Section 501 (21 U.S.C. 351) is amended by adding at the end the
following flush text: ‘‘For purposes of paragraph (a)(2)(B), the term ‘current
good manufacturing practice’ includes the implementation of oversight and controls
over the manufacture of drugs to ensure quality, including managing the risk of
and establishing the safety of raw materials, materials used in the
manufacturing of drugs, and finished drug products.’’.
INTRODUCTION:
Selection of raw materials and
excipients to be used in manufacturing process and identification of critical
material attributes to define material control strategies at development stage
of product life cycle, this includes the following:
·
Discovery research (including all stages of
clone development) and
·
Toxicology studies
All users involved in vector development, clone development and process
development shall follow the procedure defined below.
Note: As activities of clone
development are considered as critical for product lifecycle, a diligent
material control with traceability of materials used in each stage shall be
demonstrated (Refer ICH Q5B & Q5D and EP 5.2.12).
CONTROL STRATEGY:
MATERIAL CLASSIFICATION:
Biological product development and manufacturing uses diverse range of
raw materials. These materials can be categorized as below:
A.
Base
on composition materials can be categorized as:
·
Inorganic Salts and liquids,
·
Organic Salts and liquids,
·
Complex chemically defined mixtures of
organic/ inorganic origin),
·
Complex materials of biological origin,
including animal origin (defined),
·
Complex materials of biological origin,
including animal origin (undefined),
·
Complex semi defined mixtures (containing
above materials),
Note: In addition to above category
there are few fixed materials used in process which though are not categorized
as raw materials but are product contact and have tendency of leaching (process)
impurities in the product e.g., filters and TFF membranes, chromatography media
etc. Criticality of such materials shall be assessed and capture in process
development report as part of process impurities.
B. Based on usage in
manufacturing process materials can be categorized as:
·
Product contact materials and
·
Product non-contact materials (such as
cleaning agents)
However, there are chances of product contamination through product
non-contact materials if cleaning procedures are not validated and may directly
impact the product CQAs.
C. Based material control strategy the materials used in manufacturing
process can be classified as under:
·
Biological Starting Materials
·
Raw Materials
·
Drug Substance (Active Pharmaceutical
Ingredient)
·
API Starting Material
·
Excipients
Note: Specific requirements for Biological Starting
material are outside scope of this document.
MATERIAL CONTROL STRATEGY:
Material control at development stage is
limited to first two elements; other elements shall be covered in the
subsequent stages of product life cycle.
Elements of material control strategies ensure
the safety (including risk of adventitious agent contamination), quality and
efficacy of the biological molecule to be manufactured. These are:
1. Selection
of material and understanding the role of the raw materials in the process and
criticality assessment of material
2. Identification
of material quality attributes
3. Developing
material testing strategies to ensure raw material quality and evaluating
specific tests to ensure consistent material quality
4. Setting
up material/supplier risk assessments for supplier qualification program
5. Having
a supplier qualification system in place which assesses all risks of a raw
material: origin risk (safety), supply risk (availability, back-up options,
audits, contractual agreements) and quality risk (testing, evaluation of
lot-to-lot consistency).
Note:
All the elements shall be revisited during initiation of cGMP manufacturing
operations such as MCB and WCB preparation, clinical batch manufacturing,
process performance qualification (validation) batch manufacturing and
commercial manufacturing.
SELECTION OF MATERIAL AND CRITICALITY ASSESSMENT:
Material for each process stage shall have
scientific basis for selection and following criteria shall be considered:
1. Role
of material in process stage
2. Impact
of the material on quality attribute of the subsequent stage product
3. Introduction
of impurities in manufacturing process (including adventitious agents).
To ensure material control, user shall
perform material risk assessment as per the table below:
Sr.
No
|
Assessment Question
|
Answer
(Yes/No)
|
Risk
(High/Medium/Low)
|
Comments/
Justification
|
1
|
Is the RM complex?
|
|||
2
|
Is the RM well defined?
|
|||
3
|
Is the material of animal/human origin?
|
|||
4
|
Is the TSE/BSE assessment available?
|
|||
5
|
Is the RM added in the late steps of the
process?
|
|||
6
|
Is there a need to demonstrate that the
process will reduce the RM level to a safe residual level?
|
|||
7
|
Is a relevant analytical method available
to assess its clearance?
|
|||
8
|
Is the level of quality of RM susceptible
to impact product CQA?
|
|||
9
|
Is the production process of the RM
generating high variability in the RM quality attributes
|
|||
Remarks: (For additional assessment and comments)
|
||||
Raw Material categorized
as: Critical ¨ /
Non-Critical ¨
|
||||
Note
1: Excipients are not
accessed based on above criteria. Procedure for excipient selection and
assessment is provided below.
