56

Validation in a Small Pharmaceutical Company

Stephen C. Tarallo
Lyne Laboratories, Inc., Brockton, Massachusetts, U.S.A.

INTRODUCTION is critical not only to meet regulatory requirements, but as

a tool for evaluating the entire process from the supply of
The following chapter provides a perspective on a API to ensuring that the drug product meets its intended
general approach to validation activities in a small stability parameters. Validation in a small company is
pharmaceutical company. As a small company with a also an excellent management tool for developing the
focus on contract manufacturing, Lyne Laboratories has knowledge and skills of key personnel.
successfully completed validation on numerous ANDAs, The design, construction, commissioning, and vali-
NDAs and OTC products. Our approach to validation dation of pharmaceutical facilities and processes pose
meets the highest industry and regulatory standards and significant challenges for project managers, engineers,
has consistently and effectively been used with small, and quality professionals. Constantly caught in the
large and virtual pharmaceutical companies. For Lyne dilemma of budget and schedule constraints, they have
Laboratories and other small companies, validation is to deliver an end product that complies with all building,
both challenging and rewarding. While it often taxes environmental, health and safety governing codes, laws,
resources and demands intense and broad-based
and regulations. The process must also comply with one
management involvement, it can also stimulate peak
very important criterion; it must be validated to meet
performance from the team and individuals within the
cGMP regulations.
company. As a crucial component in pharmaceutical
The cost of validation is determined by time spent
manufacturing, managing the validation process requires
on documentation, development of protocols and SOPs,
leadership skills in addition to technical and scientific
and time spent on actual fieldwork, data collection and
competency.
analysis. Often, varying validation practices and method-
Validation principles date back approximately 30
ologies result in inefficient implementation and costly
years, and yet, even today these principles remain a
delays. Too often, the validation process reveals a large
standard for all new manufacturing processes. With
burden of unfinished commissioning business, resulting
advanced technologies, the scientist has been afforded
in a delay in start-up.
more accurate means to accomplish these activities. This
In some cases, validation is carried out but involves
has greatly improved the quality process and thereby
a limited number of personnel within the organization.
provided better scientific data.
This lack of information sharing increases the misunder-
Pharmaceutical companies of all sizes typically
standing of a manufacturing process by the most
dedicate considerable resources, in terms of time,
important people within the company—manufacturing
money and specialized personnel, to validate a cGMP
and quality personnel.
facility or process. The regulatory agencies, appropriately,
It is easy to lose sight of overall objectives during the
do not distinguish or make exceptions in terms of
validation cycle. Companies can get very focused on the
validation for small companies versus large companies.
scientific aspect of pharmaceutical manufacturing and
For a small pharmaceutical company, technical and
forget that it is a business. A company must run efficiently,
financial resources will undoubtedly be challenged. In
produce quality products and meet the demands of the
many cases, resources outside the company may be called
marketplace. Validation data should provide the baseline
upon to complement existing skills. Balancing internal
information, which will become the reference data and
and external resources is essential in order to maintain
parameters for a given product during the product’s
ultimate control and responsibility for the overall process.
lifecycle. The emphasis for the validation process should
This can be overwhelming to a small company or plant
be to develop as much information before, during and
with limited resources, so it is important to structure the
after validation since the process is not likely to change
validation team carefully. Leaders of small pharma-
during the product’s lifecycle. A product process is
ceutical companies must realize that process validation
evaluated annually to assess any changes or annual
trends that may force the process out of control. This is
Abbreviations used in this chapter: ANDAs, Abbreviated New Drug part of the cGMP annual product review and ISO 9000
Applications; API, active pharmaceutical ingredients; cGMPs,
annual product review.
current good manufacturing practices; GMP, Good Manufacturing
Practice; HVAC, heating, ventilation and air-conditioning; IQ, instal-
With potential limitations on technical, financial
lation qualification; NDAs, New Drug Applications; OQ, operational and staffing resources placing pressure on the organiz-
qualification; OTC, over-the-counter; PQ, performance qualification; ation and process, successful validation at a small
QA, quality assurance; R&D, Research and Development; SOPs, pharmaceutical manufacturing company requires great
standard operating procedures. planning, organization and vision. When the entire
704 X: GENERAL TOPICS

