GMP in API Development

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Process Validation
General Principies & Practices

FDA Guidance for Industry of Jan. 2011

Dr. Reiner Kirrstetter

Frankfurt/Main, Germany

May 2011
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Overview
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• Applieation of this Guidanee

• General Principies & Regulatory Requirements
• Stage 1: Proeess Design
• Stage 2: Proeess Qualifieation

• Stage 3: Continued Proeess Verification

• Other Relevant Topies on this Guidanee

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 Statement of FDA Personnel in 2009

"Process Validation -

Still Key Area leading to 483 's"

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Important Notice at the Begining

• This Guidance conveys FDA' s current thinking on process

validation. "Recornrnendations" are provided.

• This Guidance is consistant with basic principIes first

introduced in the FDA Guidance of 1987.

• This Guidance replaces the 1987 Guidance.

• This revised Guidance (Draft was issued in Nov. 2008) also

provides recornrnendations that reflect sorne goals of FDA' s
Initiative entitled "Pharrnaceutical CGMPs for the 21st Century
- A Risk Based Approach"

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Application of this Guidance
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• This Guidance outlines the general principies and approaches

that FDA considers appropriate elements of process validation
for the manufacture of human and animal drugs, biological
and biotech products, including APIs.
• This Guidance aligns process validation activities with the
product lifecycle concept and with existing FDA Guidance.
• This Guidance supports process improvement and innovation
through sound science.
• This Guidance describes the process validation activities in 3
stages.
• A new definition on "Process Validation" is provided.

Definition of Process Validation

• "Process Validation is defined as the collection and evaluation

of data, from the process design stage through commercial
production, which establishes scientific evidence that a
process is capable of consistently delivering quality products"
(FDA,2011)

• "Process Validation is establishing documented evidence

which provides a high degree of assurance that a specific
process will consistently produce a product meeting its
predetermined specifications and quality characteristics."
(FDA, 1987; WHO 2005)

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 What is not covered by this Guidance
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• This Guidance does not cover Type A medicated articles and

medicated feed, medical devices, dietarv supplements, and
human tissues intended for transplantation.

• This Guidance does not specify what information should be

included as part of a regulatory submission.

• This Guidance also does not specifically discuss the validation

of automated process control systems (i.e. computer hardware
and software interfaces) which are commonly integrated into
modern drug manufacturing equipment.

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Additional Background Information

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• "FDA has the authority and responsibility to inspect and

evaluate process validation performed by the manufacturers"

• "Effective process validation contributes significantly to

assuring drug quality"

• "Quality, safety, and efficacy are designed or built into the

product"

• "Each step of a manufacturing process is controlled to assure

that the finished product meets all quality attributes including
specifications."

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 General Principies (1)
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• Before a batch is commercially distributed for use by

consumers, the manufacturer should have gained a high
degree of assurance in the performance of the manufacturing
process, such that it will consistently produce APIs and drug
products meeting all quality attributes.

• This assurance should be obtained from objective information

and data from laboratory-, pilot-, and/or commercial- scale
studies.
• A successful validation program depends upon information and
knowledge from product and process development. This
knowledge and understanding is the basis for establishing an
approach to control the manufacturing process.

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General Principies (2)

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• Focusing only on qualification efforts without process

understanding and associated variations may not lead to
adequate assurance of quality.

• After establishing and confirming the process, manufacturers

must maintain the process in a state of control over the life of
the process, even as materials, equipment, personnel,
production environment, and manufacturing procedures
change.

• Manufacturers should use ongoing programs to collect and

analyze product and process data to evaluate the state of
control of the process.

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 General Principies (3)

• FDA recommends an integrated team approach to process

validation that ineludes expertise from a variety of disciplines.

• Project plans, along with the full support of senior

management, are essential elements for success.

• The degree of control over quality attributes and process

parameters should be commensurate with their risk to the
process and process output.

• Homogeneity within the batch and consistency between

batches are the main goals of process validation activities.

What about the "older" Products?

