process design understanding the product and process ... · guidance. approach to process...

FDA Lifecycle Approach to Process Validation—What, Why, and How? ............................................................... 3

The Forgotten Origins of Quality by Design ....................................................................................................... 14

Understanding Physicochemical Properties for Pharmaceutical Product

Development and Manufacturing—Dissociation, Distribution/Partition, and Solubility ....................................... 19

Understanding Physicochemical Properties for Pharmaceutical Product Development

and Manufacturing II: Physical and Chemical Stability and Excipient Compatibility ........................................... 30

Patent Potential .............................................................................................................................................. 42

First Steps in Experimental Design—The Screening Experiment ........................................................................ 46

First Steps in Experimental Design II: More on Screening Experiments .............................................................. 54

A Further Step in Experimental Design (III): The Response Surface ................................................................... 63

Estimation: Knowledge Building with Probability Distributions .......................................................................... 71

Understanding Hypothesis Testing Using Probability Distributions .................................................................... 86

PQ=Confirmation ........................................................................................................................................... 102

PROCESS DESIGN

UNDERSTANDING THE PRODUCT

AND PROCESS

LIFECYCLE APPROACH TO PROCESS

VALIDATION – FDA STAGE 1

PROCESS VALIDATION – Process Design 3

Paul L. Pluta

[For more Author

information,

go to

gxpandjvt.com/bios

“PQ Forum” provides a mechanism for validation practitioners to share information about Stage 2 process qualification in the validation lifecycle. Information about supporting activities such as equipment and analytical validation is shared. The information provided should be helpful and practical so as to enable application in actual work situations.

Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Please contact column coordinator Paul Pluta at [email protected] or managing editor Susan Haigney at [email protected] with comments, suggestions, or topics for discussion.

KEY POINTSThe following key points are discussed:

The US Food and Drug Administration issued

Process Validation: General Principles and Practices

in January 2011, which has given widespread

visibility to the lifecycle approach concept.

The process validation guidance integrates

strategy and approaches to provide a

comprehensive approach to validation. Three

stages in the lifecycle approach are identified.

The lifecycle concept links development,

validation performance, and product or process

maintenance in a state of control during routine

commercial production.

Understanding the sources of variation and

control of variation commensurate with risk is a

key component of the lifecycle approach.

FDA has provided recommendations for the

general lifecycle and stages 1, 2, and 3. Specific

expectations are discussed.

Stage 1—Process Design may be generally

described as “process understanding.” Stage

1 work is ultimately reflected in the master

production record and control records.

Stage 2—Process Qualification may be

described as “validation performance.” This

stage comprises demonstration of final process

performance by means of conformance lots.

Stage 2 confirms the development work of Stage

1 Process Design.

Stage 2 specific recommendations are provided

for design of a facility and qualification of

utilities and equipment, process performance

qualification (PPQ), PPQ protocol, and PPQ

protocol execution and report.

Stage 3—Continued Process Verification

may be simply described as “maintaining

validation.” This stage comprises the ongoing

commercial manufacturing of the product

under the same or equivalent conditions as

demonstrated in Stage 2 Process Qualification.

The integration of development work, process

conformance, and continuing verification

provides assurance the product or process will

consistently remain in control throughout the

entire product lifetime.

The lifecycle approach integrates various

strategies, approaches, and expectations that

had been mentioned in multiple previously

published documents, guidelines, and

presentations for many years.

ABOUT THE AUTHOR

Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive industrial development, manufacturing, and management experience. Dr. Pluta is also an adjunct associate professor at the University of Illinois-Chicago College of Pharmacy. Dr. Pluta may be contacted by e-mail at [email protected].

FDA Lifecycle Approach to Process Validation— What, Why, and How?Paul L. Pluta

4 PROCESS VALIDATION – Process Design

Paul L. Pluta

The concepts identified in the respective

stages of the FDA process validation

guidance—understanding, performance, and

maintenance—serve as a model for all areas of

validation and qualification.

The new guidance affects many areas of site

validation programs including organizational

aspects, validation performance specifics, risk

analysis, training, and documentation.

Senior and functional management support

is needed to transition organizations to the

lifecycle approach to validation. Risk analysis

is key to development and prioritization of a

suitable program that will be embraced and

supported.

INTRODUCTIONThe US Food and Drug Administration issued

Process Validation: General Principles and Practices

(1) in January 2011. This guidance has given

widespread visibility to the lifecycle approach

concept. Validation managers are now responding

to questions and comments about the guidance

from their colleagues. The following discusses

these and other areas of concern raised by

attendees at validation meetings in Montreal

(2010), Philadelphia (2010), and Amsterdam

(2011). These are relevant “hands-on” questions

from people that face validation problems every

day. Topics addressed in this discussion include

the following:

What is different about the lifecycle approach?

What is its emphasis compared to the 1987 FDA

process validation guidance (2)?

Why the lifecycle approach? Is it really a new

approach?

Should the lifecycle approach be applied to

other areas of validation and qualification?

What about using the lifecycle approach to

other processes and to equipment, HVAC,

computer systems, and other qualifications?

How does the guidance affect our current

validation programs? What areas need to

be modified to be compliant with the new

guidance?

THE LIFECYCLE APPROACHThe January 2011 process validation guidance

(1) has integrated information, strategy,

and approaches discussed in various US

and international documents to provide a

comprehensive approach to validation (i.e., the

lifecycle approach). The guidance provides specific

and detailed recommendations for each stage of the

lifecycle approach.

The definition of process validation stated in the

2011 guidance is as follows:

“Process validation is defined as the collection

and evaluation of data, from the process design

stage throughout 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.”

The guidance describes process validation

activities in the following three stages:

“Stage 1—Process Design: The commercial

process is defined during this stage based on

knowledge gained through development and

scale-up activities.

Stage 2—Process Qualification: During this

state, the process design is confirmed as

being capable of reproducible commercial

manufacturing.

Stage 3—Continued Process Verification:

Ongoing assurance is gained during routine

production that the process remains in a state of

control.”

These sections of the 2011 guidance clearly

identify the key difference between the lifecycle

approach compared to validation in the 1987 FDA

guidance. The 2011 lifecycle approach to process

validation encompasses product and process

activities beginning in development and continuing

throughout the commercial life of the product. The

1987 definition and subsequent discussion in the

guidance placed major emphasis on the validation

protocol, testing, results, and documentation—what

is now considered to be Stage 2 in the lifecycle

approach. Development work and post-validation

monitoring were not emphasized in the 1987

guidance.

Approach to Process Validation–Stages 1, 2, and 3The approach to process validation stated in the

2011 guidance clearly emphasizes contemporary

concepts and expectations for pharmaceutical

manufacturing. The manufacturer should

have great confidence that the performance of

manufacturing will consistently produce active

pharmaceutical ingredients (APIs) and drug

products meeting expected attributes. This

confidence is obtained from objective information

and data from laboratory, pilot, and commercial-

scale studies (i.e., the work of Stage 1). After

completion of Stage 1 development, Stage 2

Process Qualification confirms the work of Stage

1. After successful Stage 2 performance, Stage

3 Continued Process Verification maintains the

validated state. The guidance states:


Paul L. Pluta

“The lifecycle concept links product and process

development, qualification of the commercial

manufacturing process, and maintenance of

the process in a state of control during routine

commercial production. This guidance supports

process improvement and innovation through

sound science.”

