Incremental GMPs for IMPs
and QP Batch Certification
Presented by: Karen S. Ginsbury
For: IFF
October 2009
PCI Pharmaceutical Consulting Israel Ltd.
Course Objective
Provide an overview of regulations and
expectations of regulatory authorities
regarding manufacture and in particular,
certification and release of clinical trials
material
PCI Pharmaceutical Consulting Israel Ltd.
To be discussed…
• EU + US legislation /
guidance for IMPs:
– FDA’s GMPs for Phase I
guidance
– EU Annex 13
• The role of the Quality
Unit vs The Qualified
Person in batch
certification and / or
release (Annex 16)
• Sponsor responsibilities
and release to sites
• Documentation
requirements –
Product Specification
File
• Contract manufacture
and analysis of
investigational
products
PCI Pharmaceutical Consulting Israel Ltd.
To be discussed…
•
•
•
Preliminary Hazard Analysis /
risk assessment tool for
determining GMP levels
Pre-clinical batches: “GMP” or
not
Risks for early / late phase:
– Analytical methods
qualification / verification /
validation
– Cleaning verification /
validation
– Facilities: dedicated /
campaign basis / potent
drugs /biological
– Vendors: qualification /
approval program / auditing
– at what stage
• Process: - when to
• define target product
profile
• identify Critical
Process Parameters
•
identify Critical Quality
Attributes
start to show
reproducibility
think about validation
packaging
stability and retest /
reuse/ expiry date
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The Playing Field
FDA
• Exempt phase I
product from
21 CFR part 211
• Continue to oversee
under STATUTORY
requirements of
FD&C Act
• Phase 2 and 3 still
under CFR
EU
Require ALL of GMP
+ Annex 13
+ Annex 16 (QP release)
For all phases
PCI Pharmaceutical Consulting Israel Ltd.
Product Control Strategy and Risk
Management
•
•
•
•
Developing a Target Product Profile
Product Specification File
Initial risk assessment
Company Strategy for controlling material
to be used to generate data for use in
regulatory submissions: pre-clinical
toxicology, phase 1 – 3
• Product specific control strategy
PCI Pharmaceutical Consulting Israel Ltd.
The Phases of Drug Development
• Pre-Clinical
• Toxicology, animals
• Phase 1
• Safety in humans
(usually first in humans)
• Phase 2
• Small scale efficacy
• Phase 3
• Large scale trial
• Phase 4
• Post marketing
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Regulation of Clinical Trials Material
US FDA
EU EMEA
• Investigational Medicinal
• Investigational New
Product Dossier (IMPD) /
Drug Application (IND)
• May “choose” to inspect Clinical Trial Application (CTA)
generally based on IND • Obliged to inspect under
clinical trial directive
review
(in third country this might be a
• Very rare for FDA to
QP audit rather than
inspect even in phase 3 competent authority)
• Inspections are common
PCI Pharmaceutical Consulting Israel Ltd.
Quality Assurance: Definition
2003/94/EC
‘pharmaceutical quality assurance’ means
the total sum of the organised
arrangements made with the object of
ensuring that medicinal products or
investigational medicinal products are of
the quality required for their intended use
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IND Phase 1 – CMC
Requirements
• Drug Substance
– Description (physical, chemical, biological)
– Manufacturer (name and address)
– Method of Preparation (brief description/ flow
diagram, reagents, solvents, catalysts)
– Analytical Methods ( brief description, proposed
criteria, certificates of analysis)
– Stability (brief description of study/test methods,
preliminary tabular data)
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IND Phase 1 – CMC
Requirements
• Drug Product
– Components (grade (e.g. USP/ NF, ACS), novel
excipients, etc.)
– Quantitative composition
– Manufacturer (name and address)
– Method of Manufacture (narrative and/or flow
diagrams, sterilization process for sterile products)
– Analytical Methods
• brief description of test methods and limits (dosage form
dependent)
– Stability of Drug product
• Information to assure the product’s stability during the
planned clinical studies
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IND Phase 1 – CMC
Requirements
• Placebo
(NOTE: EU wants placebo / comparator
product released by QP)
– Description
– Composition and Controls
– Control
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FD&C Act
• 501(a)(2)(B) requires all drug products be
manufactured in accordance with current
good manufacturing practice (CGMP)
• CGMP Regulations, published in 1978
and codified in 21 CFR 210 and 211
primarily directed to commercial
manufacturing of approved drugs and
biologics
PCI Pharmaceutical Consulting Israel Ltd.
