Gmp (q7 ich guide) & Stem cells-based therapy product manufacturing

GOOD MANUFACTURING PRACTICE
GUIDE FOR ACTIVE
PHARMACEUTICAL INGREDIENTS
(add: guideline for stem cells therapy product)
ICH Q7
Current Step 4 version
dated 10 November 2000
Muhammad Agung Sumantri
19 August 2017

Objective of
Guidance ICH Q7
• To provide guidance
regarding good
manufacturing practice
(GMP) for the
manufacturing of active
pharmaceutical ingredients
(APIs) under an appropriate
system for managing
quality.
<1> Introduction

Concept: Manufacturing
• ICH Q7: include all operations of:
– receipt of materials,
– production,
– packaging, repackaging, labeling,
relabeling,
– quality control,
– release,
– storage and
– distribution of APIs and
– the related controls
<1> Introduction

Relationship
with Other
Regulations
• This Guide is not intended to define
registration/filing requirements or
modify pharmacopoeia 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> Introduction

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.
• Includes:
– APIs that are manufactured by chemical synthesis, extraction, cell
culture/fermentation, by recovery from natural sources, or by
any combination of these processes.
• Excludes:
– All vaccines, whole cells, whole blood and plasma, blood and
plasma derivatives (plasma fractionation), and gene therapy APIs.
However, it does include APIs that are produced using blood or
plasma as raw materials.
<1> Introduction

Definition:
API Starting
Materials
• 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)
– produced in-house
• API Starting Materials normally have defined
chemical properties and structure.
<1> Introduction

• The guidance normally is applied to
the steps shown in gray in Table 1
(note: It does not imply that all steps
shown should be completed)
• This Guide does not apply to steps
prior to the introduction of the
defined "API Starting Material".
• How to determine the starting point:
– For synthetic processes:
• point at which "API Starting Materials"
are entered into the process.
– For other processes (e.g. fermentation,
extraction, purification, etc.):
• 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)
<1> Introduction

<2> Quality Management
• Each manufacturer should establish, document, and
implement an effective QMS (Quality Management System):
– Organizational structure
– Procedures
– Processes
– Resources
– Activities
necessary to ensure confidence that the API will meet its intended
specifications for quality and purity.
Note:
All quality related activities should be defined and documented.
<2.1> Principles:

• Any deviation from
established
procedures should be
documented and
explained.
• Critical deviations
should be investigated,
and the investigation
and its conclusions
should be documented
<2.1> Principles:
Picture from:
Deviation Management in the context of ICH Q9/Q10, R Canadell Heredia et.al.,
European Journal of Parenteral & Pharmaceutical Sciences, 2008

• 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.).
<2.1> Principles:

• The main responsibilities of the independent quality unit(s) should not be
delegated:
– 1. Releasing or rejecting all APIs.
– 2. Establishing a system to release or reject raw materials, intermediates, packaging and
labeling 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
<2.2> Responsibilities of the Quality Unit

• 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.
<2.3> Responsibilities of the Production Activities

• Regular internal audits should be performed
in accordance with an approved schedule to
verify compliance with the principles of
GMP for APIs,
• 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
<2.4> Internal Audits (Self Inspection)

• Reviews should normally be conducted and documented annually
and should include at least:
– Critical in-process control (CPP) and critical API test results (CQA);
– Batches that failed to meet established specification(s) (Rejected
Batches);
– Critical deviations or non-conformances and related investigations;
– Changes carried out to the processes or analytical methods;
– Results of the stability monitoring program;
– Quality-related returns, complaints and recalls; and
– Adequacy of corrective actions.
• Assessment made of whether corrective action or any revalidation
should be undertaken.
• Agreed corrective actions should be completed in a timely and
effective manner.
<2.5> Product Quality Review

<3> Personnel
• 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.
• The responsibilities of all personnel engaged in the manufacture of
intermediates and APIs should be specified in writing.
• 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.
• <3.3> Consultant:
– Should have sufficient education, training, and experience, or any combination
thereof
– Records should be maintained stating the name, address, qualifications, and
type of service provided by these consultants.
<3.1> Personnel Qualification; <3.3> Consultant

<3> Personnel
• Personnel should practice good sanitation and health habits
• Personnel should wear clean clothing (changed when appropriate), head,
face, hand, and arm coverings
• Personnel should avoid direct contact with intermediates or APIs.
• Smoking, eating, drinking, chewing and the storage of food should be
restricted to certain designated areas separate from the manufacturing
areas.
• 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, until condition is corrected or
determined that the person's inclusion would not jeopardize the safety or
quality of the APIs.
<3.2> Personnel Hygiene