Successful validation depends on knowledge

and understanding from product and process

development. Specific key areas mentioned in the

guidance include the following:

“Understanding the sources of variation

Detect the presence and degree of variation

Understanding the impact of variation on the

process and ultimately on product attributes

Control the variation in a manner

commensurate with the risk it represents to the

process and product.”

FDA RecommendationsThe 2011 guidance discusses several areas

and provides specific details. These include

recommendations for the general lifecycle and

stages 1, 2, and 3. The entire recommendations

section of the guidance is provided online at FDA.

gov.

General considerations. These considerations

are applicable to all stages in the lifecycle. For

example, an integrated team approach that includes

expertise from multiple disciplines and project

plans is recommended. The support of senior

management is termed “essential.” Other general

topics discussed include the initiation of studies

to further understand product and process during

the lifecycle, attribute evaluation, and the need for

higher levels of control for parameters associated

with higher risk.

Stage 1—process design. This stage may be

generally described as “process understanding.”

Studies are conducted during this stage to develop

and characterize product and process. The work of

Stage 1 should be commensurate with the identified

or expected risk for the product and process.

Stage 1 recommendations address development

activities that will ultimately be reflected in the

master production record and control records. The

guidance clearly states the goal of stage 1: “To

design a process suitable for routine commercial

manufacturing that can consistently deliver a

product that meets its quality attributes.” The

following two topics are discussed:

Building and capturing process knowledge

and understanding. This section discusses

the role of product development and uses

terminology common to the quality-by-design

(QbD) initiative—quality attributes, design of

experiments (DOE) studies, and so on.

Establishing a strategy for process control. This

section addresses reducing input variation,

adjustment for input variation during

processing, and related topics.

Stage 2—process qualification. This

stage may be simply described as “validation

performance.” This stage is most similar to

the traditional definition and performance

of validation. The testing of Stage 2 should be

commensurate with the risk identified for the

product and process.

Stage 2 comprises demonstration of commercial

process performance by means of conformance lots.

This stage confirms the development work of Stage

1. Successful stage 2 performance demonstrates

that the proposed manufacturing process is capable

of reproducible commercial manufacture. Process

performance qualification (PPQ) conformance

lot manufacturing includes increased testing

to demonstrate acceptability of the developed

formulation and process.

The 2011 validation guidance provides several

specific recommendations for the respective stages

of process validation. Validation managers must

become familiar with these requirements and

incorporate them into their site training programs.

The guidance discusses the following in Stage 2.

Facility, utilities, and equipment. The FDA 2011

guidance specifies the following regarding facility,

equipment, and utilities:

Utilities and equipment construction materials,

operating principles, and performance

characteristics must be appropriate for their

specific use.

Utilities systems and equipment must be

built and correctly installed, according to

manufacturer’s directions, and then properly

maintained and calibrated.

Utility system and equipment must be

qualified to operate in the ranges required in

processing. The equipment should have been

qualified under production-level loads and for

production-level durations. Testing should also

include interventions, stoppage, and start-up as

is expected during routine production.

The 2011 guidance provides specific expectations

for a plan to qualify facility, equipment, and

utilities, as follows:

The plan should include risk management to

prioritize activities and documentation

The plan should identify

(1) Studies or tests to use

(2) Criteria appropriate to assess outcomes

(3) Timing of qualification activities


Paul L. Pluta

(4) Responsibilities

(5) The procedures for documenting and

approving the qualification

Change evaluation policy

Documentation of qualification activities

Quality assurance (QA) approval of the

qualification plan.

The above is a clear directive to the site

validation approval committee (VAC) as to

FDA’s expectations for facilities, equipment, and

utilities qualification.

Process performance qualification. The PPQ is

intended to confirm the process design and

development work and demonstrate that the

commercial manufacturing process performs as

expected. This stage is an important milestone in

the product lifecycle. The PPQ should be based on

sound science and experience. The PPQ should

have a higher level of testing and sampling. The

goal of the PPQ is to demonstrate that the process

is reproducible and will consistently deliver quality

products.

PPQ protocol. A written protocol is essential and

should discuss the following:

Manufacturing conditions, process parameters,

process limits, and raw material inputs

How data are to be collected and evaluated

Testing and acceptance criteria

Sampling plan including sampling points and

number of samples

Number of samples should demonstrate

statistical confidence

Confidence level based on risk analysis

Criteria for a rational conclusion of whether the

process is acceptable

Statistical methods used to analyze data

Provision to address deviations and

non-conformances

Design of facilities, qualification of equipment

and facilities

Personnel training and qualification

Verification of sources of materials and

containers and closures

Analytical method validation discussion

Approval by appropriate departments and the

quality unit.

PPQ protocol execution and report. Protocol

execution should not start until the protocol has

been approved. Changes to the approved protocol

must be made according to established procedures.

The routine manufacturing process and procedures

must be followed (i.e., usual conditions, personnel,

materials, environments, etc.). The PQ report

should do the following:

Discuss and cross-reference all aspects of the

protocol

Summarize and analyze data

Evaluate unexpected observations and

additional data not specified in the protocol

Discuss deviations and non-conformances

Describe corrective actions

State a clear conclusion whether the process

is validated or if not, what should be done to

validate the process

Be approved by appropriate departments and

the quality unit.

Stage 3—Continued process verification.

This stage may be simply described as “maintaining

validation,” or “maintaining the validated state.”

Maintenance activities of Stage 3 should be

commensurate with the risk identified for the

product and process.

Assuming good development of the process,

identification of potential variation, and control of

same, the manufacturer must maintain the process

under control over the product lifetime (i.e., the

work of Stage 3). This control must accommodate

expected changes in materials, equipment,

personnel, and other changes throughout the

commercial life of the product based on risk

analysis.

Stage 3 comprises the ongoing commercial

manufacturing of the product under the same

or equivalent conditions as demonstrated in

Stage 2. This phase continues throughout the

entire commercial life of the product or process.

Specific topics discussed in this section include the

following:

Ongoing program to collect and analyze process

data, including process trends, incoming

materials, in-process material, and finished

products

Statistical analysis of data by trained personnel

Procedures defining trending and calculations

Evaluation of inter-batch and intra-batch

variation

Evaluation of parameters and attributes at

PPQ levels until variability estimates can be

established

Adjustment of monitoring levels based on the

above

Timely assessment of defect complaints, out-of-

specification (OOS) findings, deviations, yield

variations, and other information

Periodic discussion with production and

quality staff on process performance

Process improvement changes

Facilities, utilities, and equipment must be

maintained to ensure process control.


Paul L. Pluta

WHY THE LIFECYCLE APPROACH?For manufacturing processes to be truly validated,

each of the stages must be addressed and

integrated. This integration of development work,

process conformance, and continuing verification

provides assurance that the product or process

will consistently remain in control throughout the

entire product lifecycle. Process validation must

not be considered a one-time event or a focused

one-time task performed just prior to commercial

launch that emphasizes only the manufacture of

three conformance lots. Acceptable manufacture of

three conformance batches must not be interpreted

as completion of validation. These lots cannot

truly represent the future manufacturing process

with unexpected and unpredictable changes.