• Manufacturers of of legacy ("older") products can take

advantage of the knowledge gained from the original process
development and qualification work, as well as manufacturing
experience to continually improve their processes.

• Implementation of the recommendations in this Guidance for

legacy products and processes would likely begin with
activities described in Stage 3.

• This is the link between "Retroperspective Validation" and

"Continued Process Verification"

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 Regulatory Requirements
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• "Process validation for drugs is a legally enforceable requirement
under Section 501(a)(2)(B) ofthe Act."
• "Process validation is required, in both general and specific
terms, by the CGMP Regulations in Parts 210 and 211."

• § 211.100(a): foundation for process validation is provided

• § 211.110(a): process must include in-process controls
• § 211.110(b): two principies to follow for IPC specifications
• § 211.160(b): batch samples must be representative
• § 211.165(a): batch must meet its predetermined specifications
• § 211.180(e): requires periodical reviews (APRs)
• § 211.42: facilities must have suitable design and construction
• § 211.63: equipment must have appropriate design, size, location
• § 211.68: equipment must be calibrated, inspected, and checked
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Stage 1: Process Design
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• Building and Capturing Process Knowledge and Understanding

• Establishing a Strategy for Process Control

"Process design is the activity of defining the commercial

manufacturing process that will be reflected in the master
production and control records:'

"The goal of this stage is to design a process suitable for routine

commercial manufacturing that can consistently deliver a
product that meets its critical quality attributes"

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 Stage 1: Process Design - More Details

• Early process design experiments do not need to be performed

under GMP conditions.
• What is needed: sound scientific methods and principies, and
good documentation practices (decisions and justifications)
• Exception: viral and impurity studies that have a direct impact on
drug safety should be performed under GMP conditions.

• Laboratory or pilot-scale models should be used to estimate

variability (to understand the impact of variation on the process
and ultimately on product quality attributes).
• Risk analysis tools can be used to screen potential variables for
DOE studies to minimize the total number of experiments.
• The Goal: Fixing the operational limits and the overall strategy
for process control (using PAT as advanced c:tr'::Ih>n,,"

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Stage 2: Process Qualification

• Design of a Facility and Qualification of Utilities and Equipment

• Process Performance Qualification (PPQ)

During this stage, the process design is confirmed as being

capable of reproducible commercial manufacture.

• PPQ Protocol (Documents to create)

• PPQ Protocol Execution and Report (Documents to create)

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 Stage 2: Process Qualification - More Details

• During this stage, CGMP - compliant procedures must be

followed.
• Successful completion of this stage is necessary before
commercial distribution.
• Product manufactured during this stage, if acceptable, can be
released (and used for the market).
• A successful PO will confirm the process design and
demonstrate that the commercial manufacturing process
performs as expected.

• The Goal: establishing scientific evidence that the process is

reproducible and will consistently deliver quality products.

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Stage 2: PPQ Protocol

A written protocol that specifies the manufacturing conditions,

controls, testing, and expected outcomes is essential.
FDA recommends to discuss the following items in the protocol:

• Manufacturing conditions including operating parameters,

processing limits, and component (raw material) input
• Data to be collected and when & how it will be evaluated
• Tests to be performed and acceptance criteria
• Sampling plan including points, numbers, frequency
• Criteria that provide for a rational conclusion: process validated
• Design of facilities, qualification of utilities and equipment
• Status of analytical method validation
• Review and approval by appropriate departments and QU

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 Stage 2: PPQ Protocol Execution and Report
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Protocol execution should not begin until the protocol is signed.

Departure from the established must be justified and approved.
Commercial process and routine procedures must be followed.

The report should adhere to the protocol and should:

• Discuss and cross-reference all aspects of the protocol

• Summarize and analyze data collected, as specified
• Evaluate any unexpected observation and data not yet specified
• Summarize and evaluate non-conformances I deviations
• Describe in sufficient details any corrective actions & changes
• State a clear conclusion: process is in the state of control
• Review and approval by appropriate departments and QU

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Stage 3: Continued Process Verification

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• The Goal of this stage is: to continually assure that the process
remains in a state of control (the validated state) during the
commercial manufacture and distribution.