Note
2: Assessment shall be performed
for all raw materials, including chromatography resins and media. In column
for ‘Answer’ enter ‘Yes’ or ‘No’, identify the risk associated in each
evaluation step and provide comments and justification for each risk
categorized (irrespective of low, medium, high) with current and recommended
mitigation plan.
|
||||
From
the above assessment a list of critical and non-critical materials will be
generated.
FOR CRITICAL MATERIALS: Higher grade material with more control on material
attributes shall be selected, preferable to use compendial grade material
manufactured under cGMP environment.
FOR NON-CRITICAL MATERIALS: Grade of material is
flexible however consistency in supply of material with identified attributes
shall be ensured.
SELECTION OF EXCIPIENTS:
Excipients are added for the purpose of production enhancement, patient
acceptability, improving stability, controlling release etc. Though termed as
inactive components, excipients can have an impact on the absorption,
distribution, metabolism and elimination process of the co-administered drug,
which is important information when selecting excipient for any formulation.
As manufacturer of the chemicals supply their material for different
applications and end users (such as cosmetics, food additives etc.), it is
responsibility of the user to select the excipient of appropriate type and
grade to meet additional quality functionality and safety requirements.
Below are the basic check points used during
selection of excipients:
1.
|
Name
of the excipient in the formulation:
|
2.
|
Is the excipient complex chemical: (Define physical and chemical properties, material
(excipient) specifications including impurities and residual solvent)
|
3.
|
Is the excipient well defined: Define physical and chemical properties, material
(excipient) specifications including impurities and residual solvent)
|
4.
|
Is the proposed material (excipient) of
animal/human origin:
|
5.
|
Is
the production process of the material (excipient ) anticipated to generate high
variability in the quality attributes:
|
6.
|
Is
the level of quality of material (excipient) susceptible to impact product
CQA. List and define critical material attributes (CMA) of the material
(excipient):
|
7.
|
Is the TSE/BSE assessment available for the
excipient:
|
8.
|
Mention
role of material (excipient) in the formulation (such as diluent, buffering
compound, antioxidant, stabilizer, enhances solubility, enhances
bioavailability etc.):
|
9.
|
Mention
intended route of administration of finished product (topical, ophthalmic,
oral, parenteral etc.):
|
10.
|
Is
the material previously selected as excipient for intended route of delivery:
|
11.
|
Is the proposed material identified as
established excipient:
(If yes,
in which IPEC category does it fall)
1.
Existing chemical excipient- first in human:
(These are
class of excipients where animal safety data does exist, as data may have
been used in another regulatory
applications)
2.
Existing chemical excipient:
(These are
excipients that have been used in man, but for another route of
administration, higher dose etc., and additional safety may be required)
3.
New modification of existing excipient:
(Established
excipient is the new modifications of combinations, which would not require
safety evaluation)
|
12.
|
Is
the excipient approved by any of the regulatory agencies: (Refer
different resources and mention wherever listed, such as EMA's Excipients Drafting
Group (ExcpDG), FDA Inactive ingredient database, Safety
and Toxicity of Excipients for Paediatrics (STEP) Database,
listed in GRAS database, FAP database, wherever available DMF File number
shall be provided).
|
13.
|
Is
an official monograph available in any of Pharmacopeia (USP-NF, EP, JP, IP
etc.):
|
14.
|
Is
the material identified as new chemical excipient:
|
15.
|
Does
the selected vendor follow IPEC (The International Pharmaceutical Excipients Council)
cGMP Guidelines:
|
16.
|
Does
the selected vendor has ISO 9001 certification:
|
17.
|
Does
the selected vendor has EXCiPACT certification:
|
18.
|
Does
the selected vendor material meet the designated Pharmacopeial requirements,
if yes, mention the pharmacopeia (attach monograph copy):
|
19.
|
Note: Though supply security and
quality agreements are not expected during discovery research and toxicology
studies, however given the criticality of the excipient and impact of change
on regulatory filing, wherever possible below expectations shall be ensured:
·
Manufacturing
process for excipient shall be sought from vendor,
·
Understanding
with the manufacturer to ensure change notification in manufacturing process
and CQA of material
·
Long
term supply commitment
Note: Regulatory filing process for
new excipients is outside the scope of this document.
|
User shall compile all the above information with relevant evidences as
annexures in single report for excipient selected.