Conformance lots are often inadvertently biased

(i.e., they may utilize well-characterized and

controlled API and excipients, be manufactured

under well-controlled conditions, be monitored

by expert individuals, and performed by most

experienced or well-trained personnel—all “best-

case” conditions). It is highly unrealistic to contend

that the manufacture of three conformance lots

under “best-case” conditions conclusively predicts

successful manufacturing over the product lifetime.

True process validation must be a process that is

never completed and is always ongoing.

Is This Really a New Approach?The lifecycle approach to process validation is not

really a new approach or a new concept (3). In an

interview with FDA investigator Kristen Evans

published in the Journal of Validation Technology in

February 2000, the investigator commented on the

failure of manufacturers to recognize a lifecycle

approach to validation (see Sidebar).

The three-stage lifecycle description of process

validation as discussed in the FDA process

validation guidance integrates various strategies,

approaches, and expectations that had been

mentioned in several published documents,

guidelines, and presentations. FDA representatives

have openly discussed the lifecycle approach to

process validation for several years (4,5,6). The

draft process validation guidance that formally

introduced the lifecycle approach for industry

comment was published in 2008 (7). The lifecycle

approach overcomes the “checklist” approach to

process validation, whereby, process validation is

considered to be a “one-time event.” Encouraging

comprehensive process understanding improves

root cause analysis when manufacturing problems

occur. Successfully manufacturing three validation

lots without sufficient process understanding does

not provide good assurance that the manufacturing

Excerpt from an interview with FDA investi-gator Kristen Evans published in the Journal of Validation Technology, Volume 6, No. 2, February 2000.

Q. What are some of the major process vali-dation problems you have seen during your inspections of manufacturing facilities in the United States?

A. I think, as a whole, the failure to recognize the lifecycle approach to validation. We see many firms, for whatever reason, thinking that once they complete their prospective three-batch validation, that’s the end and they’re on their way. I like to say that pro-spective validation is not the end. It’s not the beginning of the end; it is hopefully the end of the beginning. But, clearly, it’s an ongo-ing process. It requires a concerted effort to really maintain confidence in the process and to be able to demonstrate that at any given time. So, when we conduct our inspections, we want to know how the firm gives itself, and therefore us, the confidence that a given process on that day is under control. And you’re not simply saying, “Well, we validated it a few years ago,” or “We’re going to do our annual review in a couple of months, and that will show us,” but rather, systems are in place at any given time to show from a big picture that it’s validated. As opposed to general problems discussed in the previous paragraph, a more specific problem that we see is a lack of scientific rationale in the pro-tocols and acceptance criteria. At least there is a lack of documentation of such rationale, which is what we’re expecting to see. We want the process to be there, that you’ve come up with a scientific study, a protocol—this is what you’re attempting to show, and this is why, and this is how it’s going to be evaluated, and then just simply executing that. That’s documentation of the scientific rationale.

Note: The above comments are the per-sonal opinions of Mr. Evans and are not FDA policy.


Paul L. Pluta

process will consistently yield an acceptable product

throughout the product commercial life.

The September 2006 FDA Quality Systems

Approach to Pharmaceutical CGMP Regulations (8)

clearly discusses expectations for maintenance of

the validated state. In discussing performance and

monitoring of operations, the regulations state,

“An important purpose of implementing a quality

systems approach is to enable a manufacturer to

more efficiently and effectively validate, perform,

and monitor operations and ensure that the

controls are scientifically sound and appropriate.”

Further, “Although initial commercial batches

can provide evidence to support the validity and

consistency of the process, the entire product

lifecycle should be addressed by the establishment

of continual improvement mechanisms in the

quality system. Thus, in accordance with the quality

systems approach, process validation is not a one-

time event, but an activity that continues through a

product’s life.” This document also discusses trend

analysis, corrective action and preventive action

(CAPA), change control, and other quality systems

programs.

The FDA Pharmaceutical cGMPs for the 21st

Century-a Risk-Based Approach (9), states the

following:

“We have begun updating our current thinking

on validation under a Cross-Agency Process

Validation workgroup led by CDER’s Office of

Compliance Coordinating Committee with

participation from CDER, CBER, ORA, and CVM.

In March of this year, FDA began this process

issuing a compliance policy guide (CPG) entitled

Process Validation Requirements for Drug Products

and Active Pharmaceutical Ingredients Subject to

Pre-Market Approval (CPG 7132c.08, Sec 490.100)

(10). The CPG stresses the importance of rational

experimental design and ongoing evaluation of

data. The document also notes that achieving and

maintaining a state of control for a process begins

at the process development phase and continues

throughout the commercial phase of a product’s

lifecycle. The CPG incorporates risk-based

approaches with respect to inspectional scrutiny;

use of advanced technologies, and by articulating

more clearly the role of conformance batches in

the product lifecycle. The document clearly signals

that a focus on three full-scale production batches

would fail to recognize the complete story on

validation.”

In the 2004 revision of FDA Compliance

Policy Guide Sec. 490.100, Process Validation

Requirements for Drug Products and Active

Pharmaceutical Ingredients Subject to Pre-

Market Approval (CPG 7132c.08), expectations

for validated processes are clearly stated. “Before

commercial distribution begins, a manufacturer

is expected to have accumulated enough data

and knowledge about the commercial production

process to support post-approval product

distribution. Normally, this is achieved after

satisfactory product and process development,

scale-up studies, equipment and system

qualification, and the successful completion of the

initial conformance batches. Conformance batches

(sometimes referred to as validation batches and

demonstration batches) are prepared to demonstrate

that, under normal conditions and defined ranges

of operating parameters, the commercial scale

process appears to make acceptable product. Prior

to the manufacture of the conformance batches

the manufacturer should have identified and

controlled all critical sources of variability.” FDA

has removed reference to manufacture of three lots

as a requirement for validation in this document.

The process validation guidance is consistent

with FDA QbD principles. The various QbD

presentations and publications strongly encourage

demonstrations of process understanding for both

API and drug product (11,12,13,14). In the 2006

FDA Perspective on the Implementation of Quality by

Design (QbD), a QbD system is defined as follows:

The API or drug product is designed to meet

patient needs and performance requirements

The process is designed to consistently meet

critical quality attributes

The impact of starting raw materials and

process parameters on quality is well

understood

The process is evaluated and updated to allow

for consistent quality over time

Critical sources of process variability are

identified and controlled

Appropriate control strategies are developed.

The various FDA guides to inspections (15,16,17),

all issued during the 1990s, emphasized the

development phase of the validated process

and associated documentation. This included

documented experiments, data, results, control

of the physical characteristics of the excipients,

particle size testing of multi-source excipients

and determination of critical process parameters.

Development data serves as the foundation for the

manufacturing procedures, and variables should be

identified in the development phase. Raw materials

were identified as a source of lot-to-lot variation,

as were equipment or processes that could impact

product effectiveness or product characteristics (i.e.,

the validated state must be maintained).