• To accomplish this goal: a system is needed to detect

unplanned deviations from the process as designed.

• An ongoing program must be established to collect and evaluate

product and process data relating to product quality (APR).

• The evaluation should determine whether action must be taken

to prevent the process from drifting out of control.

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 3: Continued Process Verification - Details
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• FDA recommends to use statistical methods, whenever feasible,

to analyze process stability and process capability.
• FDA recommends also to scrutinize intra-batch as well as inter-
batch variation as part of a "comprehensive continued process
verification program"

• FDA recommends that the Quality Unit meet periodically with

production staff to evaluate data, discuss possible trends or
drifts in the process, and coordinate any correction or follow-up
actions by production.
• Maintenance of the facility, utilities, and eguipment is another
important aspect of ensuring that the process remains in the
state of control.
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Other Relevant Topies on this Draft

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• Concurrent Release of PPQ Batches

• Docurnentation

• Analytical Methodology

• Cornrnents to this FDA Guidance

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 Concurrent Release of PPQ Batches (1)
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• Definition of Concurrent Release: Releasing for distribution a lot
of finished product, manufactured followig a qualification
protocol, that meets the lot release criteria established in the
protocol, but before the entire study protocol has been
executed.

• FDA expects that concurrent release is rarely used.

• In most cases, the PPQ study needs to be completed
successfully and a high degree of assurance in the process
achieved before commercial distribution.

• Concurrent release might be appropriate for processes used

infrequently or for drugs that are medically necessary.

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Concurrent Release of PPQ Batches (2)
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• Circumstances and rationale for concurrent release should be

fully described in the PPQ protocol.

• Any lot released concurrently must comply with all cGMPs,

regulartory approval requirements, and the lot release criteria
estblished in the PPQ protocol.

• When this approach is used, there should be a system in place

for careful oversight of the distributed batches to facilitate
rapid customer feedback.

• FDA recommends that each batch is put under stabilitv testing.

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Documentation

• Documentation at each stage of the process validation lifecycle

is essential (Information transparent and accessible).

• Studies in Stages 2 and 3 must conform to cGMP and must be

approved by the Quality Unit.

• Key output of Stage 1 are the CGMP documents for commercial

manufacturing (master batch production and control records).

• FDA recommends that firms create "Process flow diagrams"

describing each unit operation, its placement in the overall
process, monitoring and control points, input materials, and
expected outputs (finished products and also data).

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Analytical Methodology
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• Process knowledge depends on accurate and precise measuring

technigues that are used to test and examine the quality of all
drug components, in-process materials, and finished products.

• Therefore, analytical methods during development must

scientifically sound( specific, sensitive, accurate), suitable and
reliable for the intended use.

• Analytical methods supporting clinical supply production,

particularly for Phase 2 and 3, must follow appropriate cGMPs.

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 Sorne Cornrnents to this FDA Guidance
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• Glossary Section was added to explain new terms and revised

definitions of existing terms. (not given in the Draft)
• Retrospective Validation is not mentioned! (but IeH Q7!)
• Revalidation & the "Three batch concept" are not mentioned!
• This new Draft is not consistent with the EU Reguirements!
< FDA Stage 1 (Process Design) is not part of process validation in EU
< FDA Stage 2 (Process Qualification) covers both Equipment
Qualification and Process Performance Qualification (equivalent to
the term "Process Validation " as understood by EMEA)
< Established terms, like DQ, IQ, OQ, are missing.
< FDA Stage 3 is covered in EU under change control and "Variations"
< "Continuous Process Verification" is defined in ICH Q8(R2) as "an
alternative approach to process validation in which manufacturing
process performance is continuously monitored and evaluated"

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Process Validation - Surnrnary

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• FDA has the authority and responsibility to inspect and

evaluate process validation performed by the manufacturers.

• Effective process validation contributes significantly to

assuring drug quality.

• A successful validation program depends upon information

and knowledge from product and process development.

• Successful completion of Process Qualification is necessary

before commercial distribution starts.

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