Good Manufacturing Practice (CGMP) for Active Pharmaceutical Ingredients( API)
1. Introduction
1.1 Objective
This
document (Guide) is intended to provide guidance regarding good manufacturing
practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs)
under an appropriate system for managing quality. It is also intended to help
ensure that APIs meet the requirements for quality and purity that they purport
or are represented to possess. In this Guide “manufacturing” is defined to
include all operations of receipt of materials, production, packaging,
repackaging, labelling, relabelling, quality control, release, storage and
distribution of APIs and the related controls. In this Guide the term “should”
indicates recommendations that are expected to apply unless shown to be
inapplicable or replaced by an alternative demonstrated to provide at least an
equivalent level of quality assurance. For the purposes of this Guide, the
terms “current good manufacturing practices” and “good manufacturing practices”
are equivalent. The Guide as a whole does not cover safety aspects for the
personnel engaged in the manufacture, nor aspects of protection of the
environment. These controls are inherent responsibilities of the manufacturer
and are governed by national laws. This Guide is not intended to define
registration/filing requirements or modify pharmacopoeial requirements. This
Guide does not affect the ability of the responsible regulatory agency to
establish specific registration/filing requirements regarding APIs within the
context of marketing/manufacturing authorizations or drug applications. All
commitments in registration/filing documents must be met.
1.2 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.
1.3 Scope
This
Guide applies to the manufacture of APIs for use in human drug (medicinal)
products. It
applies
to the manufacture of sterile APIs only up to the point immediately prior to
the APIs
being
rendered sterile. The sterilization and aseptic processing of sterile APIs are
not covered by this guidance, but should be performed in accordance with GMP
guidelines for drug (medicinal) products as defined by local authorities. This
Guide covers APIs that are manufactured by chemical synthesis, extraction, cell
culture/fermentation, by recovery from natural sources, or by any combination
of these processes. Specific guidance for APIs manufactured by cell
culture/fermentation is described in Section 18. This Guide excludes all
vaccines, whole cells, whole blood and plasma, blood and plasma derivatives
(plasma fractionation), and gene therapy APIs. However, it does include APIs
that are produced using blood or plasma as raw materials. Note that cell
substrates (mammalian, plant, insect or microbial cells, tissue or animal
sources including transgenic animals) and early process steps may be subject to
GMP but are not covered by this Guide. In addition, the Guide does not apply to
medical gases, bulk-packaged drug (medicinal) products, and
manufacturing/control aspects specific to radiopharmaceuticals. Section 19
contains guidance that only applies to the manufacture of APIs used in the
production
of drug (medicinal)
products specifically for clinical trials (investigational medicinal products).
An “API Starting
Material” is a raw material, intermediate, or an API that is used in the
production of an API and that is incorporated as a significant structural
fragment into the structure of the API. An API Starting Material can be an
article of commerce, a material purchased from one or more suppliers under
contract or commercial agreement, or produced inhouse. API Starting Materials
normally have defined chemical properties and structure.
The company should
designate and document the rationale for the point at which production of the
API begins. For synthetic processes, this is known as the point at which
"API Starting Materials" are entered into the process. For other
processes (e.g. fermentation, extraction, purification, etc), this rationale
should be established on a case-by-case basis. Table 1 gives guidance on the
point at which the API Starting Material is normally introduced into the
process. From this point on, appropriate GMP as defined in this Guide should be
applied to these intermediate and/or API manufacturing steps. This would
include the validation of critical process steps determined to impact the
quality of the API. However, it should be noted that the fact that a company
chooses to validate a process step does not necessarily define that step as
critical.
The
guidance in this document would normally be applied to the steps shown in gray
in Table.
It does
not imply that all steps shown should be completed. The stringency of GMP in
API manufacturing should increase as the process proceeds from early API steps
to final steps, purification, and packaging. Physical processing of APIs, such
as granulation, coating or physical manipulation of particle size (e.g.
milling, micronizing), should be conducted at least to the standards of this
Guide. This GMP Guide does not apply to steps prior to the introduction of the
defined "API Starting Material".
Table : Application of this Guide to API Manufacturing
c
2.1 Principles
2.10 Quality should be the responsibility of all
persons involved in manufacturing.
2.11
Each manufacturer should establish, document, and implement an effective system
for managing quality that involves the active participation of management and
appropriate manufacturing personnel.
2.12 The
system for managing quality should encompass 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. All quality related activities should be defined and documented.
2.13
There should be a quality unit(s) that is independent of production and that
fulfills both
quality
assurance (QA) and quality control (QC) responsibilities. This can be in the form
of separate QA and QC units or a single individual or group, depending upon the
size and structure of the organization.
2.14 The
persons authorised to release intermediates and APIs should be specified.
2.15 All
quality related activities should be recorded at the time they are performed.
2.16 Any
deviation from established procedures should be documented and explained.
Critical deviations should be investigated, and the investigation and its
conclusions should be documented.
2.17 No
materials should be released or used before the satisfactory completion of
evaluation
by the
quality unit(s) unless there are appropriate systems in place to allow for such
use (e.g. release under quarantine as described in Section 10.20 or the use of
raw materials or intermediates pending completion of evaluation).
2.18
Procedures should exist for notifying responsible management in a timely manner
of regulatory inspections, serious GMP deficiencies, product defects and
related actions (e.g. quality related complaints, recalls, regulatory actions,
etc.).
2.2 Responsibilities of the Quality Unit(s)
2.20 The
quality unit(s) should be involved in all quality-related matters.
2.21 The
quality unit(s) should review and approve all appropriate quality-related
documents.
2.22 The
main responsibilities of the independent quality unit(s) should not be
delegated.
These
responsibilities should be described in writing and should include but not
necessarily be limited to:
1.
Releasing or rejecting all APIs. Releasing or rejecting intermediates for use
outside
the
control of the manufacturing company;
2.
Establishing a system to release or reject raw materials, intermediates,
packaging
and
labelling materials;
3.
Reviewing completed batch production and laboratory control records of critical
process
steps before release of the API for distribution;
4.
Making sure that critical deviations are investigated and resolved;
5.
Approving all specifications and master production instructions;
6. Approving all procedures impacting the quality of intermediates
or APIs;
7. Making sure that internal audits (self-inspections) are
performed;
8. Approving intermediate and API contract manufacturers;
9. Approving changes that potentially impact intermediate or API
quality;
10. Reviewing and approving validation protocols and reports;
11. Making sure that quality related complaints are investigated
and resolved;
12. Making sure that effective systems are used for maintaining
and calibrating critical
equipment;
13. Making sure that materials are appropriately tested and the
results are reported;
14. Making sure that there is stability data to support retest or
expiry dates and storage
conditions on APIs and/or intermediates where appropriate; and
15. Performing product quality reviews (as defined in Section 2.5)
2.3 Responsibility for Production Activities
The responsibility for production activities should be described
in writing, and should include but not necessarily be limited to:
1. Preparing, reviewing, approving and distributing the
instructions for the production of intermediates or APIs according to written
procedures;
2. Producing APIs and, when appropriate, intermediates according
to pre-approved instructions;
3. Reviewing all production batch records and ensuring that these
are completed and signed;
4. Making sure that all production deviations are reported and
evaluated and that critical deviations are investigated and the conclusions are
recorded;
5. Making sure that production facilities are clean and when
appropriate disinfected;
6. Making sure that the necessary calibrations are performed and
records kept;
7. Making sure that the premises and equipment are maintained and
records kept;
8. Making sure that validation protocols and reports are reviewed
and approved;
9. Evaluating proposed changes in product, process or equipment;
and
10. Making sure that new and, when appropriate, modified
facilities and equipment are qualified.
2.4 Internal Audits (Self Inspection)
2.40 In order to verify compliance with the principles of GMP for
APIs, regular internal audits should be performed in accordance with an
approved schedule.
2.41 Audit findings and corrective actions should be documented
and brought to the attention of responsible management of the firm. Agreed
corrective actions should be completed in a timely and effective manner.
2.5 Product Quality Review
2.50 Regular quality reviews of APIs should be conducted with the
objective of verifying the consistency of the process. Such reviews should
normally be conducted and documented annually and should include at least:
- A review of critical in-process control and critical API test
results;
- A review of all batches that failed to meet established
specification(s);
- A review of all critical deviations or non-conformances and
related investigations;
- A review of any changes carried out to the processes or
analytical methods;
- A review of results of the stability monitoring program;
- A review of all quality-related returns, complaints and recalls;
and
- A review of adequacy of corrective actions.
2.51 The results of this review should be evaluated and an
assessment made of whether corrective action or any revalidation should be undertaken.
Reasons for such corrective
action should be documented. Agreed corrective actions should be
completed in a timely and effective manner.
3 .Personnel
3.1 Personnel Qualifications
3.10 There should be an adequate number of personnel qualified by
appropriate education, training and/or experience to perform and supervise the
manufacture of intermediates and APIs.
3.11 The responsibilities of all personnel engaged in the
manufacture of intermediates and APIs should be specified in writing.
3.12 Training should be regularly conducted by qualified
individuals and should cover, at a minimum, the particular operations that the
employee performs and GMP as it relates to the employee's functions. Records of
training should be maintained. Training should be periodically assessed.
3.2 Personnel Hygiene
3.20 Personnel should practice good sanitation and health habits.
3.21 Personnel should wear clean clothing suitable for the
manufacturing activity with which they are involved and this clothing should be
changed when appropriate. Additional protective apparel, such as head, face,
hand, and arm coverings, should be worn when necessary, to protect
intermediates and APIs from contamination.
3.22 Personnel should avoid direct contact with intermediates or
APIs.
3.23 Smoking, eating, drinking, chewing and the storage of food
should be restricted to certain designated areas separate from the
manufacturing areas.
3.24 Personnel suffering from an infectious disease or having open
lesions on the exposed surface of the body should not engage in activities that
could result in compromising the quality of APIs. Any person shown at any time
(either by medical examination or supervisory observation) to have an apparent
illness or open lesions should be excluded from activities where the health
condition could adversely affect the quality of the APIs
until the condition is corrected or qualified medical personnel
determine that the person's inclusion would not jeopardize the safety or
quality of the APIs.
3.3 Consultants
3.30 Consultants advising on the manufacture and control of
intermediates or APIs should have sufficient education, training, and
experience, or any combination thereof, to advise on the subject for which they
are retained.
3.31 Records should be maintained stating the name, address,
qualifications, and type of service provided by these consultants.
4. Buildings and
Facilities
4.1 Design and Construction
4.10 Buildings and facilities used in the manufacture of
intermediates and APIs should be located, designed, and constructed to
facilitate cleaning, maintenance, and operations as appropriate to the type and
stage of manufacture. Facilities should also be designed to minimize potential
contamination. Where microbiological specifications have been established for the
intermediate or API, facilities should also be designed to limit exposure to
objectionable microbiological contaminants as appropriate.