Paul L. Pluta

Some of the key concepts in the 2011 process

validation guidance were originally mentioned in

the FDA 1987 guidance. For example, the 1987

guidance states, “...adequate product and process

design...quality, safety, and effectiveness must

be designed and built into the product...” and

“During the research and development (R&D)

phase, the desired product should be carefully

defined in terms of its characteristics, such as

physical, chemical, electrical, and performance

characteristics.” In addition to discussing actual

validation protocols, the document mentions

several post-validation considerations, as follows:

“...quality assurance system in place which requires

revalidation whenever there are changes in

packaging, formulation, equipment, or processes

which could impact product effectiveness or

product characteristics, and whenever there

are changes in product characteristics. The

quality assurance procedures should establish

the circumstances under which revalidation is

required.”

The 2011 process validation guidance clearly states

its consistency with International Conference on

Harmonisation (ICH) Q8, Q9, and Q10 documents

(18). These documents provide current global

thinking on various aspects of the product lifecycle

from development through commercialization. They

provide a comprehensive and integrated approach

to product development and manufacturing to be

conducted over the lifecycle of the product. ICH Q8

discusses information for regulatory submission

in the ICH M4 Common Technical Document

format (19). ICH Q8 describes a comprehensive

understanding of the product and manufacturing

process that is the basis for future commercial

manufacturing including QbD concepts. ICH Q9

provides a systematic approach to quality risk

management through various risk assessment tools.

ICH Q9 also suggests application of risk management

methods to specific functions and business processes

in the organization. ICH Q10 complements Q8 and

Q9, and discusses the application of the various

quality system elements during the product lifecycle.

Elements of the quality system include process

performance monitoring, CAPA, change control, and

management review. These quality system elements

are applied throughout the various phases of the

product lifecycle.

The 2000 ICH Q7 Good Manufacturing Practice

Guide for Active Pharmaceutical Ingredients (20)

discusses activities conducted prior to and post

validation. For example, ICH Q7 states that critical

parameters or attributes should be identified during

development, and these critical process parameters

should be controlled and monitored. Non-critical

parameters should not be included in validation.

Regarding post validation, there should be periodic

review of validated systems.

Medical Device Validation GuidanceAlthough the 2011 process validation guidance

does not apply to medical devices, medical device

documents espouse an equivalent comprehensive

approach to process validation. In the January

2004 Global Harmonization Task Force (GHTF)

Study Group 3, Quality Management Systems—Process

Validation Guidance (21), activities conducted during

product or process development to understand

the process are described. For example, “The use

of statistically valid techniques such as screening

experiments to establish key process parameters

and statistically designed experiments to optimize

the process can be used during this phase.” This

document also describes activities conducted post-

validation to maintain the product or process. For

example, “Maintaining a state of validation” by

monitoring and control including trend analysis,

changes in processes or product, and continued

state of control of potential input variation such as

raw materials. Tools including statistical methods,

process capability, control charts, design of

experiments, risk analysis, and other concepts are

described.

The 1997 FDA Medical Device Quality Systems

Manual (22) further emphasizes activities to be

conducted post validation. It states, “Process and

product data should be analyzed to determine what

the normal range of variation is for the process

output. Knowing what is the normal variation

of the output is crucial in determining whether

a process is operating in a state of control and is

capable of consistently producing the specified

output. Process and product data should also

be analyzed to identify any variation due to

controllable causes. Appropriate measures should

be taken to eliminate controllable causes of

variation...Whether the process is operating in a

state of control is determined by analyzing day-to-

day process control data and finished device test

data for conformance with specifications and for

variability.”

The 1997 Guide to Inspections of Medical Device

Manufacturers (23) states, “It is important to

remember that the manufacturer needs to maintain

a validated state. Any change to the process,

including changes in procedures, equipment,

personal, etc. needs to be evaluated to determine

the extent of revalidation necessary to assure

the manufacturer that they still have a validated

process.”


Paul L. Pluta

APPLYING THE LIFECYCLE APPROACHThe concepts identified in the respective stages

of the FDA process validation guidance—process

design (understanding), process qualification

(performance), and continued process verification

(maintaining validation)—serve as a model for all

areas of validation and qualification. Although

not specifically mentioned in the FDA guidance,

the sequence of understanding, performance,

and maintaining the validated state is certainly

applicable and desirable for other processes in

pharmaceutical manufacturing including packaging,

cleaning, analytical, and so on. Further applying

this sequence to equipment qualification, HVAC,

computer systems, and other areas is also appropriate

and desirable. Presentations on these associated

topics at validation meetings have already been

structured according to this model. The installation

qualification-operational qualification-performance

qualification (IQ/OQ/PQ) model (24) and the

ASTM E2500 (25) model are consistent with

understanding, qualifying, and maintaining

qualification through calibration, preventive

maintenance, change control, and associated

activities. Applying the stages 1, 2, and 3 sequence of

activities to all validation and qualification unifies

the site approach to project management activities,

standardizes expectations, facilitates training, and

generally simplifies organizational thinking.

THE AFFECT ON CURRENT VALIDATION PROGRAMSA major concern of validation practitioners gets to

the “bottom line”—How does the 2011 guidance

affect current validation programs, and how can the

new guidance be implemented?

Organizational AspectsThe lifecycle approach to process validation

requires commitment from many areas in the

organization. The lifecycle approach must become

part of organizational strategy. This will require a

comprehensive and continuing view of validation

rather than focus on the performance of the usual

three conformance lots—and “job done.” Many

firms organize their operations in distinct silos

(e.g., R&D, manufacturing, and quality). The silos

create barriers to communication and cooperation.

The R&D organization develops the product. After

development is completed, the product is transferred

to manufacturing. Commercial operations

personnel “adjust” the process and make it ready for

validation and routine production. The validation

function coordinates process validation. After

the conformance lots are successfully completed,

the validation effort is finished. Manufacturing

then continues routine commercial production

with oversight by the quality unit or the qualified

person (QP). Often there is minimal ongoing

constructive interaction between R&D, validation,

manufacturing, and quality during the product

lifetime.

The lifecycle approach to validation is

clearly different than the above described

situation. Product R&D and technical support

should approach their work as supporting the

entire product lifecycle including commercial

manufacturing. They must be involved in

monitoring and maintenance of the validated

state. Their work should provide the technical

basis or justification for all aspects of

manufacturing including any changes and

necessary improvements. The validation group

should coordinate the process qualification stage

of manufacturing based on technical development

work, and should participate in determining

the ongoing control strategy. The validated state

must be maintained through process monitoring,

technical data evaluation, and change control.

Manufacturing “fixes” or “tweaks” should be

evaluated by technical people, and should ideally

be supported by data or sound technical judgment

whenever possible. R&D should be involved in

process improvements and provide the technical

justification for these improvements. Organizations

should foster development of a continuous

business process beginning in R&D and continuing

throughout the entire product lifecycle with

ongoing collaboration and communication among

all relevant organizational areas. The lifecycle

approach to process validation must become a

comprehensive organizational effort.

Validation Performance SpecificsThe 2011 guidance describes many specific details

and expectations for Stage 2 and Stage 3. Validation

and quality managers should evaluate their practices

and procedures regarding these specifics. FDA

recommendations for Stage 2 PPQ protocol-related

activities are substantial. FDA recommendations for

Stage 3 post-validation monitoring are significantly

different from a traditional “Annual Product Review”

approach. Deficiencies in site programs should be

identified and corrective actions or improvements

prioritized. Risk to the patient and to the

organization should be considered in prioritization.