company is aware of a new process startup and all A Validation Master Plan could include some of the
participants are trained in their respective areas of items listed below:
expertise, validation can proceed smoothly and add
valuable information, knowledge and processes to Building Design and construction
an organization. HVAC Design and IQs
Process water Design, IQ
Utilities Electricity, gases, steam,
VALIDATION PLANNING refrigeration, design, IQs
Process equipment Design, construction,
The scope of validation work needs to be developed early installation, OQ
in the project to help facilitate the writing of a Validation Laboratory Analytical and microbial
Master Plan. Validation planning allows the project validation methods
and validation managers to prepare resource and Product process Validation
scheduling requirements, and ensures that design engin-
eer specifications and detailed design are suitable for
validation. The key to successful project implementation is a
The Validation Master Plan should be designed to well-defined project scope, which enables the validation
encompass all facets of validation activity that the team to determine the degree of effort and level of
company expects to employ at present and for future resources required, enabling them to focus on its
validation activities. The Plan should be a structured, defined responsibilities. It is the function of the facility,
detailed record defining all the testing, acceptance criteria, equipment, or utility that determines what level of
and documentation required to satisfy the regulatory commissioning and qualification are needed. Developing
authorities and support the validation process. Based on the project commissioning and validation scope is
an impact assessment, the plan will also clearly define the normally accomplished by conducting a risk analysis or
scope and extent of the qualification or validation process impact assessment, whereby the impact of a system on
product quality is evaluated, and the critical components
by listing the matrix of products, processes, equipment, or
within those systems are identified (Fig. 1).
systems affected.
These are some of the critical areas that need to be
The Validation Master Plan applies to all facilities,
considered when writing a Validation Plan:
equipment and processes that are subject to requirements
of cGMPs. This includes but is not limited to facilities,
process utility systems, manufacturing and finishing IQ
The documented verification that an equipment/system
equipment, analytical equipment, calibration, test equip-
installation adheres to approved specifications and
ment and computer-related systems.
achieves design criteria. IQ documentation and protocols
The Validation Master Plan assigns responsibilities
are developed from process and instrumentation
for developing and executing validation program activi-
diagrams, electrical drawings, piping drawings, purchase
ties, and gives a first look at an anticipated testing
specifications, purchase orders, instrument lists, engin-
execution schedule. There are many variables that must eering specifications, equipment operating manuals and
be taken into consideration during the planning process. other necessary documentation.
For example, a small pharmaceutical manufacturing
company must determine whether outside analytical
OQ
testing laboratories will be used because that will
The documented verification that the equipment/system
usually add significant time to the schedule.
performs per design criteria over all defined operating
At the inception of a project, it is necessary, and in ranges. Systems and equipment must function reliably
fact essential, that the project team and project sponsor under conditions approximating those of normal use.
approve the Validation Master Plan to enable the release Draft SOPs must be prepared for the operation of
of sufficient financial and staffing resources to support the each system and piece of equipment, if applicable.
entire project. Those procedures are to be finished and formally
The Validation Master Plan should include the approved after completion of the PQ evaluation of
various technical support personnel within the each system.
company who will have direct responsibility for facets
of the Validation Plan. By means of a GMP audit, for Process PQ
example, early involvement by QA should provide clear The purpose of PQ is to provide testing to demonstrate
communication of regulatory requirements, ensuring that the effectiveness and reproducibility of the equipment,
effective procedures and practices are established up system or process. In entering the PQ phase, it is under-
front for incorporation into the project. Since validation stood that the equipment has been judged acceptable on
activities assess the critical aspects of a given manufac- the basis of suitable installation and operational studies.
turing process, the development department, from bench, Critical operating parameters must be independently
pilot and scale-up, should be focused on a successful measured and documented in each trial. Equipment,
process transfer. At the start of process development, the systems or processes should perform as intended, with
focus should be on the commercial scale-up process. This expected yields, volumes, and flow rates as described in
will minimize the potential for problems during tech- appropriate SOPs. Components, materials and products
nology transfer and manufacturing of scaled up processed by each system or piece of equipment should
engineering batches. conform to appropriate specifications.
 56: VALIDATION IN A SMALL PHARMACEUTICAL COMPANY 705