<4> Building and Facilities
• located, designed, and constructed to facilitate cleaning,
maintenance, and operations
• orderly placement of equipment and materials; appripriate flow of
materials and personnel  to prevent mix-ups and contamination.
• Clean washing and toilet facilities:
– hot and cold water as appropriate,
– showering and/or changing clothes as appropriate,
– soap or detergent,
– air driers or single service towels
– separate from, but easily accessible to, manufacturing areas
• Laboratory areas/operations should normally be separated from
production areas. (in-process controls laboratory can be located in
production areas  as far not adversely affect the accuracy of the
measurements)
<4.1> Design and Construction

• Utilities (that could impact to product):
– Water
– Steam
– Gases & compressed air
– HVAC
• Should:
– qualified
– Monitored
– action should be taken when limits are exceeded
– Availability of drawing
• Pipework should be appropriately identified  identifying
individual lines, documentation, computer control systems, or
alternative means
<4.2> Utilities

• Unless otherwise justified,
process water (feed water)
should, at a minimum,
meet World Health
Organization (WHO)
guidelines for drinking
(potable) water quality.
• Drains should be provided
with an air break or a
suitable device to prevent
back-siphonage
<4.3> Water

• Dedicated production area (facilities, air handling equipment and/or
process equipment):
– highly sensitizing materials (penicillins or cephalosporins)
– infectious nature
– high pharmacological activity or toxicity (certain steroids or cytotoxic
anti-cancer agents)
• Personnel/ materials, etc moving from one dedicated area to
another  should be controlled
• Any production activities, handling and storage of highly toxic non-
pharmaceutical materials (herbicides and pesticides) should not be
conducted using the buildings and/or equipment being used for the
production of APIs.
<4.4> Containment

• Adequate lighting should be provided in all areas to facilitate cleaning,
maintenance, and proper operations.
• Sewage, refuse, and other waste in and from buildings and the immediate
surrounding area should be disposed of in a safe, timely, and sanitary
manner  EHS Concern
• Containers and/or pipes for waste material should be clearly identified.
• Written procedures should be established:
– assigning responsibility for sanitation
– cleaning schedules,
– methods, equipment, and materials to be used in cleaning buildings and
facilities
<4.5> Lighting; <4.6> Sewage and Refuse;
<4.7> Sanitation and Maintenance

<5> Process Equipment
• Should:
– appropriate design (current drawings should be maintained)
– adequate size
– suitably located
– appropriately identified.
– used within its qualified operating range
– Surface Contact  do not alter the quality of the intermediates and
APIs
• Lubricants, heating fluids or coolants, should not contact to
materials (wherever possible, food grade lubricants and oils should
be used)
• Closed or contained equipment should be used whenever
appropriate. (Where open equipment is used  precautions should
be taken to minimize the risk of contamination
<5.1> Design and Construction

• Preventative maintenance:
– Schedules
– Procedures
– Responsibility
• Cleaning procedures:
– Schedules
– Procedures
– Responsibility
– Its subsequent release for use should be available
– complete description of the methods and materials
– Instructions for the removal of previous batch identification
– Instructions for the protection from contamination prior to use;
– Inspection of equipment for cleanliness immediately before use
– Establishing the maximum time that may elapse between the completion of processing and equipment
cleaning
• For campaign production , equipment should be cleaned at appropriate
• Non-dedicated equipment should be cleaned between production of different materials
• Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should
be defined and justified.
• Cleanliness status should be able to be identified
<5.2> Equipment Maintenance and Cleaning

• Measuring Equipment (critical for assuring the
quality) should be calibrated
• Standards traceable to certified standards
• Records should be maintained.
• Calibration status should be known and
verifiable
• Deviations from acceptance criteria  should
be investigated and assessed (scope: since the
last successful calibration)
<5.3> Calibration

• Procedure and Operation
– Written procedures should be available for the operation and maintenance of computerized
systems.
– Additional check on the accuracy of the entry (by a second operator or by the system itself)
– Incident should be recorded and investigated
– Change should be formally authorized, documented and tested
– Data can be recorded by a second means in addition to the computer system
• Validation
– GMP related computerized systems should be validated (IQ, OQ, PQ)
– Existing system not validated at time of installation  retrospective validation (if appropriate
documentation is available)
• Access Limitation
– Have sufficient controls to prevent unauthorized access or changes to data
– Controls to prevent omissions in data (e.g. system turned off and data not captured)
– Record of data change (previous entry, who and when)
• Back-up
– Data protection should be established for all computerized systems
– Back-up system should be provided
<5.4> Computerized Systems