Risk AnalysisRisk assessment has a critical role in all of the

activities described herein. All activities conducted

in the organization should be conducted with risk

in mind. ICH Q9 describes various risk assessment


Paul L. Pluta

methods and potential applications of risk

assessment. There are numerous applications of risk

management used during the entire process validation

lifecycle. Examples cited in ICH Q9 relevant to process

validation include product and process development,

facilities and equipment design, hygiene aspects

in facilities, qualification of equipment, facility, or

utilities, cleaning of equipment and environmental

control, calibration and preventive maintenance,

computer systems and computer controlled

equipment, and so on. In brief, risk assessment helps

to identify the most important potential problems

in all three stages of process validation, and then

addresses these problems appropriately. There should

be consistency between the risk-based activities in all

three stages of process validation. Risk management

must become pervasive in the organization.

TrainingThe issuance of the 2011 FDA guidance requires

appropriate training for all involved in validation-

related activities. All involved in validation and

validation- or qualification-related activities must

be aware of the 2011 process validation guidance

and concepts therein. Personnel who previously

considered themselves to be apart or distant from

commercial product validation (e.g., development

scientists) must now be included in validation

training.

Especially important are personnel who

write validation plans, protocols, results, and

associated documents. These writers must think

comprehensively, incorporating pre-validation

development information as well as considerations for

post-validation maintenance of the validated state into

their validation documentation.

Also critically important for training are the site

VAC members. There must be a clear understanding

and agreement among VAC members and the

validation group as to their functions and

responsibilities. Clearly stating the responsibilities

of the VAC provides focus and expectations for the

VAC. Clearly stating the responsibilities of the VAC

provides clear expectations for those submitting

protocols, validation plans, and other documents

for VAC review and approval. VAC members must

maintain awareness and compliance with the 2011

process validation guidance. The VAC members

should consider themselves to be a surrogate FDA

(or other regulatory agency) auditor. The VAC should

assume responsibility for site preparedness for

future regulatory audits of the validation function.

Future audits will certainly include concepts and

recommendations stated in the 2011 process

validation guidance.

TerminologyThe terminology associated with the various

phases of validation has had minor variations over

the years. The 2011 process validation guidance

describes process design, process qualification, and

continued process verification stages in the validation

lifecycle. Stage 2 Process Qualification includes

PPQ manufacturing of commercial lots. The 1987

FDA validation guidance describes installation and

operational qualification, process performance

qualification, and product performance qualification.

Products lots manufactured in the process

qualification phase were termed “conformance lots.”

PPQ batches have also been named “demonstration

lots,” “qualification lots,” “PQ lots,” and “validation

lots,” in past years. Stage 2 process qualification

phase also includes equipment, facilities, and utilities

qualification.

While the variety of terminology used may

cause difficulties in communicating, the intent

of all validation programs is the same: Sequential

process understanding, validation performance,

and maintaining the validated state as described

herein comprise the validation lifecycle continuum.

Validation programs addressing these phases of

the product or process lifecycle, no matter what

specific terminology is used or how categorized

in documentation, will meet the expectations

robustness, repeatability, and reliability for validated

process. Regulatory investigators are knowledgeable

and able to interpret different organizational

terminology as long as the sequence of process

understanding, validation performance, and

maintaining the validated state are demonstrated.

DocumentationAll work associated with process validation in

all stages of the validation lifecycle must be

documented. This includes product and process

design, experimental and development studies for

process understanding, risk analysis in development,

designed experiments, process parameter

optimization, validation and qualification protocols,

and process monitoring to maintain the validated

state. Development scientists must understand that

their work is integral to the validation lifecycle.

Development reports may be requested in regulatory

audits. Summary documents are recommended,

especially when multiple documents must be

integrated by the reader. All work associated with

equipment, facilities, and utilities qualification and

analytical validation must also be documented.

Document quality is important; in many cases,

documents are reviewed literally years after they

are written and long after authors have moved on

to new careers inside or outside of the company. All

Validation Answers from GXP Experts ................................................................................................................ 3

Reduced Validation Effort—Approaches Used and Lessons Learned ................................................................... 9

Engineering Runs: An Insider’s Perspective ...................................................................................................... 16

Risk Management for Aseptic Processing ........................................................................................................ 22

Case Study #2—Questionable Equipment Qualification ..................................................................................... 31

Validation Report Conclusion–Is It Validated? .................................................................................................. 34

Responsibilities of the Validation Approval Committee...................................................................................... 38

Sampling Errors in Validation ........................................................................................................................... 43

Design and Execution of a Shipping Qualification for a Vaccine Drug Substance ................................................ 51

Improving Validation Through the Use of Confidence Statements Based on

Attributes Acceptance Sampling ...................................................................................................................... 58

PQ Documentation–Three Simple Rules ............................................................................................................ 65

Original Data Supporting PQ............................................................................................................................. 71

Sampling Pages .............................................................................................................................................. 79

Should Acceptable Product Yield be a Validation Requirement? Validation Case Study #6 ................................. 86

Statistical Tools for Process Qualification ........................................................................................................ 93

PROCESS QUALIFICATION

DEMONSTRATING PROCESS

ACCEPTABILITY



PROCESS VALIDATION – Process Qualification 3

Jerry Lanese and Alan SmithJerry Lanese and Alan Smith

Our sister journal, the Journal of GXP Compliance,

features the ongoing column, “GXP Talk,” a column

for discussion of issues identified by readers of

the journal and the current good practice for

resolution of those issues. Between 1993 and 2000,

the US Food and Drug Administration prepared a

series of communications from FDA headquarters

to field investigators in which headquarters

answered questions submitted by the field. These

communications were made available to the

Industry as a mechanism for communicating

current acceptable practice and interpretations

of the regulations. Based on these FDA “Good

Manufacturing Practice Notes,” editors Jerry Lanese

and Alan Smith began a forum where current

good manufacturing practices (CGMPs) could be

discussed by journal readers and experts.

Over the years, the editors of “GXP Talk” have

received reader questions on various validation

topics. Some of these questions and the editors’

responses are listed in the following sections.

For more information about the Journal of GXP

Compliance and “GXP Talk,” visit www.IVThome.

com/GXPTalk.

LIMS AND QUALITY ASSURANCE

Reader QuestionWe are entering instrumental data directly into

a validated laboratory information management

system (LIMS), that data is processed within the

LIMS using a validated macro; the results are

maintained in the LIMS and then reported on a

Certificate of Analysis to quality assurance. Is a

second review by the laboratory required? What

should be included in that review? What data or

records should be reviewed by quality assurance (1)?

Editors’ Response [1]Since we are clearly dealing with electronic

records and we are told that the LIMS is validated,

we assume in this response that the validation

considered the requirements for electronic records

and electronic signatures and the system is

compliant with 21 Code of Federal Regulations

(CFR) 211 (2). Therefore, we should consider the

requirements of the predicate rule, 21 CFR 211.