General CGMP Requirements
Quality Control Function:
– established for every manufacturer of IND
products
– responsibilities documented in writing and
include:
• examination of components, containers,
closures, in-process materials, packaging and
labeling materials
• review and approval of production and testing
procedures, acceptance criteria
• review of completed production records for
release or rejection of each clinical batch
– is responsibility of all staff involved in production
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Multi-product Facilities
• An area or room can be used for multiple
purposes and products, provided that:
– only one product is produced in an area at
any given time
– appropriate cleaning and change over
procedures are in place to ensure there is no
carry-over of materials or products or mix-ups
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Biological and Biotechnological
Products
• Additional safeguards
– Some production systems may warrant
additional safeguards to protect personnel
(e.g., pathogenic microorganisms, some
products made from spore-forming
microorganisms, live viral vaccines and gene
therapy vectors)
– Equipment qualification and controls in
production assure success of unit operations
with safety-related functions (e.g., viral
clearance, virus/ toxin attenuation,
pasteurization)
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FDA Guidance, July 2008
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GMP for Phase I
A.
B.
C.
D.
E.
Personnel
QC Function
Facility & Equipment
Component control
Manufacturing and
Records
F. Laboratory controls
G. Packaging, Labeling,
distribution
H. Record-keeping
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EU Clinical Trials Directive
2001/20/EC
• Laws, regulations relating to
implementation of good clinical practice in
the conduct of clinical trials on medicinal
products for human use
(12) The principles of good
manufacturing practice should
be applied to investigational
medicinal products.
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EU Clinical Trials Directive - 2
2001/20/EC
3. Take all appropriate measures to
ensure that the qualified person is
responsible for ensuring:
– (b) in the case of investigational medicinal
products manufactured in a third country, that
each production batch has been manufactured
and checked in accordance with:
• standards of good manufacturing practice
• product specification file
• The clinical trial authorisation (CTA)
PCI Pharmaceutical Consulting Israel Ltd.
EU Clinical Trials Directive – 3: Article 15
Verification of compliance of investigational medicinal
products with good clinical and manufacturing practice
• Member States shall appoint inspectors to
inspect:
– the trial site or sites
– the manufacturing site of the investigational
medicinal product
– any laboratory used for analyses in the clinical
trial
– and/or the sponsor's premises.
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EU Clinical Trials Directive – 4: Article 15
Verification of compliance of investigational medicinal
products with good clinical and manufacturing practice
4. The Commission, upon receipt of a
reasoned request from a Member State or
on its own initiative may propose that the
trial site and/or the sponsor's premises
and/or the manufacturer established in a
third country undergo an inspection. The
inspection shall be carried out by duly
qualified Community inspectors.
PCI Pharmaceutical Consulting Israel Ltd.
The meaning of the Directive
• As of 01 May 2004 all manufacturers of
IMPs including Phase 1 are open to
inspection
• QPs need to demonstrate competence
and have required qualifications to certify
(NOT release) IMPs
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The meaning of the Directive – 3
Voluntary Inspection Findings
• Voluntary inspections ceased 01/05/04
• Findings:
– Poorly developed quality systems
– Inadequate facilities
– Inadequate validation
– Poorly defined QP responsibilities
– Poor labeling / packaging practices
– Poor TSE / BSE management
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EU GMP Directive
2003/94/EC
• Principles and guidelines of good
manufacturing practice in respect of
medicinal products for human use and
investigational medicinal products for
human use
• “investigational medicinal product”
appears 27 times
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Importer’s Responsibility
2003/94/EC
• For … investigational medicinal products
imported from third countries
• the importer shall ensure that:
– products have been manufactured in accordance with
standards equivalent to the good manufacturing
practice standards laid down by the Community
– by a manufacturer notified to the competent
authorities and accepted by them for that purpose.