MATERIAL CONTROL STRATEGY
As the scope of this document is limited to discovery research and toxicology
studies, material control strategy for these stages is defined below.
Drug Discovery:
·
Material and vendor selection as per study
plan (assessment defined in 5.3.2 can be performed and recorded)
·
COA and expiry of all incoming process material
documented for use in relevant documents (LNBs, protocols & records etc.)
·
Material (Safety Data Sheet) (MSDS/ SDS)
understood and to be made available at site of usage for ready reference along
with COA.
·
Storage and expiry as per vendor recommendation.
·
Material for each unit operation stage is
fixed based on the development data (assessment defined in 5.3.2 mandatory and
shall be compiled in single report with relevant annexures). Specification of
all the materials to be listed with test method references wherever available.
Toxicology
Studies:
·
Material and vendor selection performed as
per 5.5.1 point number v. Refer table in section 5.6 for requirements for each
stage.
·
Details of expiry of all incoming process
material documented in Batch Manufacturing Record and COA’s attached to it
·
MSDS understood and to be made available at
site of usage for ready reference.
·
Storage and expiry as per vendor
recommendation.
·
Compilation of material and vendor
documentation in a single report.
DOCUMENTATION DURING DEVELOPMENT AND TOXICOLOGY BATCH
MANUFACTURING:
Collection of following documents for all
materials (where applicable) as below:
Material Documentation Requirements
|
Drug Discovery
|
Toxicology Batch
|
- Material
Name
|
ü
|
ü
|
- Material
grade
|
ü
|
ü
|
- Vendor
Name
|
ü
|
ü
|
- Vendors
Address
|
ü
|
ü
|
- Vendor
Catalogue Number
|
ü
|
ü
|
- Vendor
Specification
|
ü
|
ü
|
- Vendor
COA
|
ü
|
ü (multiple batches)
|
- List
of potential impurities
|
ü
|
ü
|
- List
of solvents used in process and residual solvents in product, if any
|
ü
|
ü
|
- MSDS/
SDS
|
ü
|
ü
|
- Certificate
of Material Origin
|
ü
|
ü
|
- Certificate
for TSE/BSE
|
ü
|
ü
|
- Risk
of Viral and other adventitious agents
|
ü
|
ü
|
- Kosher
/ HALA certifications
|
Optional
|
ü
|
- Allergen
certificate
|
Optional
|
ü
|
- Aflatoxin
certificates
|
Optional
|
ü
|
- Certification/
accreditations of vendor
|
Optional
|
ü
|
- Manufacturing
Process Flow
|
Optional
|
ü
|
- Characterization
Data
|
Optional
|
ü
|
- Toxicological
data
|
Optional
|
ü
|
- Logistic
mapping and supply change map
|
Optional
|
ü
|
Note: Material control strategy for
clinical and commercial manufacturing are part of corporate/global systems,
however for the sake for clarity highlights of material control strategy for
subsequent stages of product life cycle are listed below:
Ø Clinical Phase 1 / 2
Manufacturing:
-
Identification
of CMA and preparation of material control specification
-
Development
of non compendial test methods
-
Verification
of vendor COA for received material against specifications
-
Testing
and release of material for parameters such as identification, appearance,
safety (bioburden, endotoxin etc) and identified CMA. Availability of approved
test methods for these attributes.
- Vendor qualification for material
traceability, supply security with logistic mapping
Ø Clinical Phase 3
Manufacturing:
-
Material
(customer) specification finalization with all CMA listed
-
Availability
of test methods for verification of all listed specification parameters for
materials.
-
Testing
and release of material as per customers’ specification. Full testing for all
critical materials.
-
Test
values vs material attributes (as per specification) to be trended for better
material control as per QMS requirements
-
Risk
assessment to be revisited for all critical materials.
-
Due
diligence and vendor audits to be performed based on risk assessment.
-
Detailed
vendor assessment and qualification.
-
Quality
agreements, supply security agreements to be executed and made available.
Ø Marketing (including
PPQ) and Post Marketing:
-
Material
to be qualified and trends for high critical tests for critical materials made
available. Specifications can be revisited for better control.