4.11 Buildings and facilities should have adequate space for the
orderly placement of equipment and materials to prevent mix-ups and
contamination.
4.12 Where the equipment itself (e.g., closed or contained
systems) provides adequate protection of the material, such equipment can be
located outdoors.
4.13 The flow of materials and personnel through the building or
facilities should be designed to prevent mix-ups or contamination.
4.14 There should be defined areas or other control systems for
the following activities:
- Receipt, identification, sampling, and quarantine of incoming
materials, pending release or rejection;
- Quarantine before release or rejection of intermediates and
APIs;
- Sampling of intermediates and APIs;
- Holding rejected materials before further disposition (e.g.,
return, reprocessing or destruction);
- Storage of released materials;
- Production operations;
- Packaging and labelling operations; and
- Laboratory operations.
4.15 Adequate, clean washing and toilet facilities should be
provided for personnel. These washing facilities should be equipped with hot
and cold water as appropriate, soap or detergent, air driers or single service
towels. The washing and toilet facilities should be separate from, but easily
accessible to, manufacturing areas. Adequate facilities for showering and/or
changing clothes should be provided, when appropriate.
4.16 Laboratory areas/operations should normally be separated from
production areas. Some laboratory areas, in particular those used for
in-process controls, can be located in production areas, provided the
operations of the production process do not adversely affect the accuracy of
the laboratory measurements, and the laboratory and its operations do not
adversely affect the production process or intermediate or API.
4.2 Utilities
4.20 All utilities that could impact on product quality (e.g.
steam, gases, compressed air, and heating, ventilation and air conditioning)
should be qualified and appropriately monitored and action should be taken when
limits are exceeded. Drawings for these utility systems should be available.
4.21 Adequate ventilation, air filtration and exhaust systems
should be provided, where appropriate. These systems should be designed and
constructed to minimise risks of
contamination and cross-contamination and should include equipment
for control of air pressure, microorganisms (if appropriate), dust, humidity,
and temperature, as appropriate to the stage of manufacture. Particular
attention should be given to areas where APIs are exposed to the environment.
4.22 If air is recirculated to production areas, appropriate
measures should be taken to control risks of contamination and
cross-contamination.
4.23 Permanently installed pipework should be appropriately
identified. This can be accomplished by identifying individual lines,
documentation, computer control systems, or alternative means. Pipework should
be located to avoid risks of contamination of the
intermediate or API.
4.24 Drains should be of adequate size and should be provided with
an air break or a suitable device to prevent back-siphonage, when appropriate.
4.3 Water
4.30 Water used in the manufacture of APIs should be demonstrated
to be suitable for its intended use.
4.31 Unless otherwise justified, process water should, at a
minimum, meet World Health Organization (WHO) guidelines for drinking (potable)
water quality.
4.32 If drinking (potable) water is insufficient to assure API
quality, and tighter chemical and/or microbiological water quality
specifications are called for, appropriate specifications for physical/chemical
attributes, total microbial counts, objectionable organisms and/or endotoxins
should be established.
4.33 Where water used in the process is treated by the
manufacturer to achieve a defined quality, the treatment process should be
validated and monitored with appropriate action limits.
4.34 Where the manufacturer of a non-sterile API either intends or
claims that it is suitable for
use in further processing to produce a sterile drug (medicinal)
product, water used in the final isolation and purification steps should be
monitored and controlled for total microbial counts, objectionable organisms,
and endotoxins.
4.4 Containment
4.40 Dedicated production areas, which can include facilities, air
handling equipment and/or process equipment, should be employed in the
production of highly sensitizing materials, such as penicillins or
cephalosporins.
4.41 Dedicated production areas should also be considered when
material of an infectious nature or high pharmacological activity or toxicity
is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless
validated inactivation and/or cleaning procedures are established and
maintained.
4.42 Appropriate measures should be established and implemented to
prevent cross contamination from personnel, materials, etc. moving from one
dedicated area to another.
4.43 Any production activities (including weighing, milling, or
packaging) of highly toxic non pharmaceutical materials such as herbicides and
pesticides should not be conducted using the buildings and/or equipment being
used for the production of APIs. Handling and storage of these highly toxic
non-pharmaceutical materials should be separate from APIs.
4.5 Lighting
4.50 Adequate lighting should be provided in all areas to
facilitate cleaning, maintenance, and proper operations.
4.6 Sewage and Refuse
4.60 Sewage, refuse, and other waste (e.g., solids, liquids, or
gaseous by-products from manufacturing) in and from buildings and the immediate
surrounding area should be disposed of in a safe, timely, and sanitary manner.
Containers and/or pipes for waste material should be clearly identified.
4.7 Sanitation and Maintenance
4.70 Buildings used in the manufacture of intermediates and APIs
should be properly maintained and repaired and kept in a clean condition.
4.71 Written procedures should be established assigning responsibility
for sanitation and describing the cleaning schedules, methods, equipment, and
materials to be used in cleaning buildings and facilities.
4.72 When necessary, written procedures should also be established
for the use of suitable rodenticides, insecticides, fungicides, fumigating
agents, and cleaning and sanitizing agents to prevent the contamination of
equipment, raw materials, packaging/labelling materials, intermediates, and
APIs.
5 Process Equipment
5.1 Design and Construction
5.10 Equipment used in the manufacture of intermediates and APIs
should be of appropriate design and adequate size, and suitably located for its
intended use, cleaning, sanitization (where appropriate), and maintenance.
5.11 Equipment should be constructed so that surfaces that contact
raw materials, intermediates, or APIs do not alter the quality of the
intermediates and APIs beyond the official or other established specifications.
5.12 Production equipment should only be used within its qualified
operating range.
5.13 Major equipment (e.g., reactors, storage containers) and
permanently installed processing lines used during the production of an
intermediate or API should be appropriately identified.
5.14 Any substances associated with the operation of equipment,
such as lubricants, heating fluids or coolants, should not contact
intermediates or APIs so as to alter their quality beyond the official or other
established specifications. Any deviations from this should be evaluated to
ensure that there are no detrimental effects upon the fitness for purpose of
the material. Wherever possible, food grade lubricants and oils
should be used.
5.15 Closed or contained equipment should be used whenever
appropriate. Where open equipment is used, or equipment is opened, appropriate
precautions should be taken to minimize the risk of contamination.
5.16 A set of current drawings should be maintained for equipment
and critical installations
(e.g., instrumentation and utility systems).
5.2 Equipment Maintenance and Cleaning
5.20 Schedules and procedures (including assignment of
responsibility) should be established for the preventative maintenance of
equipment.
5.21 Written procedures should be established for cleaning of
equipment and its subsequent release for use in the manufacture of intermediates
and APIs. Cleaning procedures should contain sufficient details to enable
operators to clean each type of equipment in a reproducible and effective
manner. These procedures should include:
- Assignment of responsibility for cleaning of equipment;
- Cleaning schedules, including, where appropriate, sanitizing
schedules;
- A complete description of the methods and materials, including
dilution of cleaning agents used to clean equipment;
- When appropriate, instructions for disassembling and reassembling
each article of equipment to ensure proper cleaning;
- Instructions for the removal or obliteration of previous batch
identification;
- Instructions for the protection of clean equipment from
contamination prior to use;
- Inspection of equipment for cleanliness immediately before use,
if practical; and
- Establishing the maximum time that may elapse between the
completion of processing and equipment cleaning, when appropriate.
5.22 Equipment and utensils should be cleaned, stored, and, where
appropriate, sanitized or sterilized to prevent contamination or carry-over of
a material that would alter the quality of the intermediate or API beyond the
official or other established specifications.
5.23 Where equipment is assigned to continuous production or campaign
production of successive batches of the same intermediate or API, equipment
should be cleaned at appropriate intervals to prevent build-up and carry-over
of contaminants (e.g. degradants or objectionable levels of micro-organisms).
5.24 Non-dedicated equipment should be cleaned between production
of different materials to prevent cross-contamination.
5.25 Acceptance criteria for residues and the choice of cleaning
procedures and cleaning agents should be defined and justified.
5.26 Equipment should be identified as to its contents and its
cleanliness status by appropriate means.
5.3 Calibration
5.30 Control, weighing, measuring, monitoring and test equipment
that is critical for assuring the quality of intermediates or APIs should be
calibrated according to written procedures and an established schedule.
5.31 Equipment calibrations should be performed using standards
traceable to certified standards, if existing.
5.32 Records of these calibrations should be maintained.
5.33 The current calibration status of critical equipment should
be known and verifiable.
5.34 Instruments that do not meet calibration criteria should not
be used.
5.35 Deviations from approved standards of calibration on critical
instruments should be investigated to determine if these could have had an
impact on the quality of the intermediate(s) or API(s) manufactured using this
equipment since the last successful calibration.
5.4 Computerized Systems
5.40 GMP related computerized systems should be validated. The
depth and scope of validation depends on the diversity, complexity and
criticality of the computerized application.
5.41 Appropriate installation qualification and operational
qualification should demonstrate the suitability of computer hardware and
software to perform assigned tasks.
5.42 Commercially available software that has been qualified does
not require the same level of testing. If an existing system was not validated
at time of installation, a retrospective validation could be conducted if
appropriate documentation is available.
5.43 Computerized systems should have sufficient controls to
prevent unauthorized access or changes to data. There should be controls to
prevent omissions in data (e.g. system turned off and data not captured). There
should be a record of any data change made, the
previous entry, who made the change, and when the change was made.
5.44 Written procedures should be available for the operation and
maintenance of computerized systems.
5.45 Where critical data are being entered manually, there should be
an additional check on the accuracy of the entry. This can be done by a second
operator or by the system itself.
5.46 Incidents related to computerized systems that could affect
the quality of intermediates or APIs or the reliability of records or test results
should be recorded and investigated.
5.47 Changes to the computerized system should be made according
to a change procedure and
should be formally authorized, documented and tested. Records
should be kept of all changes, including modifications and enhancements made to
the hardware, software and any other critical component of the system. These
records should demonstrate that the system is maintained in a validated state.
5.48 If system breakdowns or failures would result in the
permanent loss of records, a back-up system should be provided. A means of
ensuring data protection should be established for all computerized systems.
5.49 Data can be recorded by a second means in addition to the
computer system.
6 .Documentation and
Records
6.1 Documentation System and Specifications
6.10 All documents related to the manufacture of intermediates or
APIs should be prepared, reviewed, approved and distributed according to
written procedures. Such documents can
be in paper or electronic form.
6.11 The issuance, revision, superseding and withdrawal of all
documents should be controlled with maintenance of revision histories.