The “Laboratory Records” paragraph of “Subpart J,

Records and Reports” states:

“21 CFR 211.194(a) Laboratory records shall include

complete data derived from all tests necessary to assure

compliance with established specifications and standards,

including examinations and assays, as follows:

performs each test and the date(s) the tests were

performed.

showing that the original records have been reviewed

for accuracy, completeness, and compliance with

established standards.”

The original record in the LIMS must be

signed and dated electronically by the individual

performing the test [211.194(a)(7)]. Although not

stated specifically, it is a regulatory expectation,

Validation Answers from GXP ExpertsJerry Lanese and Alan Smith

John (Jerry) Lanese, Ph.D., is an independent consultant in the areas of quality system and CGMP compliance. he can be contacted at [email protected]. Alan J. Smith, Ph.D., is an independent consultant specializing in quality management and the application of CGMPs. He can be reached at [email protected].

For more Author infor-

mation, go to ivthome.

com/bios[

4 PROCESS VALIDATION – Process Qualification

Jerry Lanese and Alan Smith

and also a reasonable scientific expectation, that

the signature of the individual performing the test

is acknowledgment that the test was performed

according to approved methods and procedures,

all defined acceptance criteria have been met, and

the reported data are accurate and complete. This

responsibility should be identified in an appropriate

laboratory procedure. This paragraph [(211.194(a)

(8)] also includes a clear requirement that a second

individual review the record(s) and verify that the

data is complete, accurate, and compliant with

internal procedures and regulatory requirements.

A second review by the laboratory is required! That

review should include all of the data entered into

the system. If any of the data is transcribed from a

notebook or worksheet, the review should verify the

accuracy of the transcription and the completeness

and compliance of the original notebook or

worksheet record.

It is reasonable to accept that the values

calculated within LIMS by the validated macro are

correct. However, 21 CFR “211.68(b) Automatic,

Mechanical, and Electronic Equipment” states:

“Appropriate controls shall be exercised over

computer or related systems to assure that

changes in master production and control

records or other records are instituted only

by authorized personnel. Input to and

output from the computer or related system

of formulas or other records or data shall

frequency of input/output verification shall be

based on the complexity and reliability of the

computer or related system.”

Although we may accept, on a day-to-day basis,

that the calculation within the LIMS is accurate,

there should be a systematic, periodic verification

that that macro is performing as intended. The

frequency of that verification should be defined in a

procedure and based on an evaluation of the science

and the risk associated with the calculation. This

includes a periodic evaluation of the accuracy of the

ultimate report, the certificate of analysis.

The question about what data or records should

be reviewed by quality assurance is not as clear.

“211.192 Production Record Review” states:

“All drug product production and control

records, including those for packaging and

labeling, shall be reviewed and approved

by the quality control unit to determine

compliance with all established, approved

written procedures before a batch is released

or distributed.”

Laboratory records are control records, and

companies differ in how they comply with the

requirement that laboratory records be reviewed

by the quality control unit. With most firms, it

is considered that the quality control laboratory

is part of the quality control unit, the second

review the laboratory meets the requirement for

the review and approval of the data and records

that up the certificate of analysis, and the quality

assurance department accepts the certificate of

analysis as an accurate report. In other firms,

quality assurance reviews all records, including the

quality control laboratory records before product

release. Either way meets the “letter of the law.”

Whatever way a firm chooses to operate, the process

must be defined in a procedure or procedures and

responsibilities clearly identified.

VALIDATION REPORTS

Reader QuestionIf you realize that a record such as a validation

report, calibration report, or environmental report

requested by a regulatory agency investigator, has

not been completed, what should you do? Should

you show the data or reports that have not been

reviewed or approved (3)?

Editors’ Response [1]When providing documents to an investigator or

auditor, it is accepted, good practice to review the

document prior to presenting it to the requester to

become familiar with it and, heaven forbid, find

problems that would need to be addressed.

If a document is incomplete or has not had the

required review and sign-offs, most importantly,

do not attempt a “quick fix” and add the missing

information or sign it; this could cause even more

problems.

Instead, begin an immediate investigation

according to your procedures. Once this

investigation has been started, present the

document and inform the investigator or auditor

that you have found something amiss and have

started an investigation. You will need to have some

information or closure to this issue by the end of

the inspection.

Generally speaking, if this is seen as a rare

occurrence, it should not be a problem (given of

course, what was missing). On the other hand, if

there are repeated problems with many documents,

it could point to a systemic issue.

PROCESS VALIDATION

Reader QuestionWith regard to process validation, at what point

during development or process transfer of the

drug product do you challenge the extremes of the



process parameters, such as time, speed, pressure,

or temperature (4)?

Editors’ Response [1]There has been an evolution in thinking of

validation in the past ten years. More firms validate

on the philosophy that they want to demonstrate

that they have control of the process during

normal, anticipated operational conditions. This

is based on the capabilities of the equipment, the

normal variation of raw materials and components,

and what have been identified as critical and

operational parameters.

In FDA’s guidance document, Sterile Drug

Products Produced by Aseptic Processing

(September 2004), a list of factors is presented that

a firm should consider as they are developing the

product and designing the validation protocol.

Although this guidance is addressed to a specific

segment of the industry, the concepts apply to other

segments of the pharmaceutical industry as well

as the development and validation of processes in

other industries.

In addressing the factors, the firm needs to give

a rationale for what it decides to examine or not

examine. This is not to say that every possible

“what if” scenario needs to be examined during

development, but rather, as the guidance states,

“closely simulate aseptic manufacturing operations

incorporating, as appropriate, worst-case activities

and conditions that provide a challenge to aseptic

operations.” A risk analysis could be part of the

evaluation of what to challenge. The extremes of

the critical process parameters, such as time, speed,

pressure, or temperature should be examined and

established during development.

Validation is where you demonstrate that

you can consistently operate in control; process

development is where you want to generate an

understanding of where the “edges of failure” are

and where the optimal operational range is.

CHANGE CONTROL

Reader QuestionAre continuous improvements and process

improvements subject to change control (5)?

Editors’ Response [1]Any change that is not covered in a procedure

reviewed and approved by the quality unit should

be handled within the change control program.

This includes improvements to the processes.

Changes will require quality unit review and

approval consistent with the change control system

and probably some level of regulatory submission

or report, such as: Prior Approval Supplement,

Change Being Effected, or Annual Report.

FDA discusses an environment that promotes

continual improvements in its recent guidance on

the Quality System Approach to Pharmaceutical

Good Manufacturing Practices (GMPs) (6).

The concept is mentioned in the International

Conference on Harmonization (ICH) Q8 (7)

document. There is an interest on the part of both

the Agency and Industry that continuous process

improvements can be made with a minimal

requirement for regulatory submissions. In order

for this to happen, some or all of the following will

have to be in place:

a previous submission, that it understands

the process and the proposed improvement is

consistent with that information

identified in an approved submission (New

Drug Application [NDA], Amended New

Drug Application [ANDA], Biologics License

Application [BLA], or other market approval

submission)

submission and meets conditions, such as

protocol, comparability testing, and acceptance

criteria, defined in the approved submission.

VIRTUAL PHARMACEUTICAL COMPANIES

Reader QuestionWhat should virtual pharmaceutical companies

expect FDA to inspect during a routine

surveillance/compliance audit (8)?