PCI Pharmaceutical Consulting Israel Ltd.
Manufacturer’s Responsibility - 3
2003/94/EC
• Appropriate technical or organisational
measures shall be taken to avoid cross
contamination and mix-ups.
• In the case of investigational medicinal
products, particular attention shall be paid
to the handling of products during and
after any blinding operation.
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Manufacturer’s Responsibility - 4
2003/94/EC
• For investigational medicinal products, the
manufacturing process shall be validated in its
entirety in so far as is appropriate:
• taking into account the stage of product
development
• At least the critical process steps, such as
sterilisation, shall be validated
• All steps in the design and development of the
manufacturing process shall be fully
documented.
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Quality Control
2003/94/EC
• For investigational medicinal products, the
sponsor shall ensure that the contract laboratory
complies with the content of the request referred
to in Article 9(2) of Directive 2001/20/EC, as
accepted by the competent authority.
• When the products are imported from third
countries, analytical control shall not be
mandatory.
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Quality Assurance / Batch Release
2003/94/EC
• During the final control of the finished product
before its release..for use in clinical trials, the
quality control system shall take into account, in
addition to analytical results, essential
information such as the production conditions,
the results of in-process controls, the
examination of the manufacturing documents
and the conformity of the product to its
specifications, including the final finished pack.
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Annex 16
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Scope of Annex 16
• This annex …gives guidance on the
certification by a Qualified Person (QP) and
• batch release within the European
Community (EC) or European Economic Area
• (EEA) of medicinal products holding a
marketing authorisation or made for export.
• The relevant legislative requirements are
contained in Article 51 of Directive
2001/83/EC or Article 55 of Directive
2001/82/EC
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Annex 16
• Certification of the finished product
batch:
the certification in a register or equivalent
document by a Q.P., as defined in Article
51 of Directive 2001/83/EC and Article 55
of Directive 2001/82/EC, before a batch is
released for sale or distribution.
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Batch Release Certificate
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Batch Release Certificate
• Investigational Medicinal Products may not be used in a
clinical trial in the EEA until completion of a two-step release
procedure. The first step is the certification by the Qualified
Person of the manufacturer or importer that the provisions of
Article 13(a), (b) or (c) of Directive 2001/20/EC have been
complied with. insofar as these provisions have been
complied with, the IMPs in question shall not have to undergo
any further checks if they move into another Member State
provided they are accompanied by batch release certification
signed by the Qualified Person.
• The GCP and GMP Inspection Services of the Member States
have agreed that the content of these certificates should be in
accordance with the attached format
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Batch Release Certificate
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Batch Release Certificate
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Annex 16
• The annex covers in particular those cases where a
batch has had different stages of production or testing
conducted at different locations or by different
manufacturers, and where an intermediate or bulk
production batch is divided into more than one finished
product batch
• It also covers the release of batches which have been
imported to the EC/EEA both when there is and is not
a mutual recognition agreement between the
Community and the third country
• The guidance may also be applied to investigational
medicinal products, subject to any difference in the
legal provisions and more specific guidance in Annex
13 to the Guide
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Annex 16
• The basic arrangements for batch release
for a product are defined by its Marketing
Authorisation
• Nothing in this annex should be taken as
overriding those arrangements
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Annex 16
• Each batch of finished product must be
certified by a QP within the EC/EEA before
being released for sale or supply in the
EC/EEA or for export
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Annex 16
The purpose of controlling batch release in this way is
• to ensure the batch was manufactured and checked in
accordance with:
– Its marketing authorisation
– the principles and guidelines of EC Good Manufacturing
Practice or the good manufacturing practice of a third
country recognised as equivalent under a mutual
recognition agreement and any other relevant legal
requirement before it is placed on the market
and
– in the event that a defect needs to be investigated or a
batch recalled, to ensure that the QP who certified the
batch and the relevant records is readily identifiable
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Annex 16
• in an industrial situation it is usually not
possible for a single QP to be closely
involved with every stage of manufacture
• The Q.P. who certifies a finished product
batch may need therefore to rely in part on
the advice and decisions of others
• Before doing so he should ensure that this
reliance is well founded, either from personal
knowledge or from the confirmation by other
QPs within a quality system which
he has accepted
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Annex 16
• When some stages of manufacture
occur in a third country it is still a
requirement that production and testing
are in accordance with the marketing
authorisation, that the manufacturer is
authorised according to the laws of the
country concerned and that
manufacture follows good
manufacturing practices at least
equivalent to those of the EC
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Annex 16
• the correct manufacture of a
particular batch of product, regardless
of how many sites are involved,
should be the overall concern of the
Q.P. who certifies the finished product
batch before release
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Annex 16
• Different batches of a product may be manufactured or
imported and released at different sites in the EC/EEA.
