Chapter 1

Life Cycle Approach to Process Validation

Abstract Process validation activities align with the product lifecycle concept of
ICH Q8, Q9, and Q10 (ICH, International Conference on Harmonisation of techni-
cal requirements for the registration of pharmaceuticals for human use (ICH) guid-
ance document: Q8 (R2): pharmaceutical development, Geneva, 2009; ICH,
International Conference on Harmonisation of technical requirements for the regis-
tration of pharmaceuticals for human use (ICH) guidance document: Q9: quality
risk management, Geneva, 2005; ICH, International Conference on Harmonisation
of technical requirements for the registration of pharmaceuticals for human use
(ICH) guidance: Q10: pharmaceutical quality system, Geneva, 2008) that link prod-
uct and process development, qualification of commercial manufacturing and main-
tenance of the process in a state of control during routine production. The regulators
and industry have been adopting process validation lifecycle concepts.

Keywords Process validation · Life cycle · Process design · Process performance

qualification · Continued process verification

As defined by the US FDA Process Validation Guidance [1], process validation is

the collection and evaluation of data, from the process design stage through com-
mercial production, which establishes scientific evidence that a process is capable
of consistently delivering quality product. Process validation involves a series of
activities taking place over the lifecycle of the product and process: Process
design (Stage 1), process qualification (Stage 2), and continued process verifica-
tion (Stage 3).
An effective process validation program ensures quality, safety, and efficacy are
designed and built into the product through its lifecycle. This is achieved by ensur-
ing all manufacturing steps are controlled, measured, and quantified by finished
product quality attribute specifications. Sound scientific principles, good knowledge
management, documentation, and pharmaceutical quality systems are required to
efficiently utilize data from all stages. This is a dramatic shift from the previous
guidance and requirements to declare a process validated. Sources of variation,
impact of the variation on the process and quality attributes, and control of the varia-
tion are required (Fig. 1.1).

© American Association of Pharmaceutical Scientists 2018 1

A. B. Pazhayattil et al., Solid Oral Dose Process Validation, AAPS Introductions
in the Pharmaceutical Sciences, https://doi.org/10.1007/978-3-030-02472-7_1
2 1 Life Cycle Approach to Process Validation

Fig. 1.1 Life cycle approach

Each phase of the process validation lifecycle is distinct as per a normal course
of development activities that occur for a product. Stage 1 or process design stage is
the initial development stage where the commercial manufacturing is defined. Stage
2 or process qualification is where the process design is evaluated and verified to
determine if the manufacturing process is capable and reproducible. Stage 3 or con-
tinued process verification [2] is where ongoing assurance of a state of control is
gained through monitoring of routine commercial batches. In some instances, activ-
ities for products may occur in multiple stages.
Some preparative Stage 2B activities may be initiated in parallel with those from
Stage 1B. However, a readiness assessment needs to be conducted to determine the
timing of sufficient information and completion of activities to support moving for-
ward with Stage 2 manufacturing. Available Stage 1 data make it unnecessary to
execute Stage 2 over the operating ranges.
The following sequence of activities is conducted as preparation for Stage 2B:
• Review of technology transfer report(s) and associated documentation
• Creation and approval of process performance qualification (PPQ) protocols
• Execution of PPQ Protocols
• Documentation, review, and acceptance of results
• Creation and approval of PPQ reports
• Notify change owner
Homogeneity within a batch and consistency between batches are goals of PPQ
activities. PPQ batches will be manufactured under conditions that reflect routine
production settings for process parameters. Challenging process ranges as part of
the PPQ exercise are included in cases where there is insufficient development data
Process Validation Stages 3

to support the proposed parameters. PPQ batches are prevented from being released
to the market before all criteria prescribed in the PPQ Protocol have been satisfied.
Process development (formulation development), optimization, and/or demonstra-
tion batches (technical operations) will not be releasable for sale, as these studies
are designed to collect data for establishment of PPQ criteria. PPQ and continued
process verification batches will be releasable for sale provided all predetermined
criteria are satisfied.
A manufacturer must gain and provide a high degree of assurance that the pro-
cess validated is capable of consistently producing drug product that meets its qual-
ity attributes relating to identity, strength, quality, purity, and potency. The degree of
assurance provided depends on sufficient scientific understanding of the product by
the manufacturer. Objective data and information can be gathered and evaluated
from trials, pilot or laboratory scale, demonstration, and commercial batches. This
is done through activities from process design, process qualification, and continued
process verification stages of the product’s lifecycle as established by a successful
validation program. Information and knowledge are used to understand a product’s
performance and establish a control strategy to ensure the manufacturing process
results in products with the desired quality attributes are met. The control strategy
includes the process, raw materials, equipment, production environment, personnel,
and procedure changes.
In order to establish an effective control strategy, it is important for manufactur-
ers to understand sources of variation, detect and measure the degree of variation,
understand the impact of the variation on the process and attributes, and control the
variation. These activities can occur over the three stages and enables a risk-based
decision-making of the process lifecycle. Criticality of attributes and parameters is
to be determined by the manufacturer and communicated to the agency. Reevaluation
of the criticality is continuous and can be done as more knowledge is gained on the
process. Parameters and attributes that pose a higher risk require a higher degree of
control. Process validation activities should provide assurance that a production
output is protected against all sources of variability, hence reducing negative impacts
on production outputs, supply chain, and patient health.