<6> DOCUMENTATION AND RECORDS
• <6.1> Documentation System and
Specifications
• <6.2> Equipment
• <6.3> Materials
• <6.4> Production Instructions
• <6.5> Batch Records
• <6.6> Laboratory Control Records
• <6.7> Batch Record Review

• All documents related to the manufacture  prepared, reviewed, approved and distributed
according to written procedures
• Revision Histories
• The retention periods should be specified:
– 1 year after the expiry date of the batch
– For APIs with retest dates: 3 years after the batch is completely distributed.
• Records entry:
– indelibly
– in spaces provided for such entries
– directly after performing the activities
– should identify the person making the entry (If electronic signatures are used, they should be authenticated
and secure)
– corrections to entries should be dated and signed and leave the original entry still readable
• Document placement  readily available where the activities occurred (promptly retrieved from
another location by electronic is acceptable)
• Specifications should be documented for:
– raw materials, intermediates
– APIs
– labelling and packaging materials
– Other materials, (could critically impact on quality)
– in-process controls (acceptance criteria)
<6.1> Documentation System and Specifications

• Record types:
– Use
– Cleaning/ sanitization and/or sterilization
– Maintenance
• Record contents:
– Date, time (if appropriate)
– Product
– Batch number of each batch processed in the equipment,
– Person who performed the cleaning/ maintenance
• For dedicated equipment:
– Individual equipment records are not necessary  if batches
follow in traceable sequence
– The records can be part of the batch record or maintained
separately
<6.2> Equipment Cleaning and Use Record

• Records needed:
– Receiving
 Name of the manufacturer
 Identity
 Quantity
 Name of the supplier; the supplier's control number(s), if known,
 Number allocated on receipt
 Date of receipt
 The results of test
– Testing
 Documentation of the examination and review of materials
 The final decision regarding rejected materials
– Use
 Records tracing the use of materials;
• Labeling materials: Master (approved) labels should be maintained for comparison
to issued labels.
<6.3> Records of Raw Materials, Intermediates, API Labelling and Packaging Materials

• Should be prepared, dated, and signed by one person and independently checked,
dated, and signed by a person in the quality unit
• Contents:
– Name of API being manufactured
– Complete list of raw materials and intermediates designated (by names or codes)
– Quantity or ratio of each materials 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
– he production location
– 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
 time limits for completion of individual processing steps and/or the total process
 expected yield ranges at appropriate phases of processing or time;
– Where appropriate, special notations and precautions to be followed
– The instructions for storage (including labelling and packaging materials, storage conditions,
with time limits)
<6.4> Master Production Instructions

• Should be checked before issuance (If produced from a separate
part of the master document, that document should include a
reference to master production instruction being used)
• Should be numbered with a unique 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)
• Written procedures should be established and followed for
– Critical deviations
– Out-of-Specification
(Note: The investigation should extend to other batches that may
impacted)
<6.5> Batch Production Records

• Should include complete data derived from all tests:
 A description of samples (material name, batch number, sampling date sample was taken,
quantity , sample receiving date)
 Reference to each test method used
 Quantity of sample tested
 Data on or cross-reference to the preparation and testing of reference standards, reagents and
standard solutions
 Complete record of all raw data generated during each test (including graphs, charts, and
spectra from laboratory instrumentation, properly identified to show the specific material and
batch tested)
 Record of all calculations performed (for example: units of measure, conversion factors, and
equivalency factors)
 Test results and how they compare with acceptance criteria;
 The signature of the person who performed test and the date(s) the tests were performed;
 The date and signature of a second person (accuracy, completeness, and compliance with
established standards)
• Complete records should also be maintained for:
– Any modifications to an established analytical method
– Periodic calibration
– Stability testing
– Out-of-specification (OOS) investigations.
<6.6> Laboratory Control Records

• Written procedures should be established for the
review and approval of batch production and
laboratory control records
• Authorities:
– critical process steps by the quality unit
– Non-critical process steps  by qualified production
personnel
• All deviation, investigation, and OOS reports should be
reviewed
• 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
<6.7> Batch Production Record Review

<7> MATERIALS MANAGEMENT
<7.1> General Controls
<7.2> Receipt and Quarantine
<7.3> Sampling and Testing of Incoming
Materials and <7.5> Re-evaluation
<7.4> Storage

• There should be written procedures:
– Receipt; Identification; Quarantine
– Storage & Handling
– Sampling & testing
– Approval or rejection
• Suppliers approved by the quality unit
• Materials should be purchased against an agreed specification
• Should have a system for evaluating the suppliers of critical materials
• 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 pproved by the
quality unit
• Changing the source of supply  follows Change Control
<7.1> General Controls