6.12 A procedure should be established for retaining all
appropriate documents (e.g., development history reports, scale-up reports,
technical transfer reports, process validation reports, training records,
production records, control records, and distribution records). The retention
periods for these documents should be specified.
6.13 All production, control, and distribution records should be
retained for at least 1 year after the expiry date of the batch. For APIs with
retest dates, records should be retained for at
least 3 years after the batch is completely distributed.
6.14 When entries are made in records, these should be made indelibly
in spaces provided for
such entries, directly after performing the activities, and should
identify the person making the entry. Corrections to entries should be dated
and signed and leave the original entry still readable.
6.15 During the retention period, originals or copies of records
should be readily available at the establishment where the activities described
in such records occurred. Records that can be promptly retrieved from another
location by electronic or other means are acceptable.
6.16 Specifications, instructions, procedures, and records can be
retained either as originals or as true copies such as photocopies, microfilm,
microfiche, or other accurate reproductions of the original records. Where
reduction techniques such as microfilming or electronic records are used,
suitable retrieval equipment and a means to produce a hard copy should be
readily available.
6.17 Specifications should be established and documented for raw
materials, intermediates where necessary, APIs, and labelling and packaging
materials. In addition, specifications may be appropriate for certain other materials,
such as process aids, gaskets, or other materials used during the production of
intermediates or APIs that could critically impact on quality. Acceptance
criteria should be established and documented for in-process controls.
6.18 If electronic signatures are used on documents, they should
be authenticated and secure.
6.2 Equipment Cleaning and Use Record
6.20 Records of major equipment use, cleaning, sanitization and/or
sterilization and maintenance should show the date, time (if appropriate),
product, and batch number of each batch processed in the equipment, and the
person who performed the cleaning and
maintenance.
6.21 If equipment is dedicated to manufacturing one intermediate
or API, then individual
equipment records are not necessary if batches of the intermediate
or API follow in traceable sequence. In cases where dedicated equipment is
employed, the records of cleaning, maintenance, and use can be part of the
batch record or maintained separately.
6.3 Records of Raw Materials, Intermediates, API Labelling and
Packaging Materials
6.30 Records should be maintained including:
- The name of the manufacturer, identity and quantity of each
shipment of each batch of raw materials, intermediates or labelling and
packaging materials for API's; the 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;
- The results of any test or examination performed and the
conclusions derived from
this;
- Records tracing the use of materials;
- Documentation of the examination and review of API labelling and
packaging materials for conformity with established specifications; and
- The final decision regarding rejected raw materials,
intermediates or API labelling and packaging materials.
6.31 Master (approved) labels should be maintained for comparison
to issued labels.
6.4 Master Production Instructions (Master Production and Control
Records)
6.40 To ensure uniformity from batch to batch, master production
instructions for each intermediate and API should be prepared, dated, and
signed by one person and independently checked, dated, and signed by a person
in the quality unit(s).
6.41 Master production instructions should include:
- The name of the intermediate or API being manufactured and an
identifying
document reference code, if applicable;
- A complete list of raw materials and intermediates designated by
names or codes sufficiently specific to identify any special quality
characteristics;
- An accurate statement of the quantity or ratio of each raw
material or intermediate to be used, including the unit of measure. Where the
quantity is not fixed, the calculation for each batch size or rate of
production should be included. Variations to quantities should be included
where they are justified;
- The production location and major production equipment to be
used;
- Detailed production instructions, including the:
- sequences to be followed,
- ranges of process parameters to be used,
- sampling instructions and in-process controls with their
acceptance criteria, where appropriate,
- time limits for completion of individual processing steps and/or
the total
process, where appropriate; and
- expected yield ranges at appropriate phases of processing or
time;
- Where appropriate, special notations and precautions to be
followed, or crossreferences to these; and
- The instructions for storage of the intermediate or API to
assure its suitability for use, including the labelling and packaging materials
and special storage conditions with time limits, where appropriate.
6.5 Batch Production Records (Batch Production and Control
Records)
6.50 Batch production records should be prepared for each
intermediate and API and should include complete information relating to the
production and control of each batch. The batch production record should be
checked before issuance to assure that it is the correct
version and a legible accurate reproduction of the appropriate
master production instruction. If the batch production record is produced from
a separate part of the master document, that document should include a
reference to the current master production instruction being used.
6.51 These records should be numbered with a unique batch or
identification number, dated and signed when issued. In continuous production,
the product code together with the date and time can serve as the unique
identifier until the final number is allocated.
6.52 Documentation of completion of each significant step in the
batch production records (batch production and control records) should include:
- Dates and, when appropriate, times;
- Identity of major equipment (e.g., reactors, driers, mills,
etc.) used;
- Specific identification of each batch, including weights,
measures, and batch numbers of raw materials, intermediates, or any reprocessed
materials used during manufacturing;
- Actual results recorded for critical process parameters;
- Any sampling performed;
- Signatures of the persons performing and directly supervising or
checking each critical step in the operation;
- In-process and laboratory test results;
- Actual yield at appropriate phases or times;
- Description of packaging and label for intermediate or API;
- Representative label of API or intermediate if made commercially
available;
- Any deviation noted, its evaluation, investigation conducted (if
appropriate) or reference to that investigation if stored separately; and
- Results of release testing.
6.53 Written procedures should be established and followed for
investigating critical deviations or the failure of a batch of intermediate or
API to meet specifications. The investigation should extend to other batches
that may have been associated with the specific failure or deviation.
6.6 Laboratory Control Records
6.60 Laboratory control records should include complete data
derived from all tests conducted to ensure compliance with established
specifications and standards, including examinations and assays, as follows:
- A description of samples received for testing, including the
material name or source, batch number or other distinctive code, date sample
was taken, and, where appropriate, the quantity and date the sample was
received for testing;
- A statement of or reference to each test method used;
- A statement of the weight or measure of sample used for each
test as described by the method; data on or cross-reference to the preparation
and testing of reference standards, reagents and standard solutions,
- A complete record of all raw data generated during each test, in
addition to graphs, charts, and spectra from laboratory instrumentation,
properly identified to show the specific material and batch tested;
- A record of all calculations performed in connection with the
test, including, for example, units of measure, conversion factors, and
equivalency factors;
- A statement of the test results and how they compare with
established acceptance criteria;
- The signature of the person who performed each test and the
date(s) the tests were performed; and
- The date and signature of a second person showing that the
original records have been reviewed for accuracy, completeness, and compliance
with established standards.
6.61 Complete records should also be maintained for:
- Any modifications to an established analytical method,
- Periodic calibration of laboratory instruments, apparatus,
gauges, and recording devices;
- All stability testing performed on APIs; and
- Out-of-specification (OOS) investigations.
6.7 Batch Production Record Review
6.70 Written procedures should be established and followed for the
review and approval of batch production and laboratory control records,
including packaging and labelling, to determine compliance of the intermediate
or API with established specifications before a batch is released or
distributed.
6.71 Batch production and laboratory control records of critical
process steps should be reviewed and approved by the quality unit(s) before an
API batch is released or
distributed. Production and laboratory control records of
non-critical process steps can be
reviewed by qualified production personnel or other units
following procedures approved
by the quality unit(s).
6.72 All deviation, investigation, and OOS reports should be reviewed
as part of the batch
record review before the batch is released.
6.73 The quality unit(s) can delegate to the production unit the
responsibility and authority for
release of intermediates, except for those shipped outside the
control of the manufacturing
company.
7. Materials Management
7.1 General Controls
7.10 There should be written procedures describing the receipt,
identification, quarantine,
storage, handling, sampling, testing, and approval or rejection of
materials.
7.11 Manufacturers of intermediates and/or APIs should have a
system for evaluating the
suppliers of critical materials.
7.12 Materials should be purchased against an agreed
specification, from a supplier or suppliers approved by the quality unit(s).
7.13 If the supplier of a critical material is not the
manufacturer of that material, the name and address of that manufacturer should
be known by the intermediate and/or API manufacturer.
7.14 Changing the source of supply of critical raw materials
should be treated according to Section 13, Change Control.
7.2 Receipt and Quarantine
7.20 Upon receipt and before acceptance, each container or
grouping of containers of materials should be examined visually for correct
labelling (including correlation between the name used by the supplier and the
in-house name, if these are different), container damage, broken seals and
evidence of tampering or contamination. Materials should be held under
quarantine until they have been sampled, examined or tested as
appropriate, and released for use.
7.21 Before incoming materials are mixed with existing stocks
(e.g., solvents or stocks in silos), they should be identified as correct,
tested, if appropriate, and released. Procedures should be available to prevent
discharging incoming materials wrongly into the existing stock.
7.22 If bulk deliveries are made in non-dedicated tankers, there
should be assurance of no cross-contamination from the tanker. Means of
providing this assurance could include one or more of the following:
- certificate of cleaning
- testing for trace impurities
- audit of the supplier.
7.23 Large storage containers, and their attendant manifolds,
filling and discharge lines should be appropriately identified.
7.24 Each container or grouping of containers (batches) of
materials should be assigned and identified with a distinctive code, batch, or
receipt number. This number should be used
in recording the disposition of each batch. A system should be in
place to identify the status of each batch.
7.3 Sampling and Testing of Incoming Production Materials
7.30 At least one test to verify the identity of each batch of
material should be conducted, with the exception of the materials described
below in 7.32. A supplier's Certificate of Analysis can be used in place of
performing other tests, provided that the manufacturer has a system in place to
evaluate suppliers.
7.31 Supplier approval should include an evaluation that provides
adequate evidence (e.g., past quality history) that the manufacturer can
consistently provide material meeting specifications. Full analyses should be
conducted on at least three batches before reducing in-house testing. However,
as a minimum, a full analysis should be performed at appropriate intervals and
compared with the Certificates of Analysis. Reliability of Certificates of
Analysis should be checked at regular intervals.
7.32 Processing aids, hazardous or highly toxic raw materials,
other special materials, or materials transferred to another unit within the
company’s control do not need to be tested if the manufacturer’s Certificate of
Analysis is obtained, showing that these raw materials conform to established
specifications. Visual examination of containers, labels, and recording of
batch numbers should help in establishing the identity of these materials. The lack
of on-site testing for these materials should be justified and documented.
7.33 Samples should be representative of the batch of material
from which they are taken. Sampling methods should specify the number of
containers to be sampled, which part of the container to sample, and the amount
of material to be taken from each container. The
number of containers to sample and the sample size should be based
upon a sampling plan that takes into consideration the criticality of the
material, material variability, past quality history of the supplier, and the
quantity needed for analysis.
7.34 Sampling should be conducted at defined locations and by
procedures designed to prevent contamination of the material sampled and
contamination of other materials.
7.35 Containers from which samples are withdrawn should be opened
carefully and subsequently reclosed. They should be marked to indicate that a
sample has been taken.
