer, quantity of contents,
and special transport conditions and any special legal
requirements should also be included on the label.
The expiry date/retest date should be indicated on the
label and Certificate of Analysis.
January 25, 2013 34
35. inspected immediately before use for line clearance
examination to ensure correct labelling
For containers transported outside of the manufacturer's
control should be sealed in a manner such that, if the
seal is breached or missing, the recipient will be alerted
to the possibility that the contents may have been
altered.
January 25, 2013 35
36. STORAGE AND DISTRIBUTION
Warehousing Procedures
Appropriate conditions (e.g. controlled temperature and
humidity when necessary).
Records should be maintained of these conditions
separate storage areas for rejected, returned, or recalled
materials
Distribution Procedures
Only after they have been released by the quality unit.
transferred under quarantine to another unit under the
company’s control when authorized by the quality unit
and if appropriate controls and documentation are in
place.
January 25, 2013 36
37. Should be transported in a manner that does not
adversely affect their quality.
Special transport or storage conditions should be stated
on the label.
Ensure that the contract acceptor (contractor) knows
and follows the appropriate transport and storage
conditions.
A system should be in place to permit its recall.
January 25, 2013 37
38. VALIDATION
Validation Policy
The company's overall policy, intentions, and approach
to validation, including the validation of production
processes, cleaning procedures, analytical methods, in-
process control test procedures, computerized systems,
and
persons responsible for design, review, approval and
documentation of each validation phase, should be
documented.
critical parameters, ranges should be defined.
January 25, 2013 38
39. Validation Documentation
how validation of a particular process is conducted.
type of validation conducted (e.g. retrospective,
prospective, concurrent)
Equipment validation
Before starting process validation activities
qualification of critical equipment and
ancillary systems should be completed i.e. DQ,
IQ, PQ, OQ
January 25, 2013 39
40. Cleaning Validation
Directed to situations or process steps where
contamination or carryover of materials poses the
greatest risk to API quality.
Sampling should include swabbing, rinsing, or
alternative methods as appropriate, to detect both
insoluble and soluble residues.
Validation of Analytical Methods
Analytical methods should be validated unless the
method employed is included in the relevant
pharmacopoeia or other recognised standard
reference.
January 25, 2013 40
41. REJECTION AND RE-USE OF MATERIALS
Rejection
failing to meet established specifications
Quarantined
reprocessed or reworked
Reprocessing
By repeating a crystallization step or other appropriate
chemical or physical manipulation steps e.g.
distillation, filtration, chromatography, milling
January 25, 2013 41
42. Recovery of Materials and Solvents
Recovery e.g. from mother liquor or filtrates of
reactants, intermediates, or the API and solvents is
considered acceptable,
provided that approved procedures exist for the recovery
and the recovered materials meet specifications suitable
for their intended use.
use of recovered solvents should be adequately
documented.
January 25, 2013 42
43. Returns
Identified and quarantined.
Reprocessed, reworked, or destroyed, as appropriate.
Records should be maintained.
COMPLAINTS AND RECALLS
CONTRACT MANUFACTURERS
(INCLUDING LABORATORIES)
should comply with the GMP defined in this Guide.
January 25, 2013 43
45. General
It is intended to address specific controls for APIs or
intermediates manufactured by cell culture or
fermentation using natural or recombinant organisms.
January 25, 2013 45
46. Products manufactured by this method
include:
Allergens extract
Antigens
Vaccines
Human whole blood and plasma derivatives etc..
Personnel
High standards of personnel hygiene and cleanliness are
essential.
Personnel should be trained in appropriate fields like
chemistry, virology, bacteriology, medicine
immunology.
All personnel should be vaccinated
January 25, 2013 46
47. PREMISES AND EQUIPMENTS
Live organisms shall be handled in equipment to ensure
that cultures are maintained in a pure state and are not
contaminated during processing.
Seed lots and cell banks should be stored separately
from other material.
Sterilized containers or that are documented as low
bioburden should be used.
Specific decontamination systems should be considered
for effluent when infectious materials are used for
production
January 25, 2013 47
48. ANIMAL QUARTER AND CARE
Accommodation shall be in separate building with self
contained ventilation system
Clean and sanitary condition shall be maintained
Separate inoculation and postmortem room should be
provided
Cages should be disinfected possible by steam
Incinerator provided for disposing of animal waste
Health status should be monitored
January 25, 2013 48
49. PRODUCTION
Media and cultures should be carefully added
under controlled condition to avoid
contamination.
If possible media should be sterilized insitu.
In line sterilizing filters for routine addition of
gases, media, acids etc to fermenters should be
used.
A wide variety of equipment if used for
chromatography such equipment should be
dedicated to purification of one product.
January 25, 2013 49
50. The lifespan of the columns and the sterilization
method shall be defined.
Particular care should be given to monitoring
microbial loads and endotoxins.
January 25, 2013 50
51. Label should include:
The name of the drug product
A list of active ingredients, amount
Batch number
Expiry date
Storage condition
Direction for use
Name and address of manufacturer.
January 25, 2013 51
52. LOT PROCESSING RECORDS AND
DISTRIBUTION RECORDS
A complete account of the manufacturing history
of each lot of a biological preparation, showing
that it has been manufactured, tested, dispensed
into containers and distributed in accordance with
the licensed procedures.
January 25, 2013 52
53. Processing record shall include;
Name and dosage form
Date of manufacture and identification number
Formulation
Yield obtained
Record of all in-process control test
Specimen of label
Identification of packaging material
January 25, 2013 53
54. Quality assurance and quality control
Principal duties
To prepare detail instruction for each analysis
To ensure adequate identification and
segregation of test sample to avoid mix up
To ensure environmental monitoring
To release and reject raw material, intermediates
and finished products
To establish expiry dates
January 25, 2013 54
55. Performance of all qualitative and quantitative
test for starting material may be replaced by
certificates issued by the producer of starting
material provided that :
There is history of reliable product
The producer is regularly audited
Sample of intermediate and final products shall be
retained in the sufficient amount in appropriate
storage condition.
January 25, 2013 55
56. http://www.ich.org/LOB/media/MEDIA433.pdf
http://whqlibdoc.who.int/publications/2004/part2.
pdf
January 25, 2013 56