Process Validation Stages

Stage 1 – Process Design (Stages 1A and 1B)

The first stage of the process validation lifecycle includes activities that define a
process suitable for commercial manufacturing that consistently delivers a product
that meets its quality attributes. Product development studies, generally performed
in non-Good Manufacturing Practice (GMP) small-scale laboratories, provide key
inputs of the process design stage such as intended dosage form, quality attributes,
and manufacturing path. All studies are to be documented and verified internally for
4 1 Life Cycle Approach to Process Validation

use at a later stage of the lifecycle following ICH Q10 recommendations. During
development limitations of commercial equipment should be considered, and any
future variability that may be contributed from different sources such as materials
(raw materials), man (operators and procedures), machine (equipment), measure-
ment (testing methods and systems), and mother nature (environmental conditions)
can be estimated in Stage 1.
In order to design an efficient process with effective controls, process knowledge
and understanding are desired. This can be gained through design of experiment
(DOE) studies that can reveal any relationships or interactions between input vari-
ables and output attributes. The studies can help determine operating ranges and
specifications for in-process controls required to maintain the finished product qual-
ity attributes. In lieu of DOE studies, computer simulations and historical data from
similar processes can be used to understand the process and mitigate any risks fore-
seen for commercial manufacturing. All activities resulting in process understand-
ing and identification of variables and controls are to be documented and justified.
The information is vital for establishing a strategy for process control that addresses
variability to assure product quality. A process control strategy for commercial pro-
duction based on early risk assessments from Stage 1 may be improved as experi-
ence is gained for a product. Risk assessment tools are to be utilized to mitigate any
residual risks and determine Stage 2 requirements for sampling and testing to assure
product quality and minimal variability of future batches.

Stage 2 – Process Qualification (Stages 2A and 2B)

The second stage of the process validation lifecycle is process qualification where
the process design of a product is evaluated to determine if it is capable of reproduc-
ible commercial production. As per 501(a)(2)(B) of the Act, any product distributed
commercially is legally required to successfully complete Stage 2 activities. This
stage has two components: Stage 2A, design of the facility and qualification of the
equipment and utilities, and Stage 2B – process performance qualification (PPQ).
Stage 2 is expected to follow compliant final commercial process. Facility, util-
ity, system, and equipment qualification stage (Stage 2A) should precede the PPQ
activities. These activities are generally termed as qualification activities.
Qualification stage includes specific activities such as defining the equipment oper-
ating principles, construction of material, performance standards etc. which are fit
for purpose. The qualification ensures that they are created and installed meeting the
user requirements specifications and/or design specifications. The installation quali-
fication, operational qualification, and performance qualification are requirements
at this stage. The commissioning activities such as factory acceptance testing (FAT)
and site acceptance testing (SAT) are to be completed prior to the initiation of quali-
fication activities [3]. Typically, the activities are conducted as an overall project
Process Validation Stages 5

plan which will include the types of studies included, timing of the qualification
steps, and the acceptance criteria.
Process performance qualification (Stage 2B) is the second stage of Stage 2.
With completion of PPQ, the process design will be confirmed and ensures that the
manufacturing process can be commercially applied with a high degree of confi-
dence. Application of scientific principles and statistical methods is pivotal in PPQ
studies. Stage 2B or PPQ will have a heightened level of sampling and testing to
justify the commercial process. The PPQ sampling and testing plans should be
based on statistics with previous credible experiences considered. Completion of
PPQ stage is a major landmark in process validation lifecycle as it marks the com-
mencement of commercial distribution of the product. PPQ studies are generally
performed in a prospective manner and in certain circumstances concurrent PPQ
studies are also acceptable. The outcome of PPQ study will demonstrate the manu-
facturer’s level of product and process understanding thus demonstrating control
over the manufacturing process.

