2008 PDA/FDA Pharmaceutical

Ingredient Supply Chain Conference

Raw Material Release Process:

Practices of a Contract Manufacturing Organization

Adam Mott
Lonza Biologics
September 11, 2008

Raw Material Release Process:

Practices of a Contract Manufacturing Organization

Discuss the Raw Material Release Process at a Contract

Manufacturing Organization (CMO).

Overview
„ Raw Material Release Process

„ Raw Material Specifications

„ Raw Material Supplier Qualification

„ Raw Material Sampling

„ Raw Material Qualification

„ Raw Material Testing

„ Raw Material Retention Samples

Adam Mott - 2008 PDA/FDA Supply Chain Conference - 11 Sep 2008 slide 2
 Contract Manufacturing Organization (CMO)
Raw Material Release Process
„ The process of releasing raw materials is similar at every
company.
Order, Receive, Inspect, Sample, Test and Release
„ A Contract Manufacturing Organization (CMO) must have
systems and processes that are:
„ compliant and should deliver equal or better quality than its
customers.
„ flexible to handle many types of products and customer
expectations.
„ efficient and should deliver products faster than what
customers could do.
„ cost effective in order to remain competitive.
„ The environment at a CMO drives both quality and
operational improvements.

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Raw Material Specification

„ Raw Material Specifications drive the release process by

specifying:
„ What to order (material name, part number, grade,
manufacturer)
„ Where to order (material vendor/supplier)
„ How much to sample
„ What testing is required
„ What strength, identity, safety, purity and quality is required
„ Raw Material specifications should be based on process,
quality and safety requirements, not on a vendor certificate
of analysis.

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 Process Requirements vs. Supplier Specifications

„ Compare Process, Quality and Safety requirements for

each material to the vendor specifications for the materials
„ If the supplier meets the Process, Quality and Safety
requirements, the material and supplier may be
considered.
„ If the supplier does not perform the analysis or meet the
required specifications:
„ Search for a higher material grade
„ Search for another supplier
„ Request the supplier to add the analysis or tighten the
specification
„ If no other option, perform required test with required
specification in-house.

Adam Mott - 2008 PDA/FDA Supply Chain Conference - 11 Sep 2008 slide 5

Supplier Qualification
„ Raw Materials should only be purchased from qualified
Suppliers.
„ ICH Q7, 7.1.1
Manufacturers of intermediates and/or APIs should have a system
for evaluating the suppliers of critical materials.
„ Eudralex, Volume 4, Annex 8, “Sampling of Starting and
Packaging Materials”
This validation (qualification of supplier) should take account of at
least the following aspects:
„ the nature and status of the manufacturer and of the supplier
and their understanding of the GMP requirements of the
Pharmaceutical Industry;
„ the Quality Assurance system of the manufacturer of the
starting material;
„ the manufacturing conditions under which the starting material
is produced and controlled;
„ the nature of the starting material and the medicinal products in
which it will be used.
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 Raw Material Sampling
„ Eudralex, Volume 4, Annex 8, “Sampling of Starting and Packaging
Materials”
Sampling is an important operation in which only a small fraction of a
batch is taken. Valid conclusions on the whole cannot be based on
tests which have been carried out on non-representative samples.
Correct sampling is thus an essential part of a system of Quality
Assurance.
The identity of a complete batch of starting materials can normally only
be ensured if individual samples are taken from all the containers and
an identity test performed on each sample. It is permissible to sample
only a proportion of the containers where a validated procedure has
been established to ensure that no single container of starting material
has been incorrectly labeled.
„ ICH Q7, 1.3
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.

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Raw Material Sampling

„ For API production of biologics, the raw materials are not

“incorporated as a significant structural fragment into the
structure of the API,” therefore are not considered starting
materials.
„ Excipients or API Final Formulation materials are
considered part of the product and tested like a starting
material.
„ 100% of containers of are sampled and tested for
Identity as suggested in Annex 8 for starting materials.
„ For all raw materials, 100% of received containers are
inspected to verify material name, lot number and
container integrity.

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 Raw Material Sampling
„ Eudralex, Annex 8
The quality of a batch of starting materials may be assessed by
taking and testing a representative sample. The samples taken for
identity testing could be used for this purpose.
The number of samples taken for the preparation of a representative
sample should be determined statistically and specified in a
sampling plan.
The number of individual samples which may be blended to form a
composite sample should also be defined, taking into account the
nature of the material, knowledge of the supplier and the
homogeneity of the composite sample.
„ ICH Q7, 7.33
Samples should be representative of the batch of material from
which they are taken. Sampling methods should specify the number
of containers to be sampled, which part of the container to sample,
and the amount of material to be taken from each container.
The number of containers to sample and the sample size should be
based on a sampling plan that takes into consideration the criticality
of the material, material variability, past quality history of the
supplier, and the quantity needed for analysis.