New/Revised Process / Existing Process/Product

Product
Define Process
Define System
Requirements
Specifications
Specifications
Equipment
Equipment
Procedures
Procedures

Define Process Design/Specify

Equipment

Qualify Equipment

Develop
Specifications Install Equipment
Procedures
Review Process
Capability
Specifications
Verify Equipment
Specifications Qualify Equipment Procedures
Procedures

Develop Validation
Protocol
Develop Validation
Protocol

3 Validation Lots Data 3 Validation Lots

Validation Report

Acceptance

Ongoing Process
Evaluation
Figure 1 Validation process
schematic.

Product PQ Validation
Establishing confidence through appropriate testing that Establishing documented evidence, which provides a
the finished product produced by a specified process high degree of assurance that a specific process will
meets all release requirements for functionality consistently produce a product meeting its predeter-
and safety. mined specifications and quality attributes.

Prospective Validation
Validation conducted prior to the distribution of either a Validation Protocol/Plan
new product, or product made under a revised manu- A written plan stating how validation will be conducted,
facturing process, where the revisions may affect the including test parameters, product characteristics, pro-
product’s characteristics. duction equipment, and decision points on what
constitutes acceptable test results.
Retrospective Validation
Validation of a process for a product already in distri-
bution based upon accumulated production, testing and Worst Case
control data. Technically, there is no such thing as A set of conditions encompassing upper and lower
revalidation since it always involves a current process. processing limits and circumstances, including those
Retrospective validation provides an opportunity to within SOPs, which pose the greatest chance of process
verify that the process remains in control and on target. or product failure when compared to ideal conditions.
706 X: GENERAL TOPICS

Such conditions do not necessarily induce product or validation work are varied and may range from phar-
process failure. macists, chemists, and microbiologists, to chemical
engineers, process engineers and others. The need for
Process Validation employees with diversified backgrounds is understand-
Establishing documented evidence that provides a high able. However, the validation group’s responsibilities
degree of assurance that a specific process will consist- require a complete understanding of technical equip-
ently produce a product meeting its predetermined ment, equipment controls, electronics, laboratory
specifications and quality characteristics. Process Vali- instrumentation and testing and product sampling and
dation will include acceptable release testing of not less testing. Team members will have to balance daily activi-
than three batches that meet the processing limits for all ties with new added validation responsibilities.
critical parameters. Some of the departments involved in validation and
their responsibilities are as follows:
Analytical Method Development Validation Research and Development
Demonstrating that the analytical procedure is suitable
Responsible for formulation development activities that
for its intended purpose. A tabular summation of the
include formulation ingredients listing and concen-
characteristics applicable to identification, control of
trations; process optimization, equipment types and
impurities and assay procedures should be included in
facility requirements; raw material and packaging com-
the method validation.
ponent specifications, as well as product specifications.