• Upon receipt, each container or grouping of containers:
– Examined visually for correct labeling (identity)
– Container damage, broken seals/ tampering, contamination
• Before incoming materials are mixed with existing stocks  Released
first
• Procedures should be available to prevent discharging incoming
materials wrongly into the existing stock.
• Receiving of non-dedicated tankers :
– Certificate of cleaning
– Testing for trace impurities
– Audit of the supplier.
• Each container or grouping of containers  identified with a
distinctive code/ batch/ receipt number  linked to disposition
record
• A system should be in place to identify the status of each batch.
<7.2> Receipt and Quarantine

• Sampling:
– Sampling method:
 Number of containers to be sampled  based on criticality and quality history
 Which part of the container to sample
 Amount of sample  based on criticality and quality history
– Prevent contamination
– Containers should be opened carefully and subsequently reclosed
– Containers should be marked to indicate that a sample has been taken.
• Testing:
– Full testing: First 3 batches
– Reduced testing:
 Identification  at least one test for each batch (exception with documented justification:
processing aids, hazardous or highly toxic raw materials, materials transferred from other
unit within the company’s control)
 Other tests  can use Supplier's CoA (note: system to evaluate suppliers should be in-place)
• Re-evaluation: Materials should be re-evaluated after prolonged storage or
exposure to heat or humidity
<7.3> Sampling and Testing and <7.5> Re-evaluation

• Prevent degradation, contamination, and cross-
contamination
• Stored off the floor (for fiber drums, bags, and boxes)
• Suitably spaced to permit cleaning and inspection
• FIFO/ FEFO
• Stored outdoors  for certain materials (note: stored in
suitable containers, provided identifying labels remain
legible, containers are appropriately cleaned before
opening and use)
• Rejected materials should be identified and controlled
under a quarantine system
<7.4> Storage

<8> PRODUCTION AND IPC
<8.1> Production Operations
<8.2> Time Limits
<8.3> In-process Sampling and Control
<8.4> Blending
<8.5> Contamination Control

• Dispensing:
– Environment does not affect material suitability for use
– Weighing and measuring devices should be accurate
– Subdivided materials, should have information:
• Material name/ item code;
• Control number;
• Weight of materials in each container
• Re-evaluation date (if appropriate)
– Should be witnessed or subjected to an equivalent control.
• Production:
– Prior to use, production should verify the materials
– Actual yields should be compared with expected yields
 Yield determination: pilot scale or manufacturing data
 Deviations in yield associated with critical process steps should be investigated
– Any deviation should be documented and explained (critical deviation should be investigated, not all
deviation  risk priority)
– Processing status of major equipment should be indicated (on the units, by appropriate
documentation, computer control systems, or alternative means)
– Materials to be reprocessed controlled to prevent unauthorized use
– <8.2> Time Limits: If time limits are specified  these time limits should be met. Intermediates
held for further processing should be stored under appropriate conditions
<8.1> Production Operations

CAPA Management
• The journey of CAPA

FDA – CAPA
(Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations, 2006)
• CAPA is a well-known CGMP regulatory concept that
focuses on investigating, understanding, and correcting
discrepancies while attempting to prevent their
recurrence.
• Quality system models discuss CAPA as three separate
concepts, all of which are used in this guidance:
– Remedial corrections of an identified problem
– Root cause analysis with corrective action to help
understand the cause of the deviation and potentially
prevent recurrence of a similar problem
– Preventive action to avert recurrence of a similar potential
problem

• Written procedures:
– To monitor CPP (Critical Process Parameter)
– Written procedure for sampling (method, plan, and procedure)  scientifically sound
– Prevent contamination/ cross-contamination, ensure the integrity of samples
• In-process controls:
– Acceptance criteria should be defined based on:
 Information gained during development stage; or
 historical data
– IPC can be performed by production
• Adjustment of process can be performed by production without prior quality unit(s)
approval if the adjustments are made within pre-established limits approved by the
quality unit(s)
• 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 *
*Note: FDA Guidance on Investigating OOS  in-process testing done solely for purposes of triggering real time
equipment or system adjustments to prevent process drift
<8.3> In-process Sampling and Controls

• In this document, blending = process of combining materials within the same
specification to produce a homogeneous intermediate or API.
– Includes:
 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.
– Excludes (considered as part of production process and not considered to be blending):
 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
• Each batch should be tested
• Out-Of-Specification batches should not be blended with other batches
• The batch record  traceable back to the individual batches that make up the blend
• If physical attributes of the API are critical (e.g., for use in solid oral/ suspension) 
blending operations should be validated to show homogeneity of the combined
batch.
• 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.
<8.4> Blending Batches of Intermediates or APIs