For example a Community marketing authorisation
may name batch release sites in more than one
member state, and a national authorisation may also
name more than one release site
• In this situation the holder of the marketing
authorisation and each site authorised to release
batches of the product should be able to identify the
site at which any particular batch has been released
and the QP responsible for certifying the batch
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Annex 16
• The Q.P. who certifies a finished product batch before release
may do so based on personal knowledge of all the facilities
and procedures employed, the expertise of the persons
concerned and of the quality system within which they
operate.
• Alternatively he may rely on the confirmation by one or more
other QPs of the compliance of intermediate stages of
manufacture within a quality system which he has accepted.
• This confirmation by other QPs should be documented and
should identify clearly the matters which have been confirmed
• The systematic arrangements to achieve this should be
defined in a written agreement in conformance with Chapter 7
(Technical Agreement / Quality Contract)
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Annex 16
• The agreement should include an
obligation on the part of the provider of
a bulk or intermediate product to notify
the recipient(s) of any deviations, outof-specification results, non-compliance
with GMP, investigations, complaints or
other matters which should be taken
into account by the QP responsible for
certifying the finished product batch
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Annex 16
• For assembly at different sites under a single
marketing authorisation, there should be one person,
normally a QP of the manufacturer of the bulk
production batch, with overall responsibility for all
released finished product batchesderived from one
bulk production batch
• The duty of this person is to be aware of any quality
problems reported on any of the finished product
batches and to co-ordinate any necessary action
arising from a problem with the bulk batch.
• While the batch numbers of the bulk and finished
product batches are not necessarily the same, there
should be a documented link between the two
numbers so that an audit trail can be established
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Annex 16
• QC laboratories authorised under
separate marketing authorisation –
QP must either take responsibility
or have alternative QP assigned
as responsible for testing and test
results and their sign off
• Same for third country
manufacture (“equivalent” GMP)
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Annex 16
• Routine duties of QP prior to batch
certification:
– Compliance with MA
– Compliance with GMP
– Manufacturing and testing processes validated
– Deviations / planned changes and notification of
CA if needed
– Documentation complete
– Audits performed
– QP’s knowledge up to date
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Retained Samples
2003/94/EC
• For an investigational medicinal product,
sufficient samples of each batch of bulk
formulated product and of key packaging
components used for each finished
product batch shall be retained for at least
two years after completion or formal
discontinuation of the last clinical trial in
which the batch was used, whichever
period is the longer
[Normally keep whole batch forever]
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Complaints
2003/94/EC
• In the case of investigational medicinal
products, the manufacturer shall, in
cooperation with the sponsor, implement a
system for recording and reviewing
complaints together with an effective
system for recalling promptly and at any
time investigational medicinal products
which have already entered the
distribution network.
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Labelling
2003/94/EC
• In the case of an investigational medicinal
product, labelling shall be such as to:
– ensure protection of the subject and
traceability
– enable identification of the product and trial
– facilitate proper use of the investigational
medicinal product.
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Annex 13 – July 2003
Manufacture of IMPs
• Investigational medicinal products should
be produced in accordance with the
principles and the detailed guidelines of
Good Manufacturing Practice for Medicinal
Products (The Rules Governing Medicinal
Products in The European Community,
Volume IV)
• [Rules to be found by entering: EudraLex
Volume 4 in search engine]
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Annex 13 cont/
• Packaging and Labeling. Self inspection
or independent audits should be used to
monitor these critical operations.
• Personnel - separate QA and production
(FDA also require this).