Cleaning Validation Regulatory

Ensuring cleaning effectiveness through a cleaning vali- Responsible for assessing the regulatory requirements to
dation program that includes initial cleaning of new implement a new process. Typically validation activities
equipment and postbatch cleaning. Cleaning methods are required due to a new product under regulatory
are developed and qualified to show that residuals or review by a regulatory organization. It will be necessary
by-products from manufacturing and cleaning have been to interpret global regulations and standards to obtain
removed. Swab and rinse samples are collected from global marketing authorization.
points identified in the cleaning validation protocols
and analyzed using a qualified method. Validation of Quality Control/Analytical Laboratory
postbatch cleaning procedures includes acceptable Responsible for preparation of SOPs related to testing of
results from not less than three batches. raw materials, in-process samples, bulk drug product,
finished drug product, cleaning validation samples,
VALIDATION TEAM product process validation samples and stability studies.

Management of the validation process is key to control- Engineering

ling the cost and time of validation. Pharmaceutical Responsible for participating in the design and installa-
companies typically require considerable resources in tion of a new facility and/or equipment; preparation of
terms of time, money and personnel to validate. In a SOPs for maintenance and set-up of equipment once the
small pharmaceutical company, a critical part of mana- equipment is qualified and the process validated; and
ging a validation project is the selection of personnel from providing technical support for postvalidation activities.
within the organization to participate in preparing and
executing the Validation Plan. Therefore, fundamental
Logistics/Material Control
project management principles should be considered,
Responsible for ordering materials used for the manu-
with the primary objective to identify a project manager.
facturing of prevalidation and validation batches.
It is essential that this individual have strong leadership
Preparation of SOPs for purchase specifications, iden-
skills and be capable of directing and motivating others.
tifying and maintaining supplier profiles and evaluating
This individual must have a good understanding of
their performance during the product life cycle.
cGMPs, pharmaceutical manufacturing processes and
good communication skills in order to interact with the
various team members and departments within Manufacturing
the organization. The project manager will constantly be Responsible for the design of the facility and equipment
challenged by monitoring performance, meeting dead- required for the manufacturing of the product to be
lines, costs, scheduling and rescheduling various validated; works closely with R&D during the develop-
activities and will need to outline the project activities ment and optimization of the manufacturing process; and
with anticipated timelines in order for the project to is responsible for all SOPs related to the manufacturing
proceed efficiently. Delays, communication problems, process.
poor coordination of activities are just some of the
problems, which may be encountered. Quality Assurance
The Project Team should be structured appropri- Responsible for review and approval of all SOPs required
ately, and roles and responsibilities clearly defined. Team for all activities from IQ through process validation,
members should be knowledgeable about validation with as well as cGMP auditing of all activities related to the
particular emphasis on the areas that they represent. The entire project including facilities, equipment, analytical,
educational backgrounds of personnel involved with manufacturing and validation; approves the validation
 56: VALIDATION IN A SMALL PHARMACEUTICAL COMPANY 707

report, ensuring that the validation process meets its & Establishing unrealistic acceptance criteria will often
intended criteria. lead to increased work loads and cost overruns.
At times, it may be necessary for a small pharma- & Document all deviations. Attempt to determine

ceutical company to seek outside resources due to assignable cause with a well-defined plan for
technical expertise limitations and/or financial reasons. corrective action.
Finding the correct resources outside the company will in & Ensuring that commissioning documentation for

some instances prevent problems and delays. It may not be process systems are planned, structured, organized
as simple as identifying and engaging the services of a and implemented so that they may become an integral
single consultant, but rather engaging a consulting firm part of the qualification support documentation.
with varied staff that can support manufacturing, cGMP Examples of qualification (IQ/OQ) documents
auditing, documentation and validation writing. In other required:
circumstances, it may be more prudent to bring in a & Building Installation