Stage 3 – Continued Process Verification (Stages 3A and 3B)

Continued process verification is a significant addition to the process validation

lifecycle concept. The first US FDA validation guidance dates back to 1987. The
Guideline on General Principles of Process Validation (1987) primarily pertained to
the current Stage 2: process performance qualification stage of process validation
lifecycle. The 1987 guidance described elements such as the validation prerequi-
sites, protocol, and report requirements. The guidance document had provisions for
postvalidation activities such as the need for quality systems to identify revalidation
requirements during changes. The significant change including addition of Stage 3
or continued process verification (CPV) stage came through with the 2011 US FDA
process validation guidance. The guidance formalized the CPV approaches that
developed and evolved through the years after the first guidance.
Stage 3 (CPV) uses the continual data collected to maintain the product quality.
The data includes process trends, critical quality attributes, and critical material
attribute, in process quality attributes. The application of statistical methods in
CPV is important. The selected trending methods should ensure minimal opportu-
nities for overreaction and underdetection. The information collected should dis-
play the level of control as the process is commercially utilized. The sources of
variability are identified though a robust CPV program. Once identified it triggers
the continuous improvement measures for product/process. Tools used for detect-
ing variability include statistical methods such as control charts. Understanding of
intra- and interbatch variability is of particular importance in batch processes.
Being an ongoing monitoring CPV ensures applying preventive measures prior to
encountering a failure mode; therefore, such programs cannot be coupled with an
annual assessment such as annual product review. However, CPV data can be used
for other quality system applications. Stage 3 can be subcategorized as Stage 3A
and Stage 3B.
6 1 Life Cycle Approach to Process Validation

Auxiliary Programs Supporting Life Cycle Process Validation

All personnel responsible for the process validation and operation of production
processes will need sufficient education, experience, and/or training to perform
the required tasks. Training is to be performed according to approved standard
operating procedures, work instructions, and documents. Process validation team
will undergo training on process validation master plan (PVMP), job-specific
Standard Operating Procedure (SOP), Work Instruction (WI) and GMP, safety,
and HR learning and development training programs as stipulated in the role-
specific training plan. Equipment cleaning procedures and routine monitoring
procedures are to be validated. Cleaning validation needs to be completed prior to.
Analytical methods that are used in the quality control (QC) laboratories to sup-
port process validation programs must be validated in accordance with the analyti-
cal quality by design concepts. PPQ batches should be placed on stability. Process
validation activities can be also triggered by regulatory/client audits and commit-
ments. The root cause of the observation is investigated and a corrective action
plan with a due date is determined prior to initiation of a study.

Regulatory Requirements

Process validation is a legally enforceable requirement under section 501(a)(2)(B)

of the Act (21 U.S.C 351(a)(2)(B)) as well as current Good Manufacturing Practices
(cGMP) requirements under 21 Code of Federal Regulations (CFR) parts 210 and
211 for finished pharmaceuticals and components. Manufacturing processes are
required to be designed, controlled, and maintained to assure that in-­process and
finished product predetermined specifications and quality attributes are met consis-
tently and reliably. Specifics for process validation are outlined in 211.100 (a) for
process design, operations, and controls that are used to ensure products meet

Fig. 1.2 Regulatory harmony

References 7

predetermined attributes. In-process specifications are required to be established,

controlled, and consistent with final drug product specifications. The specifications
established should be determined using statistical procedures if applicable and data
from previous acceptable process mean and process variability estimates. The reg-
ulations also define activities for all stages of the process validation life cycle.
Section 211.180 9 (e) requires periodic review and ongoing feedback of product
quality and process performance to determine if any changes are needed to main-
tain the product quality (Fig. 1.2).
The regulations also require that the facilities and equipment used to manufac-
ture drug products are of suitable size, construction, and location to facilitate suit-
able operations. All equipment used that is automated, mechanical, and electronic is
required to have written programs for calibration, inspection, and maintenance to
assure proper performance.

References

1. US FDA. Guidance for industry, process validation: general principles and practices. White
Oak: US Food and Drug Administration; 2011. www.fda.gov/downloads/Drugs/Guidances/
UCM070336.pdf
2. Alsmeyer D, Pazhayattil A. A case for stage 3 continued process verification. Pharma Manuf
J. 2014.; http://www.pharmamanufacturing.com/articles/2014/stage3-continued-process-
verification
3. European Commission (EC). Guidelines on good manufacturing practice for medicinal
products, Annex 15. 2014.