• Batch release by qualified person (QP)
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Annex 13 cont/
• Product Specification File
• A reference file containing, or referring to files
containing, all the information necessary to
draft the detailed written instructions on
processing, packaging, quality control testing,
batch release and shipping of an
investigational medicinal product
– constantly updated
– QP needs to be familiar with it prior to certification
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Annex 13 cont/
44. Investigational medicinal products should remain
under the control of the Sponsor until after
completion of a two-step release procedure:
– certification by the Qualified Person
– release following fulfilment of the requirements of
Article 9 (Commencement of a clinical trial) of
Directive 2001/20/EC
– The sponsor should ensure that these are consistent
with the details actually considered by the Qualified
Person
– Both releases should be recorded and retained in the
relevant trial files held by or on behalf of the sponsor
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Annex 13 cont/
• Manufacturing and Packaging Records
• Production
– Starting materials should be well defined and
documented.
– Written procedures for generating
randomization codes and blinding.
• QC.
• Complaints, returns, recalls, destruction.
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ICH Quality Vision (July 2003)
Q8, Q9, Q10 – The Trilogy
“Develop a harmonized pharmaceutical
quality system applicable across the life
cycle of the product emphasizing an
integrated approach to quality risk
management and science.”
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Definitions: Target Product Profile
• A target product profile is a prospective
and dynamic summary of the quality
characteristics of a drug product that
ideally will be achieved to ensure that the
desired quality, and hence the safety and
efficacy, of a drug product is realised
• The target product profile forms the basis
of design for the development of the
product
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Quality Attribute
Target
Route of
administration
Oral
Dosage form
Capsule, size 2, maximum fill weight 280mg
Strength
0.6mg
Packaging
Securitainer, plastic cap and alu overseal, dessicant
Stability
3 yrs at room temperature
Pharmacokinetics
Immediate release enabling tmax in 2 hours or less
Appearance
White opaque cap and body, hard gelatin capsule
filled with white to off-white granulate
Assay
90-110%
Impurities
Impurity A: NMT 0.5%, Impurity B: NMT 0.5%
Total Impurities: NMT 2%
Content Uniformity
Meets USP
Dissolution
NLT 70% of labeled amount is dissolved in 30 min :
(500 ml water; USP apparatus II {paddles}; 50 rpm)
Microbiology
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Pharmaceutical
Meets
USP
criteria (NMTConsulting
1000cfu /g; 100cfu fungi)
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Control Strategy: Definition
• A planned set of controls, derived from current
product and process understanding, that
assures process performance and product
quality
• The controls can include parameters and
attributes related to drug substance and drug
product materials and components, facility and
equipment operating conditions, in-process
controls, finished product specifications, and the
associated methods and frequency of monitoring
and control (ICH Q10)
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Definitions
Critical Quality Attribute (CQA):
• A physical, chemical, biological or
microbiological property or characteristic that
should be within an appropriate limit, range, or
distribution to ensure the desired product quality
Critical Process Parameter:
• A process parameter whose variability has an
impact on a critical quality attribute and therefore
should be monitored or controlled to ensure the
process produces the desired quality
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Control Parameters vs CQAs
Process Control Parameters
– Risk assessment can be used
to identify material attributes
and process parameters that
can affect CQAs
– Risk assessment tools can be
used to identify and rank
parameters (e.g., operational,
equipment, input material) with
potential to have an impact on
product quality based on prior
knowledge and initial
experimental data
– Batch production records are
developed with paramter ranges
designed to ensure the CQAs
are achieved
Critical Quality Attributes
– physical, chemical, biological,
or microbiological property or
characteristic that should be
within an appropriate limit,
range, or distribution to ensure
the desired product quality
– CQAs are generally associated
with the drug substance,
excipients, intermediates, and
drug product
– Drug product CQAs include the
properties that impart the
desired quality, safety, and
efficacy
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Product Specification File – Annex 13
• Should be continually updated during development to
allow traceability to previous versions (audit trail)
• Includes (but not necessarily limited to):
– Specifications and analytical methods for starting materials,
packaging materials
– intermediate, bulk and finished product
– Manufacturing methods
– In-process testing and methods
– Approved label copy
– Relevant clinical trial protocols and randomisation codes
– Relevant technical agreements with contract givers
– Stability data
– Storage and shipment conditions
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Product Specification File – Annex 13
• The contents will vary depending on the product and
stage of development
• The information should form the basis for assessment of