-
Vendors
to be audited and compliance ensured. All agreements in place.
-
Alternate
vendor development can be initiated.
-
Risk
assessment based reduced testing can be explored.
DEFINITIONS
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. (Reference ICH Q7).
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. (Reference ICH Q7).
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. (Reference ICH Q7)
Control Strategy:
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. (Reference ICH Q10)
Critical Material Attribute:
A physical, chemical, biological or microbiological property or characteristic
of an input material that should be within an appropriate limit, range, or
distribution to ensure the desired quality of output material. (Reference Raw
Materials in the Manufacture of Biotechnology Products: Regulatory
Considerations Ruth Cordoba-Rodriguez of the FDA’s Center for Drug Evaluation
and Research (CDER in Bethesda, MD)
Excipient: Substances other
than the API that have been appropriately evaluated for safety and are
intentionally included in a drug delivery
system. (Reference: USP <1078>)
Impurity: Any
component present in the intermediate or API that is not the desired entity. (Reference ICH Q7)
Lifecycle:
All phases in the life
of a product from the initial development through marketing until the product’s
discontinuation (Reference ICH Q8)
Raw material: Any element or component used in the
manufacture of a biotechnology product that comes in contact with the API or
the API starting material. A raw material can be reactive or non-reactive with
the API. (Reference Raw Materials in the Manufacture of Biotechnology
Products: Regulatory Considerations Ruth Cordoba-Rodriguez of the FDA’s Center
for Drug Evaluation and Research (CDER in Bethesda, MD)
Materials: A general term used to denote starting
materials, reagents, and solvents intended for use in the production of
intermediates or APIs. (Reference ICH Q7)
Starting material for biological
medicinal products: Any
substance of biological origin such as micro-organisms, organs and tissues of
either plant or animal origin, cells or fluids (including blood or plasma) of
human or animal origin, and biotechnological cell constructs (cell substrates,
whether they are recombinant or not, including primary cells).” (Reference Dir. 2001/83/EC)
Biological starting materials: starting materials derived from a
biological source that mark the beginning of the manufacturing process of a
drug, as described in a marketing authorization or licence application, and
from which the active ingredient is derived either directly (for example,
plasma derivatives, ascitic fluid and bovine lung) or indirectly (for example,
cell substrates, host/ vector production cells, eggs and viral strains). (WHO TRS 999, Annex 2)
REFERENCES:
BioProcess International September
2009: Raw Material Control Strategies
for Bioprocesses by Gregory Beck, Mark Schenerman, John Dougherty, Ruth
Cordoba-Rodriguez, Christopher Joneckis, Anthony Mire-Sluis, and Lorna D.
McLeod.
EBE Concept Paper: Management and Control of Raw Materials
Used in the Manufacture of Biological Medicinal Products, 29 November 2017, Version 1.
European Journal of
Pharmaceutical Sciences, 2015: Pharmaceutical excipients — quality, regulatory and biopharmaceutical
considerations. David P. Elder, Martin Kuentz, René Holm.
Dir. 2001/83/EC: Directive 2001/83/EC of The European
Parliament and of the Council. The Community Code Relating To Medicinal
Products For Human Use.
EP 5.2.12: Raw
materials of biological origin for the production of cell-based and gene
therapy medicinal products.
ICH Q5B: Quality of Biotechnological Products:
Analysis of the expression Construct in Cells used for Production of r-DNA
Derived Protein Products.
ICH Q5D: Derivation and Characterisation of Cell
Substrates Used for Production of Biotechnological/Biological Products.
ICH Q10: Pharmaceutical Quality System.
ICH Q11: Development and Manufacture
of Drug Substances (Chemical Entities and Biotechnological/ Biological
Entities).
ICH Q7: Good Manufacturing Practice.
ICH Q8 Pharmaceutical Development.
ICH Q9: Quality Risk Management.
IPEC Europe, 2008: Qualification of Excipients for
Pharmaceutical Use.
PDA TR 56 (Revised 2016): Application of Phase-Appropriate Quality
System and cGMP to the Development of Therapeutic Protein Drug Substances (API
of Biological Active Substance).
USP 1078: Good
Manufacturing Practices for Bulk Pharmaceutical Excipients.
WHO TRS 999, Annex 2: WHO good manufacturing practices for biological products.
perfect and interesting information
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