• Residual carryover (from successive batches)
 Should not result in the carryover of
Degradants  ensure: adversely alter the established impurity
profile
Microbial contamination
 Examples:
Residue adhering to the wall of a micronizer,
Residual layer of damp crystals remaining in a centrifuge bowl after
discharge,
Incomplete discharge of fluids or crystals from a processing vessel
• Contamination by other materials  critical: handling
after purification
<8.5> Contamination Control

<9> PACKAGING AND IDENTIFICATION
LABELLING
<9.1> General
<9.2> Packaging Materials
<9.3> Label Issuance and Control
<9.4> Packaging and Labeling Operations

• Document required (for Packaging and labeling materials):
– Specification for Packaging and labelling materials
– Required Procedures:
• Receipt, Identification, Quarantine
• Sampling, examination and/or testing and release, and
• Handling
– Records (for each shipment):
• Receipt,
• Examination/ testing, disposition (accepted or rejected)
• Containers of Packaging Materials:
– adequate protection against deterioration or contamination
– Clean  If re-used: cleaning procedures + all previous labels
should be removed or defaced.
– Not reactive, additive, or absorptive
<9.1> General; <9.2> Packaging Materials

• Access control to storage area
• Procedure to reconcile the quantities (issued, used, and
returned  compare with actual containers labeled) 
Discrepancy should be investigated
• Control:
– Printing devices: should be controlled to ensure printing
conformity
– Labels:
• Excess labels  should be maintained, stored, proper identified to
prevent mix-ups, and then destroyed
• Obsolete and outdated labels  destroyed
• Printed labels  should be examined (for identity and conformity to
specifications; examination results should be documented) &
included in the batch record.
<9.3> Label Issuance and Control

• Required Procedures  how to ensure correct packaging materials and labels are used
• Labeling Operations:
– Physical or spatial separation  to prevent mix-ups
– Label (contains):
 the name or identifying code
 the batch number
 storage conditions
– If the intermediate or API is intended to be transferred (outside the control of the manufacturer’s
material management system) labels should contain:
• The name and address of the manufacturer,
• Quantity of contents,
• Special transport conditions
• Expiry date indicated on the label and Certificate of Analysis
• Retest date  indicated on the label and/or Certificate of Analysis
• Packaging Operations:
– Facilities should be inspected immediately before use to ensure that all not needed materials have
been removed  inspection results documented
– Ensure that containers and packages of the batch have the correct label  inspection results
documented
– Containers should be sealed  for alert if seal is breached or missing
<9.4> Packaging and Labeling Operations

<10> STORAGE AND DISTRIBUTION
• Warehouse (storage):
– Adequate storage condition (temperature & humidity)  records
should be maintained
– Separate area for temporary storage (quarantined, rejected,
returned, or recalled materials)  unless there is an alternative
system to prevent the unintentional or unauthorized use
• Distribution:
– Materials to be distributed (to 3rd party or another unit under
company’s control )  Should be released first by Quality
– Transportation should not adversely affect the quality:
• Storage condition should be stated on the label
• Contractor of transportation should know and follows required storage
condition
– System should be in place by which the distribution can be readily
determined to permit its recall

<11> LABORATORY CONTROL
 <11.1> General
 <11.2> Testing and <11.3> Method Validation
 <11.4> CoA
 <11.5> Stability Monitoring
 <11.6> Expiry/ Retest Date
 <11.7> Retention Samples

*Specifications should include:
– Impurity Control (Organic, Inorganic, Residual Solvent)
– Microbial Limit and/ or Endotoxin (if any)
**Specifications in addition to those in the registration/filing is permitted.
<11.1> General
Required Document Approved Scientifically
Sound
Aligned with
registration
filing
Aligned with
accepted
standard
Disposition Procedures Yes
Data recording and
storage Procedures
Yes
Sampling Procedures
(including sampling plan)
Yes (by Quality Unit) Yes
Test procedures Yes (by Quality Unit) Yes Yes
Specifications* Yes (by Quality Unit) Yes Yes** Yes
Documentation

• OOS Handling Procedure:
– Investigation and Documentation
– Analysis of the data
– Assessment of impact
– Allocation of the tasks for corrective actions
– Conclusions
– Resampling and/or retesting
<11.1> General
Out-of-Specification (OOS) Handling

• Required Procedure:
– Preparation of reagent/ standard solution
– Labeling of reagent/ standard solution
– Standardization and Requalification of Secondary Reference Standard
• “Use by” dates (expiration)  reagent/ standard solution shelf life
• References Standard (RS):
– Primary RS
 Source (documented)
 Officially recognized source,  no testing needed as long as stored under supplier’s recommendations.
 “in-house primary standard” (if officially recognized source is not available)  Appropriate testing
should be performed to establish fully the identity and purity (documentation of this testing should be
maintained)
 Storage (recorded)
 Use (recorded)
– Secondary RS
 Appropriately prepared, identified, tested, approved, and stored.
 The suitability of each batch of secondary RS prior to first use (comparing against a primary RS)
 Periodically re-qualified
<11.1> General
Reagents and Standards

