The document provides guidance on good manufacturing practices for the production of active pharmaceutical ingredients. It discusses quality management, personnel, facilities, equipment, documentation, materials management, production controls, and other quality assurance aspects of API manufacturing. The objective is to help ensure APIs meet quality and purity standards.

1. Prepared by: PARTH
M.Pharm (sem-II) Q.A
EN-Roll no.:4003
DEPARTMENT OF QUALITY
ASSURANCE(SSPC)
January 25, 2013 1

2. January 25, 2013 2

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
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4. CONTI.....
 Validation
 Rejection and re-use of materials
 Complaints and recalls
 Contract manufacturers
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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.
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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.
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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.
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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.
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9. QUALITY MANAGEMENT
Principle
 Responsibility of all persons involved in
manufacturing.
 Each manufacturer should establish, document, and
implement an effective system for managing quality
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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.
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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.
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12. PERSONNEL
 Adequate number
 Qualified
 Responsibilities of all personnel should be specified in
writing.
 Adequate training.
 Personnel Hygiene should be maintained.
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13. BUILDINGS AND FACILITIES
Following points should be considered:
 Design and Construction
 Utilities
 Water
 Lighting
 Sewage and Refuse
 Sanitation and Maintenance
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14. PROCESS EQUIPMENT
Following points should be considered
 Design and Construction
 Equipment Maintenance and Cleaning
 Calibration
 Computerized Systems
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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
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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.
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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;
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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.
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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.
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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
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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
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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
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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
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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.
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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.
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44. BIOTECHNOLOGY DERIVED PRODUCT
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45. General
 It is intended to address specific controls for APIs or
intermediates manufactured by cell culture or
fermentation using natural or recombinant organisms.
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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
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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
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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
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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.
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50.  The lifespan of the columns and the sterilization
method shall be defined.
 Particular care should be given to monitoring
microbial loads and endotoxins.
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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.
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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.
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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
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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
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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.
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56.  http://www.ich.org/LOB/media/MEDIA433.pdf
 http://whqlibdoc.who.int/publications/2004/part2.
pdf
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57. January 25, 2013 57