the suitability for certification and release of a particular
batch by the Qualified Person and should therefore be
accessible to him/her
• Where different manufacturing steps are carried out at
different locations under the responsibility of different
• Qualified Persons, it is acceptable to maintain separate
files limited to information of relevance to the activities at
the respective locations
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Risk Assessment in R&D: Control Parameters
Ishikawa (Fishbone) Diagram
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Q8 R1: Risk Management in R&D
• A cross-functional team of experts could work together to
develop an Ishikawa (fishbone) diagram that identifies all
potential variables which can have an impact on the
desired quality attribute
• The team could then rank the variables based on
probability, severity, and detectability using failure mode
effect analysis
• (FMEA) or similar tools based on prior knowledge and
initial experimental data
• Design of experiments or other experimental approaches
could then be used to evaluate the impact of the higher
ranked variables, to gain greater understanding of the
process, and to develop a proper control strategy
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Control Strategy
• Controls should be based on product,
formulation and process understanding and
should include, at a minimum, control of the
critical parameters and attributes
• A comprehensive pharmaceutical development
approach will generate process and formulation
understanding that identifies sources of
variability
• Critical sources of variability that can lead to
product failures should be identified,
appropriately understood, managed or controlled
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Control Strategy
• Understanding sources of variability and their
impact on downstream processes or processing,
intermediate products and finished product
quality can provide flexibility for shifting of
controls upstream and
• minimise the need for end product testing
• Control of process parameters allows variability
of raw materials to be compensated for in an
adaptable process to deliver consistent product
quality
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Recommendations for complying with
CGMP Requirements - FDA
• Utilize appropriate quality control (QC)
standards, i.e.:
– well defined procedures
– adequately controlled equipment
– accurate recording of all data
• Application of QC standards leads to
implementation of CGMPs consistent with
good scientific methodology
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Annex 13 - Principle
• Procedures flexible to provide for changes
as knowledge of the process increases,
and appropriate to the stage of
development of the product
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Quality System - SOPs
• There is a need for a quality system in any
functional organization
• A quality system means:
– Quality policy
– Management commitment
– CAPA system (of some description)
– Monitoring, evaluation and continual
improvement activities
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Process Performance and Product Quality
Monitoring Through Lifecycle
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Application of CAPA Through Lifecycle
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Change Management Through Lifecycle
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Management Review Through the Lifecycle
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Recommendations for complying
with CGMP Requirements (FDA)
• Use available technology and resources to
facilitate product development, CGMP
compliance, and lessen CGMP burden,
i.e.:
– disposable equipment and process aids
– prepackaged water for injection (WFI) and
sterilized containers
– contract manufacturing and testing facilities
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Recommendations for complying
with CGMP Requirements (FDA)
• Prevent contamination and crosscontamination:
– evaluate production environment to identify
potential hazards
– ensure that substances (i.e. chemicals,
adventitious agents) from previous or
concurrent research or production are
removed
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General CGMP Requirements
• Personnel:
– education, experience and training, (or any
combination of the three) to perform assigned
functions, e.g. training to include GMPs
outlined in guidance
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Batch Release – Annex 13
• The Qualified Person should be
responsible for ensuring that there are
systems in place that meet the
requirements of this Annex and should
therefore have a broad knowledge of
pharmaceutical development and clinical
trial processes
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Batch Release – Annex 13
• IMPs should remain under control of the sponsor until
after completion of a two-step procedure: certification by
the Qualified Person and release by the sponsor for use
in a clinical trial following fulfillment of the requirements
of Article 9 (Commencement of a clinical trial) of
Directive 2001/20/EC
• Both steps should be recorded and retained in the
relevant trial files held by or on behalf of the sponsor
• The Sponsor should ensure that the details set out in the
clinical trial application and considered by the Qualified
Person are consistent with what is finally accepted by
the Competent Authorities
• Arrangements should be established to meet this
requirement e.g. through a change control process for
the Product Specification File and defined in a Technical
Agreement between the QP and the Sponsor
PCI Pharmaceutical Consulting Israel Ltd.