• Each batch should be tested against its specification
• Impurity Profile (note: not necessary for APIs from herbal or
animal tissue origin):
– Identified and Unidentified impurities
– identity or some qualitative analytical designation (e.g. retention
time)
– the range of each impurity observed
– classification of each identified impurity (e.g. inorganic, organic,
solvent)
• The impurity profile should be compared against the impurity
profile in the regulatory submission or historical  to detect
changes in raw materials, equipment, or the production process
• <11.3> Analytical Method/ Procedures should be validated/
verified
<11.2> Testing

• Issued for each batch
• Information included:
– Name API (including its grade, if any)
– Batch number
– Release date
– Retest/ Expiry Date
Expiry date indicated on the label and Certificate of Analysis
Retest date  indicated on the label and/or Certificate of Analysis
– List of each test (including limits, and [numerical] results)
– Sign and date of authorized personnel of the quality unit
– Name, address and telephone number of the original manufacturer *
<11.4> Certificates of Analysis
*If analysis is carried out by a re-packer/re-processor  the CoA should show the name, address and telephone
number of the re-packer/re-processor and reference to the name of the original manufacturer
* If new Certificates are issued by or on behalf of re-packer/re-processor , agents or brokers  Certificates should
show the name, address and telephone number of the laboratory that performed the analysis and reference to
original certificate and name and address of the original manufacturer (copy of original should be attached)

• Types:
– On-going at least 1 batch/ year
• Frequency:
– For stable API (2 years or more)  Annually
– For short shelf life APOI More frequent (e.g. tested monthly for the first three
months, and at three month intervals after that)
– Study (shelf life determination)  Normally first three commercial
batches (If previous studies show stable at least for two years, fewer
than three batches can be used)
• Should have stability testing program
• The test procedures should be stability indicating and validated
• Stability samples should be stored in containers that simulate
the market container (same or smaller-scale drums with
identical composition)
• Stability storage conditions  ICH guidelines on stability.
<11.5> Stability Monitoring

• Common practice is to use a retest date, not an expiration
date
• Definition:
– Expiry Date: after this date, API should not be used
– Retest Date: after this date, API should be re-examined to
ensure compliance with the specification
• Notes (FDA Guideline):
 After successful re-examination, API is used immediately
 API can be retested multiple times and a different portion of the batch used
after each retest, as long as it continues to comply with the specification.
 For most biotechnological/biological substances known to be labile, it is more
appropriate to establish a shelf life than a retest period. The same may
• Notes (PhRMA Perspectives):
 New retest date period  Should be based on current retest results, stability
data, sound scientific principles, the retest period filed in the NDA/DMF, and
cGMP requirements
<11.6> Expiry and Retest Dating

• Purpose:
– For future evaluation of the quality of batches of API
– not for future stability testing purposes
• Retention Period:
– 1 year after the expiry date or 3 years after distribution, whichever is the longer.
– For APIs with retest dates  3 years after distribution
• Storage condition:
– The same packaging system or equivalent or more protective than the marketed
packaging system
• Quantity:
– At least two full compendia analyses
– At least two full specification analyses (if not compendia)
<11.7> Reserve/Retention Samples

<12> VALIDATION
 <12.1> Policy and <12.2> Documentation
 <12.3> Qualification
 Process Validation:
 <12.4> Approach
 <12.5> Process Validation Program
 <12.6> Periodic Review
 <12.7> Cleaning Validation
 <12.8> Analytical Method Validation

<12> VALIDATION
“WHO: GMP – main principals, Annex 2, TRS 986, 2013”:
 Action of proving (systematic, documented), that any
 procedure,
 process,
 equipment,
 material,
 activity,
 system
 personnel
 measurement/ testing method
 actually leads to the expected results

Process validation
Traditional vs new paradigm
Post
approval
changes/cha
nge
controls/risk
analysis
Development-
Basic
Process
validation- 3
batches
Pilot batch
manufacturing
Enhanced-
Development and
process
qualification
Control
Strategy
Continuous and
extensive monitoring of
CQAs and CPPs for each
production batch
ICH Q9
and Q10
ICH Q8,
QbD