validation expert consultant to direct the team and & Building Utilities—electrical, plumbing
& HVAC
delegate responsibilities within the staff. In either case,
& Compressed Air
the key is for management to maintain control of the entire
& Utility Piping
process and ensure that outside resources are comp-
& Process Piping
lementary and accountable to the head of the project team.
& Filling Equipment
Identifying and selecting consultants adds value as
& Packaging Equipment
well as time to the validation process. If possible, a small
& Process Equipment
manufacturing company should strive, as a regular
& Analytical Instrumentation
course of business to regularly network and become
knowledgeable about the available expertise in the Examples of process validation documents
marketplace. Developing and maintaining industry required:
& Standard Compounding Instructions
contacts can save significant amounts of time when an
& Standard Packaging Instructions
outside resource is needed to supplement those already
& In-Process Testing Documents
within the company.
& Finished Product Testing Documents
& Cleaning Procedures
DOCUMENTATION & Cleaning Validation Protocols
& Analytical Testing Documents
The documentation required during validation organiz- & Sampling Protocols
ation is paramount to the success of the validation plan.
The types of documents required range from qualification
to process validation and include analytical testing docu-
ments and standard manufacturing and packaging
VALIDATION IMPLEMENTATION AND EXECUTION
documents. All of this information is requisite to the In order to meet the intended objectives of a successful
execution of the validation plan; any void will result in validation plan, scheduling for validation is critical and
delays with poor integration of data. Typical documen- offers a significant challenge to the project manager. Since
tation for the qualification (IQ/OQ) of a facility or many departments of a small pharmaceutical company
building might include protocols that define the test are involved with the validation plan, the project
procedures, documentation, references and acceptance manager must prepare and organize the activities well
criteria that will establish that the facility has met in advance so that adequate time is allocated to meet
intended qualification. milestone targets. The project manager will need to
In order to streamline the validation process, the develop integrated schedules with direct input from
validation team will need to perform gap analysis to team members to ensure everyone remains committed
determine the required documents. Technical infor- to meeting the overall timeline. Leadership becomes a
mation should become available to the team as detailed very important aspect of project management during the
design proceeds. This enables the team to begin devel- implementation period. Clear, effective and unwavering
oping a schedule of activities, staffing schedules, direction is required for successful validation.
validation protocols, sampling plans, test plans and There is constant change during the project lifecycle
training materials. especially if it involves construction and/or new equip-
Approaches to streamline the amount of paperwork ment purchases. The project manager will need to
required to give sufficient documented evidence of vali- identify, track and coordinate the changes. It may
dation could include: be necessary to establish a strategic meeting schedule
& Standardizing protocols and report templates wher- to discuss such changes with the validation team. This
ever possible, so that reviewers become used to will undoubtedly lead to changes in the master timeline
protocol formats and contents. and possible delays, if the project manager has not added
& Structuring executed protocols as reports to prevent extra time to the schedule in anticipation of such delays.
the need for writing a separate report. Of course it is impossible to predict where the delays
& Combining IQ and OQ documents, resulting in fewer might occur, but good planning before initiating activities
documents to develop, review and approve. should minimize the downtimes.
& Validation acceptance criteria should be established It is recommended that all systems go through a
based upon process capabilities and thereby meeting shakedown or debugging phase before beginning quali-
product quality standards. fication activities. This should improve the efficiency of
708 X: GENERAL TOPICS