7.4 Storage
7.40 Materials should be handled and stored in a manner to prevent
degradation, contamination, and cross-contamination.
7.41 Materials stored in fiber drums, bags, or boxes should be
stored off the floor and, when appropriate, suitably spaced to permit cleaning
and inspection.
7.42 Materials should be stored under conditions and for a period
that have no adverse affect on their quality, and should normally be controlled
so that the oldest stock is used first.
7.43 Certain materials in suitable containers can be stored
outdoors, provided identifying labels remain legible and containers are
appropriately cleaned before opening and use.
7.44 Rejected materials should be identified and controlled under
a quarantine system designed to prevent their unauthorised use in
manufacturing.
7.5 Re-evaluation
7.50 Materials should be re-evaluated as appropriate to determine
their suitability for use (e.g., after prolonged storage or exposure to heat or
humidity).
8. Production and
In-Process Controls
8.1 Production Operations
8.10 Raw materials for intermediate and API manufacturing should
be weighed or measured
under appropriate conditions that do not affect their suitability
for use. Weighing and
measuring devices should be of suitable accuracy for the intended
use.
8.11 If a material is subdivided for later use in production
operations, the container receiving
the material should be suitable and should be so identified that
the following information
is available:
- Material name and/or item code;
- Receiving or control number;
- Weight or measure of material in the new container; and
- Re-evaluation or retest date if appropriate.
8.12 Critical weighing, measuring, or subdividing operations
should be witnessed or subjected
to an equivalent control. Prior to use, production personnel
should verify that the materials are those specified in the batch record for
the intended intermediate or API.
8.13 Other critical activities should be witnessed or subjected to
an equivalent control.
8.14 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 in yield associated with critical process steps
should be investigated to determine their impact or potential impact on the
resulting quality of affected batches.
8.15 Any deviation should be documented and explained. Any
critical deviation should be investigated.
8.16 The processing status of major units of equipment should be
indicated either on the individual units of equipment or by appropriate
documentation, computer control systems, or alternative means.
8.17 Materials to be reprocessed or reworked should be
appropriately controlled to prevent unauthorized use.
8.2 Time Limits
8.20 If time limits are specified in the master production
instruction (see 6.41), these time limits should be met to ensure the quality
of intermediates and APIs. Deviations should be documented and evaluated. Time
limits may be inappropriate when processing to a target value (e.g., pH
adjustment, hydrogenation, drying to predetermined specification) because completion
of reactions or processing steps are determined by in-process sampling and testing.
8.21 Intermediates held for further processing should be stored
under appropriate conditions to ensure their suitability for use.
8.3 In-process Sampling and Controls
8.30 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.
8.31 The acceptance criteria and type and extent of testing can
depend on the nature of the intermediate or API being manufactured, the
reaction or process step being conducted, and the degree to which the process
introduces variability in the product’s quality. Less stringent in-process
controls may be appropriate in early processing steps, whereas tighter controls
may be appropriate for later processing steps (e.g., isolation and purification
steps).
8.32 Critical in-process controls (and critical process
monitoring), including the control points and methods, should be stated in
writing and approved by the quality unit(s).
8.33 In-process controls can be performed by qualified production
department personnel and the process adjusted without prior quality unit(s)
approval if the adjustments are made within pre-established limits approved by
the quality unit(s). All tests and results should be fully documented as part
of the batch record.
8.34 Written procedures should describe the sampling methods for
in-process materials, intermediates, and APIs. Sampling plans and procedures
should be based on scientifically sound sampling practices.
8.35 In-process sampling should be conducted using procedures
designed to prevent contamination of the sampled material and other
intermediates or APIs. Procedures should be established to ensure the integrity
of samples after collection.
8.36 Out-of-specification (OOS) investigations are not normally
needed for in-process tests that are performed for the purpose of monitoring
and/or adjusting the process.
8.4 Blending Batches of Intermediates or APIs
8.40 For the purpose of this document, blending is defined as the
process of combining materials within the same specification to produce a
homogeneous intermediate or API. In-process mixing of fractions from single
batches (e.g., collecting several centrifuge loads from a single crystallization
batch) or combining fractions from several batches for further processing is
considered to be part of the production process and is not considered to be
blending.
8.41 Out-Of-Specification batches should not be blended with other
batches for the purpose of meeting specifications. Each batch incorporated into
the blend should have been manufactured using an established process and should
have been individually tested and
found to meet appropriate specifications prior to blending.
8.42 Acceptable blending operations include but are not limited
to:
- Blending of small batches to increase batch size
- Blending of tailings (i.e., relatively small quantities of
isolated material) from batches of the same intermediate or API to form a
single batch.
8.43 Blending processes should be adequately controlled and
documented and the blended batch should be tested for conformance to
established specifications where appropriate.
8.44 The batch record of the blending process should allow
traceability back to the individual batches that make up the blend.
8.45 Where physical attributes of the API are critical (e.g., APIs
intended for use in solid oral dosage forms or suspensions), blending
operations should be validated to show homogeneity of the combined batch. Validation
should include testing of critical attributes (e.g., particle size
distribution, bulk density, and tap density) that may be affected by the
blending process.
8.46 If the blending could adversely affect stability, stability
testing of the final blended batches should be performed.
8.47 The expiry or retest date of the blended batch should be
based on the manufacturing date of the oldest tailings or batch in the blend.
8.5 Contamination Control
8.50 Residual materials can be carried over into successive
batches of the same intermediate or API if there is adequate control. Examples
include residue adhering to the wall of a micronizer, residual layer of damp
crystals remaining in a centrifuge bowl after discharge, and incomplete
discharge of fluids or crystals from a processing vessel upon transfer of the
material to the next step in the process. Such carryover should not result in
the carryover of degradants or microbial contamination that may adversely alter
the established API impurity profile.
8.51 Production operations should be conducted in a manner that
will prevent contamination of intermediates or APIs by other materials.
8.52 Precautions to avoid contamination should be taken when APIs
are handled after purification.
9. Packaging and
Identification Labelling of APIs and Intermediates
9.1 General
9.10 There should be written procedures describing the receipt,
identification, quarantine, sampling, examination and/or testing and release,
and handling of packaging and labelling
materials.
9.11 Packaging and labelling 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.
9.12 Records should be maintained for each shipment of labels and
packaging materials showing receipt, examination, or testing, and whether
accepted or rejected.
9.2 Packaging Materials
9.20 Containers should provide adequate protection against
deterioration or contamination of the intermediate or API that may occur during
transportation and recommended storage.
9.21 Containers should be clean and, where indicated by the nature
of the intermediate or API, sanitized to ensure that they are suitable for
their intended use. These containers should not be reactive, additive, or
absorptive so as to alter the quality of the intermediate or API
beyond the specified limits.
9.22 If containers are re-used, they should be cleaned in
accordance with documented procedures and all previous labels should be removed
or defaced.
9.3 Label Issuance and Control
9.30 Access to the label storage areas should be limited to
authorised personnel.
9.31 Procedures should be used to reconcile the quantities of
labels issued, used, and returned and to evaluate discrepancies found between
the number of containers labelled and the
number of labels issued. Such discrepancies should be
investigated, and the investigation should be approved by the quality unit(s).
9.32 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.
9.33 Obsolete and out-dated labels should be destroyed.
9.34 Printing devices used to print labels for packaging
operations should be controlled to ensure that all imprinting conforms to the
print specified in the batch production record.
9.35 Printed labels issued for a batch should be carefully
examined for proper identity and conformity to specifications in the master
production record. The results of this examination should be documented.
9.36 A printed label representative of those used should be
included in the batch production record.
9.4 Packaging and Labelling Operations
9.40 There should be documented procedures designed to ensure that
correct packaging
materials and labels are used.
9.41 Labelling operations should be designed to prevent mix-ups.
There should be physical or spatial separation from operations involving other
intermediates or APIs.
9.42 Labels used on containers of intermediates or APIs should
indicate the name or identifying code, the batch number of the product, and
storage conditions, when such information is critical to assure the quality of
intermediate or API.
9.43 If the intermediate or API is intended to be transferred
outside the control of the manufacturer’s material 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. For intermediates or APIs with an expiry date, the
expiry date should be indicated on the label and Certificate of
Analysis. For intermediates or APIs with a retest date, the retest date should
be indicated on the label and/or Certificate of Analysis.
9.44 Packaging and labelling facilities should be inspected
immediately before use to ensure that all materials not needed for the next
packaging operation have been removed. This
examination should be documented in the batch production records,
the facility log, or other documentation system.
9.45 Packaged and labelled intermediates or APIs should be
examined to ensure that containers and packages in the batch have the correct
label. This examination should be part of the packaging operation. Results of
these examinations should be recorded in the batch production or control
records.
9.46 Intermediate or API containers that are 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.
10. Storage and
Distribution
10.1 Warehousing Procedures
10.10 Facilities should be available for the storage of all
materials under appropriate conditions (e.g. controlled temperature and
humidity when necessary). Records should be maintained
of these conditions if they are critical for the maintenance of
material characteristics.
10.11 Unless there is an alternative system to prevent the
unintentional or unauthorised use of quarantined, rejected, returned, or
recalled materials, separate storage areas should be assigned for their
temporary storage until the decision as to their future use has been taken.
10.2 Distribution Procedures
10.20 APIs and intermediates should only be released for
distribution to third parties after they have been released by the quality
unit(s). APIs and intermediates can be transferred under quarantine to another
unit under the company’s control when authorized by the quality unit(s) and if
appropriate controls and documentation are in place.
10.21 APIs and intermediates should be transported in a manner
that does not adversely affect their quality.
10.22 Special transport or storage conditions for an API or
intermediate should be stated on the label.
10.23 The manufacturer should ensure that the contract acceptor
(contractor) for transportation of the API or intermediate knows and follows
the appropriate transport and storage conditions.
10.24 A system should be in place by which the distribution of
each batch of intermediate and/or API can be readily determined to permit its
recall.
11. Laboratory
Controls
11.1 General Controls
11.10 The independent quality unit(s) should have at its disposal
adequate laboratory facilities.
11.11 There should be documented procedures describing sampling,
testing, approval or rejection of materials, and recording and storage of
laboratory data. Laboratory records should be maintained in accordance with
Section 6.6.
11.12 All specifications, sampling plans, and test procedures
should be scientifically sound and appropriate to ensure that raw materials,
intermediates, APIs, and labels and packaging materials conform to established
standards of quality and/or purity. Specifications and test procedures should
be consistent with those included in the registration/filing. There can be
specifications in addition to those in the registration/filing. Specifications,
sampling plans, and test procedures, including changes to them, should be
drafted by the appropriate organizational unit and reviewed and approved by the
quality unit(s).