Editors’ Response [1]First, we should give some background information

on this topic. As our society has become more

technologically advanced and specialized, it is

difficult for industry to do everything itself and

remain competitive. Because of this, companies are

relying on the expertise and capabilities in other

organizations. More companies are looking to

outsource services and functions and concentrate

on their core competencies, thus, the trend toward

companies “going virtual” is on the rise.

FDA has not published guidance, or other

document, specifically on what quality systems

they expect virtual pharmaceutical companies

to employ and what they will look for during an

investigation of a virtual pharmaceutical company.

The response is based on some assumptions:

6 PROCESS VALIDATION – Process Qualification


applicable submission (Investigational New

Drug Application [IND], NDA, BLA, or other

appropriate registration document)

labels and labeling for the product

team that provides the leadership through the

product lifecycle (design, develop, transfer,

produce, package, distribute, monitor,

decommission).

Two efforts of FDA to encourage the

pharmaceutical industry to embrace contemporary

quality concepts and implement contemporary

quality systems are as follows:

The section of this guidance that is the most

relevant is MANAGEMENT RESPONSIBILITY.

Within this, the section, “Oversight of

Outsourced Materials,” stands out.

“A pharmaceutical company can outsource

activities at all stages of the product lifecycle.

the management responsibilities described

in this section, extends to the oversight and

review of outsourced activities. Normally,

under a contract, the contract giver should

be responsible for assessing the suitability and

competence of the contract acceptor to carry

out the work required. Responsibilities for

quality-related activities of the contract giver

and contract acceptor should be specified in a

written agreement.” (9)

Quality System Approach to Pharmaceutical

CGMP Regulations (10). The most pertinent

section in this guidance is also Management

Responsibilities. Management responsibilities

include:

1. Provide leadership:

plans

review

2. Structure the organization and identify

authorities and responsibilities to achieve

the goals through the product lifecycle

3. Build the Quality System to assure

compliance through the product lifecycle

4. Establish and implement appropriate

policies, procedures, objectives, and plans

5. Review the system.

In July 2007, the Center for Biologics Evaluation

and Research (CBER) issued a draft guidance

(11), Cooperative Manufacturing Arrangements

for Licensed Biologics, that is directly applicable

to virtual companies involved with licensed

biologics. The concepts apply to all pharmaceutical

firms through the product lifecycle. That guidance

states:

“Contract Manufacturing Arrangements.

For the purposes of this document, contract

manufacturing refers to a situation in which

a license manufacturer establishes a contract

with another entity(s) to perform some or all

of the manufacture of a product as a service to

the license manufacturer.

“Responsibilities of License Manufacturer.

A license manufacturer that establishes a

contract with another entity to perform some

or all of the manufacture is responsible for:

with the provisions of the BLA and the applicable

regulations, including, but not limited to, 21 CFR

standards.”

The virtual company is accountable for

everything that goes on during the product

lifecycle. FDA will look for the evidence of an

appropriate quality system that exhibits the

following criteria:

with the objectives, plan, product, and

processes

and quality through the various stages of the

lifecycle

ACCOUNTABILITY AND RESPONSIBILITY

Reader QuestionThe terms accountability and responsibility are

frequently used in quality standards and guidances,

but are not defined by any major document. It is

not clear whether these terms are synonyms with

no difference in meaning or whether there are

significant or subtle differences in meaning. How

are these terms to be interpreted or applied within

a standard or an internal policy or procedure (12)?

Editors’ Response [1]In addition to being used in quality standards, the

terms responsibility and accountability are used

often in both management and political circles.

Their definitions are, therefore, of wide concern.



The problem is that their usage in both professional

and everyday language varies.

Dictionaries tend to regard the terms as

synonymous. However, we, the editors, are aware

that these words are sometimes used in different

contexts and can have graduated shades of meaning

as in the use of “directly responsible” versus

“indirectly responsible.” Accordingly, we surveyed

many of our colleagues for their opinions. They

provided a wide range of opinion with about half

considering the terms to be synonymous (i.e., “A

is responsible for performing X type actions” is the

same as “A is accountable for performing X type

actions”). The issue becomes more challenging

when the two words appear in the same sentence

(e.g., “A is accountable for the results of actions

performed within his/her areas of responsibility.”).

In the latter case, it is as though responsibilities

are action areas which have been assigned

(i.e., authorized) by a higher body and that

accountability is recognition by interested parties

as to who can be “officially held to account” for

performance within those areas.

We both hold the view that whenever a firm, or

any organization, communicates or documents its

practices, it should avoid ambiguity by defining

each term that it uses so that its meaning is

individually distinct. This would include making

sure each synonym used has a separate and distinct

meaning. We maintain that each organization

should do this and consider such definitions

to be internally published “as used in our

documentation.” We thus propose the following as

definitions for consideration:

action or duties being assumed by or formally

granted to an organizational unit.

identity of the persons, or organizational units,

who can be held to account for the adequacy of

performance of work done or to be done.

Under this arrangement, responsibility is

something which is assumed or assigned and

accountability concerns who should be identified

with the adequacy of performance. The definition

of accountability would allow not only those who

actually perform the work to be accountable but

also those to whom they report either directly or

less directly through the defined organization.

It is becoming a well-established principle that

the highest individual in the organization is

accountable. This was understood by President

Harry Truman by his display of the placard on his

desk in the Oval Office, which read: “The Buck

Stops Here.”

GMPS AND DEVELOPMENT ACTIVITIES

Reader QuestionHow much do GMPs apply to development

activities? What development data can FDA

investigators inspect during a site or pre-approval

inspection (13)?

Editors’ Response [1]Most people tend to regard GMPs as government

regulation for “product manufacturing” with which

firms must comply. However, it is more realistic

to regard the term as embracing practices that

industry uses to consistently produce a quality

product. Indeed, in keeping with this, FDA used

the term, CGMP, where “C” stood for the word

“current” when, in 21 CFR Sections 210 and 211, in

1978 and ever since, FDA adhered to the concept of

assessing the “up-to-dateness” of a firm’s practices

when performing inspections.

When Parts 210 and 211 were first issued,

they were intended to be the official regulations

governing the manufacture of batches intended

for commercial use. They were not intended

to apply to development activities with the

exception of clinical batch manufacture, which

was referred to in the preamble. However, since

the issuance of Parts 210 and 211, there has been

a veritable plethora of non-regulation documents

issued by FDA, and other organizations, that

have discussed the development work necessary

to produce a quality product. Paramount

among these has been the ICH Q series, which

identify “product knowledge” data that should

be included in the product submission (NDA,

ANDA), and are therefore, available before

marketing. FDA has provided members of the

expert work groups that developed the ICH

Guidelines. The ICH guidelines are thus officially

recognized as Guidance for Industry by FDA.

Because good development is a precursor to good

commercial production, FDA expects such good

development and looks for this feature when

performing pre-approval inspections. An even

greater emphasis is placed on good development

in the recent Quality Systems Guidance (6), ICH

Q8 (7) and ICH Q9 (14), and further emphasis is

expected in ICH Q10 (9).