Latest guidelines
FDA, January 2011 WHO, Revised Annex 7 of
WHO GMP guide (draft for
comment)
EMA, February 2014
Continuous process
verification (CPV)
Continuous process
verification (CPV)
Alternative approaches:
-Traditional approach
-Continuous process
verification
-Hybrid approach
Process design and Initial
validation (process
qualification- PPQ) are initial
phases of CPV
Process design and initial
validation (initial process
verification) are initial phases
of CPV
CPV protocol to be supported
by extensive development
information and lab or pilot
scale data. Executed on each
production batch
No mention of number of
batches for initial process
performance
qualification/validation (rather
must be justified based on
overall product and process
understanding)
Mentions data on at least
three pilot or production
batches collected as part of
process design
Number of batches specified
for traditional approach
- minimum of three production
batches unless other wise
justified

<12> VALIDATION
• <12.1> Policy:
– Policy, intentions, and approach
– Coverage:
• production processes
• cleaning procedures
• analytical methods
• in-process control test procedures
• computerized systems
– Persons responsible for design, review, approval and documentation of each validation phase
• <12.2> Documentation:
– Validation protocol
• approved by quality unit
• specify CPP and CQA
• type of validation (e.g. retrospective, prospective, concurrent)
• the number of process runs
– Validation Report
• Cross-references to the validation protocol
• Summarizing the results obtained,
• Commenting on any deviations observed
• Conclusions (including recommending changes to correct deficiencies )
– Any variations from protocol should be documented and justified

<12> VALIDATION
• Object to be qualified:
– Critical equipment
– Ancillary systems (supporting)/ facilities
• Stages:
– Design Qualification (DQ)
• to ensure proposed design is suitable for the intended purpose
– Installation Qualification (IQ)
• to ensure installed equipment/system/facility comply with the approved
design/requirements
– Operational Qualification (OQ)
• to ensure equipment/system/facility perform as intended throughout the anticipated
operating ranges.
– Performance Qualification (PQ)
• to ensure equipment/system/facility , as connected together, can perform effectively
and reproducibly as per intended purpose
<12.3> Qualification

<12> VALIDATION
• Three (3) approaches:
– Prospective (preferred)  completed before the commercial distribution
– Concurrent  not completed while commercial distribution is still on going
> API batches are produced infrequently
> Prior to the completion of concurrent validation, batches can be released based on thorough
monitoring and testing of the API batches.
– Retrospective  Batches Review (for well established processes that have been used without
significant changes )
Pre-requisites: IPC, CQA, CPP, Impurity profile are available & no significant failure
• Life Cycle of GMP Validation (PV Program)
• 1. Validation master plan
• 2. Validation protocol
– The number of runs: 3 batches for Prospective and Concurrent, 10-30 batches for retrospective
• 3. Execution of validation
• 4. Validation report
• Includes: CQA (KQA), CPP, and Impurity Profile
• Impurity profile can be determined from history or pivotal clinical and toxicological studies
• 5. Preparation of SOPs
• 6. Periodic Review (any change? Trend?)
Process Validation (<12.4> Approach, <12.5> PV Program, & <12.6> Periodic Review)

<12> VALIDATION
• Cleaning validation should be directed to situations or process steps
where contamination or carryover of materials poses the greatest risk to
API quality.
• If various APIs are manufactured in the same equipment and the
equipment is cleaned by the same process, a representative API can be
selected for cleaning validation (based on This selection solubility and
difficulty of cleaning and potency, toxicity, and stability)
• 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
• Validated analytical methods having sensitivity to detect residues or
contaminants should be used.
<12.7> Cleaning Validation

<12> VALIDATION
• Validation (USP 1225) VS Verification (USP 1226)
• Appropriate qualification of analytical equipment
should be considered before starting validation of
analytical methods.
<12.8> Analytical Method Validation

<12> VALIDATION
• USP <61> TAMC/TYMC
• USP <62> Identification
• USP <71> Sterility Test
• USP <85> Endotoxin
• USP <1227> Validation of Microbial Recovery
• USP <1033> Validation of Biological Assays
• USP <1231> Water for Pharmaceutical Purposes
• USP <797> Environmental Monitoring Program Design and Application
• USP <1116> Microbial Evaluation and Classification of
• Cleanrooms and Other Controlled Environments.
<12.8> Analytical Method Validation

<13> CHANGE CONTROL
 A formal change control system should be established to evaluate all
changes that may affect the production and control of the
intermediate or API:
 raw materials, specifications, analytical methods, facilities, support systems,
equipment (including computer hardware), processing steps, labeling and
packaging materials, and computer software.
 Written procedures should be provided
 Drafted (description + reason + pre-change actions + post-change actions )
 Post –change actions: First Batch Evaluation, Re-validation, Stability Study, BPOM
Notification, Registration
 Reviewed, and approved by the appropriate organizational units (Impact
Assessment)
 Reviewed and approved by the quality unit(s).
 Change Implementation
 Post-change Approval by the quality unit(s).