11.13 Appropriate specifications should be established for APIs in
accordance with accepted standards and consistent with the manufacturing
process. The specifications should include a control of the impurities (e.g.
organic impurities, inorganic impurities, and residual solvents). If the API
has a specification for microbiological purity, appropriate action limits for
total microbial counts and objectionable organisms should be established and
met. If the API has a specification for endotoxins, appropriate action limits
should be established and met.
11.14 Laboratory controls should be followed and documented at the
time of performance. Any departures from the above described procedures should
be documented and explained.
11.15 Any out-of-specification result obtained should be
investigated and documented according to a procedure. This procedure should
require analysis of the data, assessment of whether a significant problem exists,
allocation of the tasks for corrective actions, and conclusions. Any resampling
and/or retesting after OOS results should be performed
according to a documented procedure.
11.16 Reagents and standard solutions should be prepared and
labelled following written procedures. “Use by” dates should be applied as
appropriate for analytical reagents or standard solutions.
11.17 Primary reference standards should be obtained as
appropriate for the manufacture of
APIs. The source of each primary reference standard should be
documented. Records should be maintained of each primary reference standard’s
storage and use in accordance with the supplier’s recommendations. Primary
reference standards obtained from an
officially recognised source are normally used without testing if
stored under conditions consistent with the supplier’s recommendations.
11.18 Where a primary reference standard is not available from an
officially recognized source, an “in-house primary standard” should be
established. Appropriate testing should be performed to establish fully the
identity and purity of the primary reference standard. Appropriate
documentation of this testing should be maintained.
11.19 Secondary reference standards should be appropriately
prepared, identified, tested, approved, and stored. The suitability of each
batch of secondary reference standard should be determined prior to first use
by comparing against a primary reference standard. Each batch of secondary
reference standard should be periodically requalified in accordance with a
written protocol.
11.2 Testing of Intermediates and APIs
11.20 For each batch of intermediate and API, appropriate
laboratory tests should be conducted to determine conformance to
specifications.
11.21 An impurity profile describing the identified and
unidentified impurities present in a typical batch produced by a specific
controlled production process should normally be established for each API. The
impurity profile should include the identity or some qualitative analytical
designation (e.g. retention time), the range of each impurity observed, and
classification of each identified impurity (e.g. inorganic, organic, solvent). The
impurity profile is normally dependent upon the production process and origin
of the API. Impurity profiles are normally not necessary for APIs from herbal
or animal tissue origin. Biotechnology considerations are covered in ICH
Guideline Q6B.
11.22 The impurity profile should be compared at appropriate
intervals against the impurity profile in the regulatory submission or compared
against historical data in order to detect changes to the API resulting from
modifications in raw materials, equipment operating parameters, or the
production process.
11.23 Appropriate microbiological tests should be conducted on
each batch of intermediate and API where microbial quality is specified.
11.4 Certificates of Analysis
11.40 Authentic Certificates of Analysis should be issued for each
batch of intermediate or API on request.
11.41 Information on the name of the intermediate or API including
where appropriate its grade, the batch number, and the date of release should
be provided on the Certificate of Analysis. For intermediates or APIs with an
expiry date, the expiry date should be provided on the label and Certificate of
Analysis. For intermediates or APIs with a retest date, the retest date should
be indicated on the label and/or Certificate of Analysis.
11.42 The Certificate should list each test performed in
accordance with compendial or customer requirements, including the acceptance
limits, and the numerical results obtained (if test results are numerical).
11.43 Certificates should be dated and signed by authorised
personnel of the quality unit(s) and should show the name, address and
telephone number of the original manufacturer. Where the analysis has been
carried out by a repacker or reprocessor, the Certificate of Analysis should
show the name, address and telephone number of the repacker/reprocessor and a
reference to the name of the original manufacturer.
11.44 If new Certificates are issued by or on behalf of
repackers/reprocessors, agents or brokers, these Certificates should show the
name, address and telephone number of the laboratory that performed the
analysis. They should also contain a reference to the name and address
of the original manufacturer and to the original batch
Certificate, a copy of which should be attached.
11.5 Stability Monitoring of APIs
11.50 A documented, on-going testing program should be designed to
monitor the stability characteristics of APIs, and the results should be used
to confirm appropriate storage
conditions and retest or expiry dates.
11.51 The test procedures used in stability testing should be
validated and be stability indicating.
11.52 Stability samples should be stored in containers that
simulate the market container. For example, if the API is marketed in bags
within fiber drums, stability samples can be packaged in bags of the same
material and in smaller-scale drums of similar or identical material
composition to the market drums.
11.53 Normally the first three commercial production batches
should be placed on the stability monitoring program to confirm the retest or
expiry date. However, where data from previous studies show that the API is
expected to remain stable for at least two years, fewer than three batches can
be used.
11.54 Thereafter, at least one batch per year of API manufactured
(unless none is produced that year) should be added to the stability monitoring
program and tested at least annually to confirm the stability.
11.55 For APIs with short shelf-lives, testing should be done more
frequently. For example, for those biotechnological/biologic and other APIs
with shelf-lives of one year or less, stability samples should be obtained and
should be tested monthly for the first three months, and at three month
intervals after that. When data exist that confirm that the
stability of the API is not compromised, elimination of specific
test intervals (e.g. 9 month testing) can be considered.
11.56 Where appropriate, the stability storage conditions should
be consistent with the ICH guidelines on stability.
11.6 Expiry and Retest Dating
11.60 When an intermediate is intended to be transferred outside
the control of the manufacturer’s material management system and an expiry or
retest date is assigned, supporting stability information should be available
(e.g. published data, test results).
11.61 An API expiry or retest date should be based on an
evaluation of data derived from stability studies. Common practice is to use a
retest date, not an expiration date.
11.62 Preliminary API expiry or retest dates can be based on pilot
scale batches if (1) the pilot batches employ a method of manufacture and
procedure that simulates the final process to be used on a commercial
manufacturing scale; and (2) the quality of the API represents the material to
be made on a commercial scale.
11.63 A representative sample should be taken for the purpose of
performing a retest.
11.7 Reserve/Retention Samples
11.70 The packaging and holding of reserve samples is for the
purpose of potential future evaluation of the quality of batches of API and not
for future stability testing purposes.
11.71 Appropriately identified reserve samples of each API batch
should be retained for one year after the expiry date of the batch assigned by
the manufacturer, or for three years after distribution of the batch, whichever
is the longer. For APIs with retest dates, similar reserve samples should be
retained for three years after the batch is completely distributed by the
manufacturer.
11.72 The reserve sample should be stored in the same packaging
system in which the API is stored or in one that is equivalent to or more
protective than the marketed packaging
system. Sufficient quantities should be retained to conduct at
least two full compendia analyses or, when there is no pharmacopoeial
monograph, two full specification analyses.
12 Validation
12.1 Validation Policy
12.10 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.
12.11 The critical parameters/attributes should normally be
identified during the development stage or from historical data, and the ranges
necessary for the reproducible operation should be defined. This should
include:
- Defining the API in terms of its critical product attributes;
- Identifying process parameters that could affect the critical
quality attributes of the API;
- Determining the range for each critical process parameter
expected to be used during routine manufacturing and process control.
12.12 Validation should extend to those operations determined to
be critical to the quality and purity of the API.
12.2 Validation Documentation
12.20 A written validation protocol should be established that
specifies how validation of a particular process will be conducted. The
protocol should be reviewed and approved by the quality unit(s) and other
designated units.
12.21 The validation protocol should specify critical process
steps and acceptance criteria as
well as the type of validation to be conducted (e.g. retrospective,
prospective, concurrent) and the number of process runs.
12.22 A validation report that cross-references the validation
protocol should be prepared, summarising the results obtained, commenting on
any deviations observed, and drawing the appropriate conclusions, including
recommending changes to correct deficiencies.
12.23 Any variations from the validation protocol should be
documented with appropriate justification.
12.3 Qualification
12.30 Before starting process validation activities, appropriate
qualification of critical equipment and ancillary systems should be completed.
Qualification is usually carried out by conducting the following activities,
individually or combined:
- Design Qualification (DQ): documented verification that the
proposed design of the facilities, equipment, or systems is suitable for the
intended purpose.
- Installation Qualification (IQ): documented verification that
the equipment or systems, as installed or modified, comply with the approved
design, the manufacturer’s recommendations and/or user requirements.
- Operational Qualification (OQ): documented verification that the
equipment or systems, as installed or modified, perform as intended throughout
the anticipated operating ranges.
- Performance Qualification (PQ): documented verification that the
equipment and ancillary systems, as connected together, can perform effectively
and reproducibly based on the approved process method and specifications.
12.4 Approaches to Process Validation
12.40 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.
12.41 There are three approaches to validation. Prospective
validation is the preferred approach, but there are exceptions where the other
approaches can be used. These approaches and their applicability are listed
below.
12.42 Prospective validation should normally be performed for all
API processes as defined in
12.12. Prospective validation performed on an API process should
be completed before the commercial distribution of the final drug product
manufactured from that API.
12.43 Concurrent validation can be conducted when data from
replicate production runs are unavailable because only a limited number of API
batches have been produced, API batches are produced infrequently, or API
batches are produced by a validated process that has been modified. Prior to
the completion of concurrent validation, batches can be
released and used in final drug product for commercial
distribution based on thorough monitoring and testing of the API batches.
12.44 An exception can be made for retrospective validation for
well established processes that have been used without significant changes to
API quality due to changes in raw materials, equipment, systems, facilities, or
the production process. This validation approach may be used where:
(1) Critical quality attributes and critical process parameters
have been identified;
(2) Appropriate in-process acceptance criteria and controls have
been established;
(3) There have not been significant process/product failures
attributable to causes other than operator error or equipment failures
unrelated to equipment suitability; and
(4) Impurity profiles have been established for the existing API.
12.45 Batches selected for retrospective validation should be
representative of all batches made during the review period, including any
batches that failed to meet specifications, and should be sufficient in number
to demonstrate process consistency. Retained samples can be tested to obtain
data to retrospectively validate the process.
12.5 Process Validation Program
12.50 The number of process runs for validation should depend on
the complexity of the process or the magnitude of the process change being
considered. For prospective and concurrent validation, three consecutive
successful production batches should be used as a guide, but there may be
situations where additional process runs are warranted to prove consistency of
the process (e.g., complex API processes or API processes with prolonged
completion times). For retrospective validation, generally data from ten to
thirty consecutive batches should be examined to assess process consistency,
but fewer batches can be examined if justified.
12.51 Critical process parameters should be controlled and
monitored during process validation studies. Process parameters unrelated to
quality, such as variables controlled to minimize energy consumption or
equipment use, need not be included in the process validation.
12.52 Process validation should confirm that the impurity profile
for each API is within the
limits specified. The impurity profile should be comparable to or
better than historical
data and, where applicable, the profile determined during process
development or for
batches used for pivotal clinical and toxicological studies.