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Raw Material Sampling

„ Representative samples are taken based on ANSI/ASQ

Z1.4 (formerly MIL-STD-105E) to assess the quality of a
Raw Material batch.
„ This sampling plan is a recognized statistical sampling plan.
„ General Inspection Level II with an AQL of 1.5 is used for
sampling raw materials to verify quality and suitability.
„ Samples are blended to form a composite sample, where
acceptable.
„ Batch quality testing is performed on the single, composite
sample.
„ Saves significant testing time
„ Compliant and capable of performing verification of
vendor testing of the material

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 Raw Material Qualification
„ 21 CFR 211, 211.84 (d) (2)
Each component shall be tested for conformity with all appropriate
written specifications for purity, strength, and quality. In lieu of such
testing by the manufacturer, a report of analysis may be accepted from
the supplier of a component, provided that at least one specific identity
test is conducted on such component by the manufacturer, and
provided the manufacturer establishes the reliability of the supplier’s
analysis through appropriate validation of the supplier’s test results at
appropriate levels.
„ ICH Q7, 7.30, 7.31
At least one test to verify the identity of each batch of material should be
conducted…A supplier’s Certificate of Analysis can be used in place of
performing other tests, provided that the manufacturer has a system in place
to evaluate suppliers.
Supplier approval should include an evaluation that provides adequate
evidence (e.g., past quality history) that the manufacturer can consistently
provide material meeting specifications. Full analyses should be conducted
on at least three batches before reducing in-house testing. However, as a
minimum, a full analysis should be performed at appropriate intervals and
compared with the Certificates of Analysis. Reliability of Certificates of
Analysis should be checked at regular intervals
Adam Mott - 2008 PDA/FDA Supply Chain Conference - 11 Sep 2008 slide 11

Raw Material Method Validation/Verification

„ Raw Materials release test methods to be used to support raw

material qualification should be validated or verified.
„ Compendial Methods are considered validated. However,
verification that the method performs as intended in your
laboratory is required (see USP chapter <1226> for a verification
procedure).
„ In-house or Supplier Methods should be validated using ICH
Q2R1 guidelines.
„ Bioburden testing should be qualified by demonstrating that the
raw material is not inhibitory to the growth of representative types
of microbial organisms that may be present.
„ Endotoxin testing should be qualified to by demonstrating that the
material does not interfere with test (e.g., inhibition,
enhancement) and any dilution or neutralization does not prevent
the analysis from meeting the specification.

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 Raw Material Qualification

„ Raw Material Qualification includes the following:

„ Qualification of Material Supplier and Manufacturer
„ Successful Full Testing of a minimum of 3 consecutive raw
material batches.
„ Full Testing includes all testing deemed necessary to ensure
material is appropriate for the intended use.
„ Full Testing verifies testing performed by the supplier is
acceptable and that the material is suitable for use.
„ Raw Material Qualification Report summarizing data and
qualification process.
„ After a raw material is qualified, release testing should be
reduced.
„ To maintain “Qualified” status of a raw material, “Full” verification
testing should be performed annually and the supplier should be
reassessed periodically.

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Reduced Raw Material Testing

„ “Reduced’ release testing must include Identity testing and
an acceptable supplier Certificate of Analysis.
„ Reduced testing may also include any testing that may be
critical to the process.
„ Specific characteristic of the material (e.g., activity, pH) that
may be critical to the process.
„ Potential of the material to contaminate the process.
Microbial tests continue to be performed depending on where
material is used and risk it may pose to the process.
„ Excipient reduced testing is typically includes more testing
since the material may be included in the vialled drug
product.
„ Additional purity testing is not required but provides
additional assurance of material suitability.
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 Raw Materials used in Clinical Trial Production

„ ICH Q7, 19.40.

Raw materials used in production of APIs for use in
clinical trials should be evaluated by testing, or
received with a supplier’s analysis and subjected to
identity testing.
„ If API production is for clinical trials, only Identity
testing is required along with an acceptable supplier
certificate of analysis.
„ Only “Reduced” testing should be performed for
release of raw materials used for clinical production
runs.
„ All raw materials should be qualified prior to process
validation (PV) runs.

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Raw Material Retain Samples

„ Retention of Raw Material samples is not a regulatory

requirement.
„ Retention should be based on risk to the process from the
material and the likelihood that the retain would be needed
in the case of an investigation.
„ At Lonza, the only materials that are retained are critical
raw materials which includes
„ Purification Resins
„ Animal Sourced Materials
„ Excipients
„ Other process specific materials deemed critical
„ Not keeping retains of all raw materials saves time, saves space
and reducing a potential safety risk.

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 Summary

„ Improvements made to the Raw Material release process which

improved both compliance and efficiency include:
„ Ensure raw material specifications are based on process,
quality and safety requirements.
„ Purchase materials from qualified suppliers.
„ Perform 100% container Identity testing only on Starting
Materials or on Excipients.
„ Perform material batch quality testing on a composite sample
formed from representative samples.
„ Perform “Reduced” testing after qualification of a raw
material.
„ Perform only “Reduced” testing to release raw materials for
clinical production runs.
„ Retain only critical raw materials.

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