transitioning from IQ to OQ activities and will help to These four steps will ensure the validation
reduce the number of changes required during the program not only is successful, but becomes part of the
qualification phase. Typically the last phase of qualifica- company’s standard routine. At the same time, it is
tion, a performance qualification is usually the part of the critical that the resources and responsibilities for imple-
validation program where product is produced on a large menting the program be committed to an individual
scale before engineering and commercial validation who can oversee, manage, schedule, coordinate, commu-
batches are produced. Because of the importance to the nicate and interact with a group of professionals from
overall plan, the project manager should allocate suf- both within and outside the company. The skills associ-
ficient time to the qualification activities which include, ated with this are not necessarily technical, but rather
but are not limited to, equipment setup and maintenance, business savvy and leadership skills, allowing oversight
equipment outputs, equipment cleaning, and personnel and management of both the financial and technical
training. resources for a given project. The ultimate responsibility
As previously mentioned, it is important to assess as far as the regulatory agencies are concerned remains
internal resources at the beginning of a project to schedule with the company—whether large or small—so it is
activities appropriately, especially in terms of analytical essential that control of the business is maintained at
testing. A small firm may be overwhelmed by the amount all times.
of test samples and commitment time required to analyze
samples. Contracting with an outside analytical testing
laboratory to back up the primary analytical laboratory BIBLIOGRAPHY
will reduce delays with respect to validation testing and Carleton F, Agallaco J, eds. Validation of Pharmaceutical
overall timelines, but can add up to three to four months Processes Sterile Products. 2nd ed. New York: Marcel
to the schedule, for the most part related to methods Dekker, Inc., 1999.
transfer. This will only pose a problem if it is not ISPE. GAMP Good Practice Guide: Validation of Process Control
accounted for early in the planning and scheduling Systems, 2003.
process. At the same time, validation costs will increase Institute of Validation Technology. J Valid Technol 2004; 10(2).
because it will be necessary to transfer the methods to an Institute of Validation Technology. J Valid Technol 2004; 10(4).
outside laboratory before validation test samples can be Kropp M. Pharma’s continuing validation challenge: remedia-
tion for 21 CFR Part 11 compliance. Am Pharm Rev 2004;
analyzed. The transfer procedure can be performed early
7(3):10–2.
in the project cycle after the methods have been validated, Loftus B, Nash R, eds. Pharmaceutical Process Validation, Vol.
so that the contract laboratory will be ready when the 23. New York: Marcel Dekker, Inc., 1984.
validation project begins. If the manufacturer does not U.S. Department of Health and Human Services, Center for
have an analytical department, it may be cost effective to Drug Evaluation and Research. Guideline on General
utilize the laboratory that developed and validated the Principles of Process Validation, May 1987.
methods to reduce redundant activities and added delays U.S. Department of Health and Human Services, Food and Drug
by searching for a new laboratory. In either case, the Administration, Center for Drug Evaluation and Research.
project manager will need to ensure that timelines accom- Chemistry, manufacturing, and controls documentation.
Draft Guidance for Industry: Analytical Procedures and
modate a need for external resources.
Methods Validation, August 2000.
U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research.
CONCLUSION
Pharmaceutical CGMPs. Guidance for Industry: PAT—A
As stated in the introduction, validation principles are a Framework for Innovative Pharmaceutical Development,
tool that, if applied properly, will result in a significant Manufacturing, and Quality Assurance, September 2004.
amount of scientific data for a given manufacturing U.S. Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research.
process. A validation program should be a baseline for
Pharmaceutical CGMPs. Draft Guidance for Industry:
the industrial pharmaceutical scientist to use in tracking Quality Systems Approach to Pharmaceutical Current
the process output throughout a product’s lifecycle. For Good Manufacturing Practice Regulations, September 2004.
small pharmaceutical companies without the resources U.S. Department of Health and Human Services, Food and Drug
available at large companies, a well-organized validation Administration, Center for Drug Evaluation and Research.
plan is essential to a smooth, cost-effective process. The Guidance for Industry: General Principles of Software
focus of the validation project manager should be to: Validation—Final Guidance for Industry and FDA Staff,
1. Prepare and define the overall validation activities for January 11, 2002.
both management and the validation team members. U.S. Food and Drug Administration, Office of Regulatory
2. Structure the activities in order to integrate them into Affairs, Office of Regional Operation, The Division of
Field Investigations. Guide to Inspections of Validation of
the overall organization without disrupting
Cleaning Processes, July 1993.
daily operations. Wrigley G, du Preez J. Facility validation: a case study
3. Identify the most competent and team-oriented indi- for integrating and streamlining the validation approach
viduals within the organization and make them part to reduce project resources. J Valid Technol 2002; 8(2):1–22.
of the validation team. Zaret E. The Value of Validation, Pharmaceutical Formulation
4. Complete the project on time and within budget. and Quality, June/July, 2002:47–8.