<14> REJECTION AND RE-USE OF
MATERIALS
 APIs failing to meet established specifications should be identified as such and quarantined.
 The final disposition of rejected materials should be recorded.
 Reprocess VS Rework
 Reprocess: The treatment of a batch or sub-batch of materials of unacceptable quality by
repeating the same steps from a defined stage of production so that its quality may be
made acceptable.
Note: However, if such reprocessing is used for a majority of batches, such reprocessing
should be included as part of the standard manufacturing process.
 Rework: The treatment of a batch or sub-batch of materials of unacceptable quality by
using a process other than that used to produce the original material so that its quality may
be made acceptable.
Note:
Before a decision is taken to rework, an investigation should be performed.
impurity profile of each reworked batch against batches manufactured by the established process.
 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.

<15> COMPLAINTS AND RECALLS
(& <14.5> Returns)
 Returns
 Returned intermediates or APIs should be identified as such and quarantined.
 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
 Complaint
 All quality related complaints, whether received orally or in writing, should be recorded and
investigated according to a written procedure
 Documentation 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 API batch
 Records of complaints should be retained in order to evaluate trends
 Recall
 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.
 In the event of a serious or potentially life-threatening situation, national authorities should be
informed and their advice sought.

<16> CONTRACT MANUFACTURERS
(INCLUDING LABORATORIES)
 All contract manufacturers (including laboratories) should comply with the GMP
defined in this Guide
 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
 The contract should permit the contract giver to audit the contract acceptor's
facilities for compliance with GMP
 Contract manufacturers (including laboratories) should be evaluated by the contract
giver to ensure GMP compliance
 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
 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
 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
 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 (Identity of original manufacturer;
Purchase orders; Name of API; Manufacturer’s batch number; Retest or expiry date)
 Should establish, document and implement an effective system of managing quality
 Should maintain records of complaints and recalls & review the complaint with the
original API manufacturer in order to determine whether any further action
 Repackaging, relabelling and holding of APIs and intermediates should be performed
under appropriate GMP controls

<18> SPECIFIC GUIDANCE FOR APIs MANUFACTURED
BY CELL CULTURE/FERMENTATION
Note: While this Guide starts at the cell culture/fermentation step, prior steps (e.g. cell
banking) should be performed under appropriate process controls.
 Appropriate equipment and environmental controls should be used to minimize the
risk of contamination (acceptance criteria, frequency of monitoring)
 Appropriate controls should be established at all stages of manufacturing to assure
intermediate and/or API quality:
− 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;
− Viral safety concerns as described in ICH Guideline Q5A Quality of Biotechnological Products: Viral
Safety Evaluation
<18.1> General

 Access to cell banks should be limited to authorized personnel
 Cell banks should be maintained under storage conditions designed to
maintain viability and prevent contamination.
 Records of the use of the vials from the cell banks and storage conditions
should be maintained.
 Where appropriate, cell banks should be periodically monitored to
determine suitability for use.
 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.
<18.2> Cell Bank Maintenance and Record Keeping

 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
 Personnel should be appropriately gowned
 Culture media should be sterilized before use when appropriate to protect the quality of the API
 Critical process parameters (temperature, pH, agitation rates, addition of gases, pressure, cell growth,
viability, productivity) should be monitored
 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.
 Cell culture equipment should be cleaned and sterilized after use.
 Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns,
as appropriate, to minimize the risk of cross-contamination.
Contained system: An area constructed and operated in such a manner (and equipped with appropriate air
handling and filtration) so as to prevent contamination of the external environment by biological agents from
within the area. [EU GMP Guide, Glossary]
<18.3> Cell Culture/Fermentation

 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.
 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.
 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.
 If open systems are used, purification should be performed under environmental
conditions appropriate for the preservation of product quality.
 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.
<18.4> Harvesting, Isolation and Purification

 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.
 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.
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
<18.5> Viral Removal/Inactivation steps

Gmp (q7 ich guide) & Stem cells-based therapy product manufacturing

Gmp (q7 ich guide) & Stem cells-based therapy product manufacturing

Recomendados

Recomendados

Más contenido relacionado

La actualidad más candente

La actualidad más candente (20)

Similar a Gmp (q7 ich guide) & Stem cells-based therapy product manufacturing

Similar a Gmp (q7 ich guide) & Stem cells-based therapy product manufacturing (20)

Último

Último (20)

Gmp (q7 ich guide) & Stem cells-based therapy product manufacturing