12.6 Periodic Review of Validated Systems
12.60 Systems and processes should be periodically evaluated to
verify that they are still
operating in a valid manner. Where no significant changes have
been made to the system or process, and a quality review confirms that the
system or process is consistently producing material meeting its specifications,
there is normally no need for revalidation.
12.7 Cleaning Validation
12.70 Cleaning procedures should normally be validated. In
general, cleaning validation should be directed to situations or process steps
where contamination or carryover of materials poses the greatest risk to API
quality. For example, in early production it may be unnecessary to validate
equipment cleaning procedures where residues are removed by subsequent
purification steps.
12.71 Validation of cleaning procedures should reflect actual
equipment usage patterns. If various APIs or intermediates are manufactured in
the same equipment and the equipment is cleaned by the same process, a
representative intermediate or API can be selected for cleaning validation.
This selection should be based on the solubility and difficulty of cleaning and
the calculation of residue limits based on potency, toxicity, and stability.
12.72 The cleaning validation protocol should describe the
equipment to be cleaned, procedures, materials, acceptable cleaning levels,
parameters to be monitored and controlled, and analytical methods. The protocol
should also indicate the type of samples to be obtained
and how they are collected and labelled.
12.73 Sampling should include swabbing, rinsing, or alternative methods
(e.g., direct extraction), as appropriate, to detect both insoluble and soluble
residues. The sampling methods used should be capable of quantitatively
measuring levels of residues remaining on the equipment surfaces after
cleaning. Swab sampling may be impractical when product contact surfaces are
not easily accessible due to equipment design and/or process
limitations (e.g., inner surfaces of hoses, transfer pipes,
reactor tanks with small ports or handling toxic materials, and small intricate
equipment such as micronizers and microfluidizers).
12.74 Validated analytical methods having sensitivity to detect
residues or contaminants should be used. The detection limit for each
analytical method should be sufficiently sensitive to detect the established
acceptable level of the residue or contaminant. The method’s attainable
recovery level should be established. Residue limits should be practical,
achievable, verifiable and based on the most deleterious residue.
Limits can be established based on the minimum known pharmacological,
toxicological, or physiological activity of the API or its most deleterious
component.
12.75 Equipment cleaning/sanitization studies should address
microbiological and endotoxin contamination for those processes where there is
a need to reduce total microbiological count or endotoxins in the API, or other
processes where such contamination could be of concern (e.g., non-sterile APIs
used to manufacture sterile products).
12.76 Cleaning procedures should be monitored at appropriate
intervals after validation to ensure that these procedures are effective when
used during routine production. Equipment cleanliness can be monitored by
analytical testing and visual examination, where feasible. Visual inspection
can allow detection of gross contamination concentrated in small areas that
could otherwise go undetected by sampling and/or
analysis.
12.8 Validation of Analytical Methods
12.80 Analytical methods should be validated unless the method
employed is included in the relevant pharmacopoeia or other recognised standard
reference. The suitability of all testing methods used should nonetheless be
verified under actual conditions of use and documented.
12.81 Methods should be validated to include consideration of
characteristics included within
the ICH guidelines on validation of analytical methods. The degree
of analytical validation performed should reflect the purpose of the analysis
and the stage of the API production process.
12.82 Appropriate qualification of analytical equipment should be
considered before starting validation of analytical methods.
12.83 Complete records should be maintained of any modification of
a validated analytical method. Such records should include the reason for the
modification and appropriate data to verify that the modification produces
results that are as accurate and reliable as the
established method.
13 Change Control
13.10 A formal change control system should be established to
evaluate all changes that may affect the production and control of the intermediate
or API.
13.11 Written procedures should provide for the identification,
documentation, appropriate review, and approval of changes in raw materials,
specifications, analytical methods, facilities, support systems, equipment
(including computer hardware), processing steps,
labelling and packaging materials, and computer software.
13.12 Any proposals for GMP relevant changes should be drafted,
reviewed, and approved by the appropriate organisational units, and reviewed
and approved by the quality unit(s).
13.13 The potential impact of the proposed change on the quality
of the intermediate or API should be evaluated. A classification procedure may
help in determining the level of testing, validation, and documentation needed
to justify changes to a validated process.
Changes can be classified (e.g. as minor or major) depending on
the nature and extent of the changes, and the effects these changes may impart
on the process. Scientific judgement should determine what additional testing
and validation studies are appropriate to justify a change in a validated
process.
13.14 When implementing approved changes, measures should be taken
to ensure that all documents affected by the changes are revised.
13.15 After the change has been implemented, there should be an
evaluation of the first batches produced or tested under the change.
13.16 The potential for critical changes to affect established
retest or expiry dates should be evaluated. If necessary, samples of the
intermediate or API produced by the modified process can be placed on an
accelerated stability program and/or can be added to the stability monitoring
program.
13.17 Current dosage form manufacturers should be notified of
changes from established production and process control procedures that can impact
the quality of the API.
14 Rejection and
Re-Use of Materials
14.1 Rejection
14.10 Intermediates and APIs failing to meet established
specifications should be identified as such and quarantined. These
intermediates or APIs can be reprocessed or reworked as described below. The
final disposition of rejected materials should be recorded.
14.2 Reprocessing
14.20 Introducing an intermediate or API, including one that does
not conform to standards or specifications, back into the process and
reprocessing by repeating a crystallization step or other appropriate chemical
or physical manipulation steps (e.g., distillation, filtration, chromatography,
milling) that are part of the established manufacturing process is generally
considered acceptable. However, if such reprocessing is used for a majority of batches,
such reprocessing should be included as part of the standard manufacturing process.
14.21 Continuation of a process step after an in-process control
test has shown that the step is incomplete is considered to be part of the
normal process. This is not considered to be reprocessing.
14.22 Introducing unreacted material back into a process and
repeating a chemical reaction is considered to be reprocessing unless it is
part of the established process. Such reprocessing should be preceded by
careful evaluation to ensure that the quality of the intermediate or API is not
adversely impacted due to the potential formation of byproducts and
over-reacted materials.
14.3 Reworking
14.30 Before a decision is taken to rework batches that do not
conform to established standards or specifications, an investigation into the
reason for non-conformance should be performed.
14.31 Batches that have been reworked should be subjected to
appropriate evaluation, testing, stability testing if warranted, and
documentation to show that the reworked product is of equivalent quality to
that produced by the original process. Concurrent validation is often
the appropriate validation approach for rework procedures. This
allows a protocol to define the rework procedure, how it will be carried out,
and the expected results. If there is only one batch to be reworked, then a
report can be written and the batch released once it is found to be acceptable.
14.32 Procedures should provide for comparing the impurity profile
of each reworked batch against batches manufactured by the established process.
Where routine analytical methods are inadequate to characterize the reworked
batch, additional methods should be used.
14.4 Recovery of Materials and Solvents
14.40 Recovery (e.g. from mother liquor or filtrates) of
reactants, intermediates, or the API is considered acceptable, provided that
approved procedures exist for the recovery and the recovered materials meet
specifications suitable for their intended use.
14.41 Solvents can be recovered and reused in the same processes
or in different processes, provided that the recovery procedures are controlled
and monitored to ensure that solvents meet appropriate standards before reuse
or co-mingling with other approved materials.
14.42 Fresh and recovered solvents and reagents can be combined if
adequate testing has shown their suitability for all manufacturing processes in
which they may be used.
14.43 The use of recovered solvents, mother liquors, and other
recovered materials should be adequately documented.
14.5 Returns
14.50 Returned intermediates or APIs should be identified as such
and quarantined.
14.51 If the conditions under which returned intermediates or APIs
have been stored or shipped before or during their return or the condition of
their containers casts doubt on their quality, the returned intermediates or
APIs should be reprocessed, reworked, or destroyed, as appropriate.
14.52 Records of returned intermediates or APIs should be maintained.
For each return, documentation should include:
- Name and address of the consignee
- Intermediate or API, batch number, and quantity returned
- Reason for return
- Use or disposal of the returned intermediate or API
15. Complaints and
Recalls
15.10 All quality related complaints, whether received orally or
in writing, should be recorded and investigated according to a written
procedure.
15.11 Complaint records should include:
- Name and address of complainant;
- Name (and, where appropriate, title) and phone number of person
submitting the complaint;
- Complaint nature (including name and batch number of the API);
- Date complaint is received;
- Action initially taken (including dates and identity of person
taking the action);
- Any follow-up action taken;
- Response provided to the originator of complaint (including date
response sent); and
- Final decision on intermediate or API batch or lot.
15.12 Records of complaints should be retained in order to
evaluate trends, product-related frequencies, and severity with a view to
taking additional, and if appropriate, immediate corrective action.
15.13 There should be a written procedure that defines the
circumstances under which a recall of an intermediate or API should be
considered.
15.14 The recall procedure should designate who should be involved
in evaluating the information, how a recall should be initiated, who should be
informed about the recall, and how the recalled material should be treated.
15.15 In the event of a serious or potentially life-threatening
situation, local, national, and/or international authorities should be informed
and their advice sought.
16 Contract
Manufacturers (including Laboratories)
16.10 All contract manufacturers (including laboratories) should
comply with the GMP defined in this Guide. Special consideration should be
given to the prevention of cross contamination and to maintaining traceability.
16.11 Contract manufacturers (including laboratories) should be
evaluated by the contract giver to ensure GMP compliance of the specific
operations occurring at the contract sites.
16.12 There should be a written and approved contract or formal
agreement between the contract giver and the contract acceptor that defines in
detail the GMP responsibilities, including the quality measures, of each party.
16.13 The contract should permit the contract giver to audit the
contract acceptor's facilities for compliance with GMP.
16.14 Where subcontracting is allowed, the contract acceptor
should not pass to a third party any of the work entrusted to him under the
contract without the contract giver's prior evaluation and approval of the
arrangements.
16.15 Manufacturing and laboratory records should be kept at the
site where the activity occurs and be readily available.
16.16 Changes in the process, equipment, test methods,
specifications, or other contractual requirements should not be made unless the
contract giver is informed and approves the changes.
17. Agents, Brokers,
Traders, Distributors, Repackers, and Relabellers
17.1 Applicability
17.10 This section applies to any party other than the original
manufacturer who may trade and/or take possession, repack, relabel, manipulate,
distribute or store an API or
intermediate.
17.11 All agents, brokers, traders, distributors, repackers, and relabellers
should comply with GMP as defined in this Guide.