In pre-approval inspections, the main focus of

FDA is on the integrity of the development data

and the adequacy of the facilities, equipment,

people, and systems to perform as prescribed in the

submission. Anything described in the submission,

or suspected omissions, can be inspected and

this will include development work. In routine

inspections, FDA generally does not focus on

GMP Monitoring—What, Why, Where, and How .................................................................................................. 3

Rational Revalidation ........................................................................................................................................ 8

Dos and Don’ts of Control Charting—Part I ....................................................................................................... 17

The Dos and Don’ts of Control Charting—Part II ............................................................................................... 21

Understanding the Process Nonconformity Concept—The Scientific Reason for Process Validation ................... 27

Variation—Past, Present, and Future ............................................................................................................... 36

Having It All .................................................................................................................................................... 42

Substandard Data and Documentation Practices—Case Study #5 ..................................................................... 47

Using Probability Distributions to Make Decisions ............................................................................................ 54

Case Study #3—Process Validation Failure of a Liquid Product Batch

Size Increase—“Identical” Manufacturing Tanks ............................................................................................. 67

Like-For-Like Changes: Is Validation Testing Needed? Validation Case Study #7 ............................................... 73

Understanding and Reducing Analytical Error—Why Good Science Requires Operational Excellence ................. 78

Meeting Specifications is Not Good Enough—The Taguchi Loss Function .......................................................... 85

Process Modeling: A Powerful Weapon in the Fight to Reduce Variation—Part 1 .............................................. 90

White Spots on Tablets—Compliance Case Study #8........................................................................................ 97

Compliance Case Study #5—Secondary Packages With Defective Glue Joints ................................................ 102

CONTINUED PROCESS VERIFICATION

MONITORING AND MAINTAINING

THE VALIDATED STATE



PROCESS VALIDATION – Continued Process Verification 3

Gamal Amer

Welcome to “Maintaining Validation.”This column addresses topics associated with

maintaining the validated state of processes, equipment, facilities, utilities, and analytical methods (i.e., anything that has been validated or qualified and must be continually maintained in the validated state). We intend this column to be a useful resource for daily work applications.

This column was suggested by attendees at the 14th International Validation Week Meeting held in Philadelphia in October of 2008. The general topic of maintaining validation was a subject of great interest. An ongoing discussion addressing these questions and associated topics is warranted and will be useful to our readers.

Validation and compliance practitioners are well aware that the conformance lots of process validation, or the IQ/OQ/PQ of equipment, are at most “snapshots in time.” These events serve to document standard performance when completed. However, they do not guarantee continued good performance. It is through monitoring, data evaluation, statistical analysis, change control, and other programs that ongoing good performance is maintained. These topics, including relevant examples, are addressed in “Maintaining Validation.”

Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Case studies submitted by readers are most welcome. We need your help to make “Maintaining Validation” a useful resource. Please send your comments and suggestions to journal coordinating editor Susan Haigney at [email protected].

KEY POINTS DISCUSSEDThe following key points are discussed in this

article:

considerations

draft guidance Process Validation: General

Principles and Practices (1) identifies continued

taken for excursions

other factors

ensure an ongoing state of control.

GMP Monitoring— What, Why, Where, and HowGamal Amer

[For more Author

information,

go to

gxpandjvt.com/bios

ABOUT THE AUTHOR

Gamal Amer, Ph.D., is principal at Premier Compliance Services, Inc., management consultants for compliance and manufacturing operations performance in the life sciences industry. He holds a Ph.D. in chemical engineering and has over 27 years of experience in the pharmaceutical and related industries. He can be reached by e-mail at [email protected] or [email protected].

4 PROCESS VALIDATION – Continued Process Verification

Gamal Amer

INTRODUCTION: WHAT IS MONITORING?

current state

initiated.

Process Validation:

General Principles and Practices (1) identifies three

WHY MONITOR?

The following is a partial list of such regulatory and

21 CFR 211.42-10(iv).

conditions.

211.110 (a).

211.122 (h).

21 CFR 820.70 (a).

820.70 (2).

820.75 (b).

820.75 (b2).

ICH Q7, Good manufacturing Practice Guide

for Active Pharmaceutical Ingredients (9). This


Gamal Amer

ICH Q8 Pharmaceutical Development

point) to ensure that the product is of the desired

ICH Q9 Quality Risk Management

in that collection and analysis of operating data

WHAT TO MONITOR IN A GMP ENVIRONMENT

surrounding the process

supplied

operation and should collect appropriate data and

operating experience.

WHERE TO MONITOR

and at the end of any critical steps are also logical

conditions at the point where the product is at

steps in the process and at the critical use points.

particulate data are collected at surfaces where


Gamal Amer

HOW TO MONITOR

recording data

taken

issues or trends are identified.

actions:

conducted if issues arise

ESTABLISHING THE PARAMETERS TO MONITOR

one can plainly see that the resulting product would

process yield or the yield of certain critical steps

products

and suggests how to deal with trends and issues

as they arise.

SUMMARY

to ensure the process is in a state of control. The

Table: Environmental sampling frequencies for aseptic manufacturing facilities.

Area Classification Sampling Frequency

Class 100 Each shift*

Support to Class 100 (Class 10,000) Each shift*

Other support areas (Class

100,000) Twice/week

Potential product/container con-

tact Twice/week

Non-product contact are

(Class 100,000 or less)

Once/week

*FDA guidance on sterile processing suggests daily monitoring (13).


Gamal Amer

The Journal of Validation Technology

REFERENCESProcess Validation: General

Principles and Practices, Draft Guidance

Q7, Good Manufacturing Practice Guide for Active

Pharmaceutical Ingredients

Q8, Pharmaceutical Development

Q9, Quality Risk Management

Pharmacopeia Forum

Sterile Drug Products

Produced by Aseptic Processing JVT

ARTICLE ACRONYM LISTINGCAPA Corrective Action and Preventive ActionCPP Critical Process ParametersCQA Critical Quality AttributesGMP Good Manufacturing PracticesFDA US Food and Drug AdministrationFMEA Failure Mode Effects AnalysisFMECA Failure Mode, Effects, and Criticality AnalysisHACCP Hazard Analysis and Critical Control PointsHAZOP Hazard Operability AnalysisUSP United States Pharmacopeia


Hosam Aleem, Tim McCarthy, and Rodger Edwards

[For more Author

information,

go to

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ABSTRACT

This discussion addresses the need for

considered.

INTRODUCTION

Q9

Rational RevalidationHosam Aleem, Tim McCarthy, and Rodger Edwards

ABOUT THE AUTHORSHosam Aleem has spent several years in the pharmaceutical industry as a validation and cali-bration engineer at both IPR owners and contract manufacturers. He may be reached by email at [email protected]. Dr. Tim McCarthy is a professor of engineering design at the University of Wollongong, NSW Australia. Dr. Rodger Edwards is a senior lecturer at the School of Mechanical, Aerospace and Civil Engineering at the University of Manchester Institute of Science & Technology and University of Manchester.


Hosam Aleem, Tim McCarthy, and Rodger Edwards

litigations).

procedure to follow in executing it. This discussion

WHY REVALIDATE?

Supplementary Guidelines on

Good Manufacturing Practices: Validation

countries.

Other regulations introduced in the past such

in focus of regulatory inspections. This is also

process design understanding the product and process ... · guidance. approach to process...

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