Batch Release – Annex 13
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batch records, including control reports, in-process test reports and release reports
demonstrating compliance with the product specification file, the order, protocol and
randomisation code
include all deviations or planned changes, and any consequent additional checks or
tests, and should be completed and endorsed by the staff authorised to do so
according to the quality system
production conditions;
the validation status of facilities, processes and methods;
examination of finished packs;
where relevant, the results of any analyses or tests performed after importation;
stability reports;
the source and verification of conditions of storage and shipment;
audit reports concerning the quality system of the manufacturer;
Documents certifying that the manufacturer is authorised to manufacture investigational
medicinal products or comparators for export by the appropriate authorities in the
country of export;
where relevant, regulatory requirements for marketing authorisation, GMP standards
applicable and any official verification of GMP compliance;
all other factors of which the QP is aware that are relevant to the quality of the batch
PCI Pharmaceutical Consulting Israel Ltd.
General CGMP Requirements
(FDA)
• Facilities:
– adequate work areas for intended tasks
– water of appropriate source and quality
– adequate air handling to prevent
contamination and cross-contamination
PCI Pharmaceutical Consulting Israel Ltd.
General CGMP Requirements
(FDA)
• Equipment:
– in proper working condition, maintained
calibrated, cleaned and sanitized at
appropriate intervals
– appropriate for intended function
– should not contaminate or be reactive,
additive or absorptive with product
– identified and documented in production
records
PCI Pharmaceutical Consulting Israel Ltd.
General CGMP Requirements
(cont’d.)
• Control of Components:
– written procedures describing handling and
control of components
– written, specified attributes or acceptance
criteria
– COA or other documentation for components
to ensure conformance with specified
attributes
– records of receipt, quantity, supplier’s name,
lot number, expiration date
PCI Pharmaceutical Consulting Israel Ltd.
General CGMP Requirements
(FDA)
• Laboratory Controls:
– tests conducted using established written
procedures under controlled conditions
– scientifically sound analytical procedures
– properly calibrated and maintained analytical
lab equipment
– initiate stability study to support use of
product in clinical investigation
PCI Pharmaceutical Consulting Israel Ltd.
General CGMP Requirements
(FDA)
• Container Closure and Labeling:
– Package to protect product from alteration,
contamination and damage during storage,
handling and shipping
– Controlled labeling to preclude mix-ups
• Distribution:
– Describes the transport of the IND product
from the point of production to the
patient/subject for consumption
PCI Pharmaceutical Consulting Israel Ltd.
General CGMP Requirements
(FDA)
• Recordkeeping
– Retain records related to quality and operation
of production processes including:
• Equipment maintenance and calibration
• Production records and related analytical test
records
• Distribution records
• All quality control functions
• Component records
– Retain records for 2 years after approval of
marketing application or until 2 years after
shipment and delivery of the product is
discontinued and FDA is notified
PCI Pharmaceutical Consulting Israel Ltd.
Multi-product Facilities
• An area or room can be used for multiple
purposes and products, provided that:
– only one product is produced in an area at
any given time
– appropriate cleaning and change over
procedures are in place to ensure there is no
carry-over of materials or products or mix-ups
PCI Pharmaceutical Consulting Israel Ltd.
Sterile/Aseptically Processed
Products
• Investigational products intended to be sterile
require specific precautions, for example:
– personnel should be properly trained in aseptic
techniques
– aseptic manipulation should be conducted in a
Class 100 environment e.g. laminar flow hood
– controls should be in place to assure appropriate
air quality of the aseptic environment
PCI Pharmaceutical Consulting Israel Ltd.
Contractors
• Don’t forget that a lot of work is outsourced
• Quality Agreements / Technical contracts are
essential – with checklists
• Batch release should always be based on a
checklist to ensure relevant documentation is
reviewed
• Procedures in Quality Agreement re: recalls,
complaints and especially for comparator and
placebo
PCI Pharmaceutical Consulting Israel Ltd.