17.2 Traceability of Distributed APIs and Intermediates
17.20 Agents, brokers, traders, distributors, repackers, or
relabellers should maintain complete traceability of APIs and intermediates that
they distribute. Documents that should be
retained and available include:
- Identity of original manufacturer
- Address of original manufacturer
- Purchase orders
- Bills of lading (transportation documentation)
- Receipt documents
- Name or designation of API or intermediate
- Manufacturer’s batch number
- Transportation and distribution records
- All authentic Certificates of Analysis, including those of the
original manufacturer
- Retest or expiry date
17.3 Quality Management
17.30 Agents, brokers, traders, distributors, repackers, or
relabellers should establish, document and implement an effective system of
managing quality, as specified in Section 2.
17.4 Repackaging, Relabelling and Holding of APIs and
Intermediates
17.40 Repackaging, relabelling and holding of APIs and
intermediates should be performed under appropriate GMP controls, as stipulated
in this Guide, to avoid mix-ups and loss of API or intermediate identity or
purity.
17.41 Repackaging should be conducted under appropriate
environmental conditions to avoid contamination and cross-contamination.
17.5 Stability
17.50 Stability studies to justify assigned expiration or retest
dates should be conducted if the API or intermediate is repackaged in a
different type of container than that used by the API or intermediate
manufacturer.
17.6 Transfer of Information
17.60 Agents, brokers, distributors, repackers, or relabellers
should transfer all quality or regulatory information received from an API or
intermediate manufacturer to the customer, and from the customer to the API or
intermediate manufacturer.
17.61 The agent, broker, trader, distributor, repacker, or
relabeller who supplies the API or intermediate to the customer should provide
the name of the original API or intermediate manufacturer and the batch
number(s) supplied.
17.62 The agent should also provide the identity of the original
API or intermediate manufacturer to regulatory authorities upon request. The
original manufacturer can respond to the regulatory authority directly or through
its authorized agents, depending on the legal relationship between the
authorized agents and the original API or intermediate manufacturer. (In this
context "authorized" refers to authorized by the manufacturer.)
17.63 The specific guidance for Certificates of Analysis included
in Section
17.7 Handling of Complaints and Recalls
17.70 Agents, brokers, traders, distributors, repackers, or
relabellers should maintain records of complaints and recalls, as specified in
Section 15, for all complaints and recalls that come to their attention.
17.71 If the situation warrants, the agents, brokers, traders,
distributors, repackers, or relabellers should review the complaint with the
original API or intermediate manufacturer in order to determine whether any further
action, either with other customers who may have received this API or
intermediate or with the regulatory authority, or both, should be initiated.
The investigation into the cause for the complaint or recall should be
conducted and documented by the appropriate party.
17.72 Where a complaint is referred to the original API or
intermediate manufacturer, the record maintained by the agents, brokers,
traders, distributors, repackers, or relabellers should include any response
received from the original API or intermediate manufacturer
(including date and information provided).
17.8 Handling of Returns
17.80 Returns should be handled as specified in Section 14.52. The
agents, brokers, traders, distributors, repackers, or relabellers should
maintain documentation of returned APIs and intermediates.
18. Specific Guidance
for APIs Manufactured by Cell Culture/Fermentation
18.1 General
18.10 Section 18 is intended to address specific controls for APIs
or intermediates manufactured by cell culture or fermentation using natural or
recombinant organisms and that have not been covered adequately in the previous
sections. It is not intended to be a stand-alone Section. In general, the GMP
principles in the other sections of this document apply. Note that the principles
of fermentation for “classical” processes for production of small molecules and
for processes using recombinant and non-recombinant organisms for production of
proteins and/or polypeptides are the same, although the degree of control will
differ. Where practical, this section will address these differences. In
general, the degree of control for biotechnological processes used to produce
proteins and polypeptides is greater than that for classical fermentation
processes.
18.11 The term “biotechnological process” (biotech) refers to the
use of cells or organisms that have been generated or modified by recombinant
DNA, hybridoma or other technology to produce APIs. The APIs produced by
biotechnological processes normally consist of high molecular weight substances,
such as proteins and polypeptides, for which specific guidance is given in this
Section. Certain APIs of low molecular weight, such as antibiotics, amino
acids, vitamins, and carbohydrates, can also be produced by
recombinant DNA technology.The level of control for these types of
APIs is similar to that employed for classical fermentation.
18.12 The term “classical fermentation” refers to processes that
use microorganisms existing in nature and/or modified by conventional methods
(e.g. irradiation or chemical mutagenesis) to produce APIs. APIs produced by
“classical fermentation” are normally low molecular weight products such as
antibiotics, amino acids, vitamins, and
carbohydrates.
18.13 Production of APIs or intermediates from cell culture or fermentation
involves biological processes such as cultivation of cells or extraction and
purification of material from living organisms. Note that there may be
additional process steps, such as physicochemical modification, that are part
of the manufacturing process. The raw materials used (media, buffer components)
may provide the potential for growth of microbiological contaminants. Depending
on the source, method of preparation, and the intended use of the API or
intermediate, control of bioburden, viral contamination, and/or endotoxins during
manufacturing and monitoring of the process at appropriate stages may be necessary.
18.14 Appropriate controls should be established at all stages of
manufacturing to assure intermediate and/or API quality. While this Guide
starts at the cell culture/fermentation step, prior steps (e.g. cell banking)
should be performed under appropriate process controls. This Guide covers cell
culture/fermentation from the point at which a vial of the cell bank is
retrieved for use in manufacturing.
18.15 Appropriate equipment and environmental controls should be
used to minimize the risk of contamination. The acceptance criteria for quality
of the environment and the frequency of monitoring should depend on the step in
production and the production conditions (open, closed, or contained systems).
18.16 In general, process controls should take into account:
- Maintenance of the Working Cell Bank (where appropriate);
- Proper inoculation and expansion of the culture;
- Control of the critical operating parameters during
fermentation/cell culture;
- Monitoring of the process for cell growth, viability (for most
cell culture processes) and productivity where appropriate;
- Harvest and purification procedures that remove cells, cellular
debris and media components while protecting the intermediate or API from
contamination (particularly of a microbiological nature) and from loss of
quality;
- Monitoring of bioburden and, where needed, endotoxin levels at
appropriate stages of production; and
- Viral safety concerns as described in ICH Guideline Q5A Quality of
Biotechnological
Products: Viral Safety Evaluation of Biotechnology Products
Derived from Cell Lines of Human or Animal Origin.
18.17 Where appropriate, the removal of media components, host
cell proteins, other process related impurities, product-related impurities and
contaminants should be demonstrated.
18.2 Cell Bank Maintenance and Record Keeping
18.20 Access to cell banks should be limited to authorized
personnel.
18.21 Cell banks should be maintained under storage conditions
designed to maintain viability and prevent contamination.
18.22 Records of the use of the vials from the cell banks and
storage conditions should be maintained.
18.23 Where appropriate, cell banks should be periodically
monitored to determine suitability for use.
18.24 See ICH Guideline Q5D Quality of Biotechnological Products: Derivation and Characterization
of Cell Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion
of cell banking.
18.3 Cell Culture/Fermentation
18.30 Where aseptic addition of cell substrates, media, buffers,
and gases is needed, closed or contained systems should be used where possible.
If the inoculation of the initial vessel or subsequent transfers or additions
(media, buffers) are performed in open vessels, there should be controls and
procedures in place to minimize the risk of contamination.
18.31 Where the quality of the API can be affected by microbial
contamination, manipulations using open vessels should be performed in a
biosafety cabinet or similarly controlled environment.
18.32 Personnel should be appropriately gowned and take special
precautions handling the cultures.
18.33 Critical operating parameters (for example temperature, pH,
agitation rates, addition of gases, pressure) should be monitored to ensure
consistency with the established process. Cell growth, viability (for most cell
culture processes), and, where appropriate, productivity should also be
monitored. Critical parameters will vary from one process to another, and for
classical fermentation, certain parameters (cell viability, for example) may
not need to be monitored.
18.34 Cell culture equipment should be cleaned and sterilized
after use. As appropriate, fermentation equipment should be cleaned, and
sanitized or sterilized.
18.35 Culture media should be sterilized before use when
appropriate to protect the quality of the API.
18.36 There should be appropriate procedures in place to detect
contamination and determine the course of action to be taken. This should
include procedures to determine the impact of the contamination on the product
and those to decontaminate the equipment and return it to a condition to be
used in subsequent batches. Foreign organisms observed during fermentation
processes should be identified as appropriate and the effect of their presence on
product quality should be assessed, if necessary. The results of such
assessments should be taken into consideration in the disposition of the
material produced.
18.37 Records of contamination events should be maintained.
18.38 Shared (multi-product) equipment may warrant additional
testing after cleaning between product campaigns, as appropriate, to minimize
the risk of cross-contamination.
18.4 Harvesting, Isolation and Purification
18.40 Harvesting steps, either to remove cells or cellular
components or to collect cellular components after disruption, should be
performed in equipment and areas designed to minimize the risk of
contamination.
18.41 Harvest and purification procedures that remove or
inactivate the producing organism, cellular debris and media components (while
minimizing degradation, contamination, and loss of quality) should be adequate
to ensure that the intermediate or API is recovered with consistent quality.
18.42 All equipment should be properly cleaned and, as
appropriate, sanitized after use. Multiple successive batching without cleaning
can be used if intermediate or API quality is not compromised.
18.43 If open systems are used, purification should be performed
under environmental conditions appropriate for the preservation of product
quality.
18. 44 Additional controls, such as the use of dedicated
chromatography resins or additional testing, may be appropriate if equipment is
to be used for multiple products.
18.5 Viral Removal/Inactivation steps
18.50 See the ICH Guideline Q5A Quality of Biotechnological Products:
Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of
Human or Animal Origin for more specific information.
18.51 Viral removal and viral inactivation steps are critical
processing steps for some processes and should be performed within their
validated parameters.
18.52 Appropriate precautions should be taken to prevent potential
viral contamination from pre-viral to post-viral removal/inactivation steps.
Therefore, open processing should be performed in areas that are separate from
other processing activities and have separate air
handling units.
18.53 The same equipment is not normally used for different
purification steps. However, if the same equipment is to be used, the equipment
should be appropriately cleaned and sanitized before reuse. Appropriate
precautions should be taken to prevent potential virus carry-over (e.g. through
equipment or environment) from previous steps.
19 APIs for Use in
Clinical Trials
19.1 General
19.10 Not all the controls in the previous sections of this Guide
are appropriate for the manufacture of a new API for investigational use during
its development. Section 19 provides specific guidance unique to these
circumstances.
19.11 The controls used in the manufacture of APIs for use in
clinical trials should be consistent with the stage of development of the drug
product incorporating the API. Process and test procedures should be flexible
to provide for changes as knowledge of the process increases and clinical
testing of a drug product progresses from pre-clinical stages through clinical
stages. Once drug development reaches the stage where the API is produced for
use in drug products intended for clinical trials, manufacturers should ensure that
APIs are manufactured in suitable facilities using appropriate production and
control procedures to ensure the quality of the API.
19.2 Quality
19.20 Appropriate GMP concepts should be applied in the production
of APIs for use in clinical trials with a suitable mechanism of approval of
each batch.
19.21 A quality unit(s) independent from production should be
established for the approval or rejection of each batch of API for use in
clinical trials.
19.22 Some of the testing functions commonly performed by the
quality unit(s) can be performed within other organizational units.
19.23 Quality measures should include a system for testing of raw
materials, packaging materials, intermediates, and APIs.
19.24 Process and quality problems should be evaluated.
19.25 Labelling for APIs intended for use in clinical trials
should be appropriately controlled and should identify the material as being
for investigational use.
19.3 Equipment and Facilities
19.30 During all phases of clinical development, including the use
of small-scale facilities or laboratories to manufacture batches of APIs for
use in clinical trials, procedures should be in place to ensure that equipment
is calibrated, clean and suitable for its intended use.
19.31 Procedures for the use of facilities should ensure that
materials are handled in a manner that minimizes the risk of contamination and
cross-contamination.
19.4 Control of Raw Materials
19.40 Raw materials used in production of APIs for use in clinical
trials should be evaluated by testing, or received with a supplier’s analysis
and subjected to identity testing. When a material is considered hazardous, a
supplier's analysis should suffice.
19.41 In some instances, the suitability of a raw material can be
determined before use based on acceptability in small-scale reactions (i.e.,
use testing) rather than on analytical testing
alone.
19.5 Production
19.50 The production of APIs for use in clinical trials should be
documented in laboratory notebooks, batch records, or by other appropriate
means. These documents should include information on the use of production
materials, equipment, processing, and scientific observations.
19.51 Expected yields can be more variable and less defined than
the expected yields used in commercial processes. Investigations into yield
variations are not expected.
19.6 Validation
19.60 Process validation for the production of APIs for use in
clinical trials is normally inappropriate, where a single API batch is produced
or where process changes during API development make batch replication
difficult or inexact. The combination of controls, calibration, and, where
appropriate, equipment qualification assures API quality during this
development phase.
19.61 Process validation should be conducted in accordance with
Section 12 when batches are produced for commercial use, even when such batches
are produced on a pilot or small scale.
19.7 Changes
19.70 Changes are expected during development, as knowledge is
gained and the production is scaled up. Every change in the production, specifications,
or test procedures should be adequately recorded.
19.8 Laboratory Controls
19.80 While analytical methods performed to evaluate a batch of
API for clinical trials may not yet be validated, they should be scientifically
sound.
19.81 A system for retaining reserve samples of all batches should
be in place. This system should ensure that a sufficient quantity of each
reserve sample is retained for an
appropriate length of time after approval, termination, or
discontinuation of an application.
19.82 Expiry and retest dating as defined in Section 11.6 applies
to existing APIs used in clinical trials. For new APIs, Section 11.6 does not
normally apply in early stages of clinical trials.
19.9 Documentation
19.90 A system should be in place to ensure that information
gained during the development and the manufacture of APIs for use in clinical
trials is documented and available.
19.91 The development and implementation of the analytical methods
used to support the release of a batch of API for use in clinical trials should
be appropriately documented.
19.92 A system for retaining production and control records and
documents should be used. This system should ensure that records and documents
are retained for an appropriate length of time after the approval, termination,
or discontinuation of an application.
20. Glossary
Acceptance Criteria
Numerical limits, ranges, or other suitable measures for
acceptance of test results.
Active Pharmaceutical Ingredient (API) (or Drug
Substance)
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. Such substances
are intended to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease or to affect
the structure and function of the body.
API Starting Material
A raw material, intermediate, or an API that is used in the
production of an API and that is incorporated as a significant structural
fragment into the structure of the API. An API Starting Material can be an
article of commerce, a material purchased from one or more suppliers under contract
or commercial agreement, or produced in-house. API Starting Materials are
normally of defined chemical properties and structure.
Batch (or Lot)
A specific quantity of material produced in a process or series of
processes so that it is expected to be homogeneous within specified limits. In
the case of continuous production, a batch may correspond to a defined fraction
of the production. The batch size can be defined either by a fixed quantity or
by the amount produced in a fixed time interval.
Batch Number (or Lot Number)
A unique combination of numbers, letters, and/or symbols that
identifies a batch (or lot) and from which the production and distribution
history can be determined.
Bio burden
The level and type (e.g. objectionable or not) of micro-organisms
that can be present in raw materials, API starting materials, intermediates or
APIs. Bioburden should not be considered contamination unless the levels have
been exceeded or defined objectionable organisms have been detected.
Calibration
The demonstration that a particular instrument or device produces
results within specified limits by comparison with those produced by a
reference or traceable standard over an appropriate range of measurements.
Computer System
A group of hardware components and associated software, designed
and assembled to perform a specific function or group of functions.
Computerized System
A process or operation integrated with a computer system.
Contamination
The undesired introduction of impurities of a chemical or
microbiological nature, or of foreign matter, into or onto a raw material,
intermediate, or API during production, sampling, packaging or repackaging,
storage or transport.
Contract Manufacturer
A manufacturer performing some aspect of manufacturing on behalf
of the original manufacturer.
Critical
Describes a process step, process condition, test requirement, or
other relevant parameter or item that must be controlled within predetermined
criteria to ensure that the API meets its specification.
Cross-Contamination
Contamination of a material or product with another material or
product.
Deviation
Departure from an approved instruction or established standard.
Drug (Medicinal) Product
The dosage form in the final immediate packaging intended for
marketing. (Reference Q1A)
Drug Substance
See Active Pharmaceutical Ingredient
Expiry Date (or Expiration Date)
The date placed on the container/labels of an API designating the
time during which the API is expected to remain within established shelf life
specifications if stored under defined conditions, and after which it should
not be used.
Impurity
Any component present in the intermediate or API that is not the
desired entity.
Impurity Profile
A description of the identified and unidentified impurities
present in an API.
In-Process Control (or Process Control)
Checks performed during production in order to monitor and, if
appropriate, to adjust the process and/or to ensure that the intermediate or
API conforms to its specifications.
Intermediate
A material produced during steps of the processing of an API that
undergoes further molecular change or purification before it becomes an API.
Intermediates may or may not be isolated. (Note: this Guide only addresses
those intermediates produced after the point that the company has defined as
the point at which the production of the API begins.)
Lot
See Batch
Lot Number see Batch Number
Manufacture
All operations of receipt of materials, production, packaging,
repackaging, labelling, relabelling, quality control, release, storage, and
distribution of APIs and related controls.
Material
A general term used to denote raw materials (starting materials,
reagents, solvents), process aids, intermediates, APIs and packaging and
labelling materials.
Mother Liquor
The residual liquid which remains after the crystallization or
isolation processes. A mother liquor may contain unreacted materials,
intermediates, levels of the API and/or impurities. It may be used for further
processing.
Packaging Material
Any material intended to protect an intermediate or API during
storage and transport.
Procedure
A documented description of the operations to be performed, the
precautions to be taken and measures to be applied directly or indirectly
related to the manufacture of an intermediate or API.
Process Aids
Materials, excluding solvents, used as an aid in the manufacture
of an intermediate or API that do not themselves participate in a chemical or
biological reaction (e.g. filter aid, activated carbon,
etc).
Process Control
See In-Process Control
Production
All operations involved in the preparation of an API from receipt
of materials through processing and packaging of the API.
Qualification
Action of proving and documenting that equipment or ancillary systems
are properly installed, work correctly, and actually lead to the expected
results. Qualification is part of validation, but the individual qualification
steps alone do not constitute process validation.
Quality Assurance (QA)
The sum total of the organised arrangements made with the object
of ensuring that all APIs are of the quality required for their intended use
and that quality systems are maintained.
Quality Control (QC)
Checking or testing that specifications are met.
Quality Unit(s)
An organizational unit independent of production which fulfills
both Quality Assurance and Quality Control responsibilities. This can be in the
form of separate QA and QC units or a single individual or group, depending
upon the size and structure of the organization.
Quarantine
The status of materials isolated physically or by other effective
means pending a decision on their subsequent approval or rejection.
Raw Material
A general term used to denote starting materials, reagents, and
solvents intended for use in the production of intermediates or APIs.
Reference Standard, Primary
A substance that has been shown by an extensive set of analytical
tests to be authentic material that should be of high purity. This standard can
be: (1) obtained from an officially recognised source, or (2) prepared by
independent synthesis, or (3) obtained from existing production material of
high purity, or (4) prepared by further purification of existing production
material.
Reference Standard, Secondary
A substance of established quality and purity, as shown by
comparison to a primary reference standard, used as a reference standard for
routine laboratory analysis.
Reprocessing
Introducing an intermediate or API, including one that does not
conform to standards or specifications, back into the process and repeating a
crystallization step or other appropriate chemical or physical manipulation
steps (e.g., distillation, filtration, chromatography, milling) that are part
of the established manufacturing process. Continuation of a process step after
an inprocess control test has shown that the step is incomplete is considered
to be part of the normal process, and not reprocessing.
Retest Date
The date when a material should be re-examined to ensure that it
is still suitable for use.
Reworking
Subjecting an intermediate or API that does not conform to
standards or specifications to one or more processing steps that are different
from the established manufacturing process to obtain acceptable quality
intermediate or API (e.g., recrystallizing with a different solvent).
Signature (signed)
See definition for signed
Signed (signature)
The record of the individual who performed a particular action or
review. This record can be initials, full handwritten signature, personal seal,
or authenticated and secure electronic signature.
Solvent
An inorganic or organic liquid used as a vehicle for the
preparation of solutions or suspensions in the manufacture of an intermediate
or API.
Specification
A list of tests, references to analytical procedures, and
appropriate acceptance criteria that are numerical limits, ranges, or other
criteria for the test described. It establishes the set of criteria to which a
material should conform to be considered acceptable for its intended use. “Conformance
to specification” means that the material, when tested according to the listed
analytical procedures, will meet the listed acceptance criteria.
Validation
A documented program that provides a high degree of assurance that
a specific process, method, or system will consistently produce a result
meeting pre-determined acceptance criteria.
Validation Protocol
A written plan stating how validation will be conducted and
defining acceptance criteria. For example, the protocol for a manufacturing
process identifies processing equipment, critical process parameters/operating
ranges, product characteristics, sampling, test data to be collected, number of
validation runs, and acceptable test results.
Yield, Expected
The quantity of material or the percentage of theoretical yield
anticipated at any appropriate phase of production based on previous
laboratory, pilot scale, or manufacturing data.
Yield, Theoretical
The quantity that would be produced at any appropriate phase of
production, based upon the quantity of material to be used, in the absence of
any loss or error in actual production.
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