Using a Delphi Survey to Assess the Value of Pharmaceutical Process Validation Part 1: Survey Methodology

By Marjo-Riitta Helle,Jukka-Pekka Mannermaa,Mika Reijonen

Despite the long history of pharmaceutical validation, process validation in pharmaceutical manufacturing continues to be topical. European regulations regarding process validation were renewed in autumn 2001, which again brought the subject under the spotlight. Many people working in pharmaceutical production are now reviewing the state of their compliance practices and posing the question: "How will we benefit from process validation?"
To estimate the value of process validation, a systematic evaluation of the collected opinions and experiences of it was performed using technology assessment (TA). TA is an evaluation process that aims to protect people/society from the consequences of rapid technological developments and attempts to identify all the possible impacts of a technology, not just the intended ones.1 Today, technology in this context refers not only to the logical products of science, but also to the attitudes, processes, apparatus and consequences associated with it, and in that wider meaning, the principles of TA are well suited to the evaluation of process validation as a tool for pharmaceutical manufacturing.

Changes in the Delphi survey

There are a number of different methods of TA; this study used the synthesis (the compilation and evaluation of all available knowledge1) method. Initially, a literature search was performed,2 which revealed a lack of European experts' comments. Therefore, during autumn 2001, an experimental survey was conducted amongst European experts in pharmaceutical fields of manufacturing, regulation and academia to unearth their opinions. Objectives The main objectives of the study were to explore the value of process validation and to ascertain the best tools to perform it. Additionally, the study provided an opportunity to test how the principles and methods of TA could be used in the field of pharmaceutical quality assurance.
Methodology Given that there is no single solution to process validation and that the value of process validation cannot be evaluated by using solid empirical measurement, but rather by informed judgement, 3 a discussion group was found to be an effective method for collecting information. For this reason, the Delphi method was chosen.
Delphi method. The procedure used in the Delphi method aims at structuring and distilling the mass of information from a selected group of experts by means of a series of questionnaires based on a structured process with controlled feedback.4 Moreover, this method was chosen for the following benefits:

• it enables participants from various countries and different fields (industry, authorities, schools) to take part
• it allows anonymous participation; a benefit that was of special value because the survey intended to facilitate discussion between the industry and its authorities, and to obtain comments from different organizational levels
• participants can take part asynchronously; that is, one may choose when to participate
• participants can choose to contribute to areas in which they are best qualified.

For development in the Delphi survey, see sidebar "Changes in the Delphi survey."

Figure 1 and Figure 2.

The Internet and e-mail. To accelerate communication, the Internet and e-mail were used. Using the Internet was also beneficial because it offered supporting tools for group communication, such as the potential for online discussion.6 Furthermore, the Internet provides a better and more illustrative means of informing the participants of the survey's key elements. Principles of the Delphi technique Although TA synthesis methods are frequently used to predict future scenarios, they can also be employed to critically examine the state-of-the-art of a given field.1,7 One of the most popular tools of synthesis is the Delphi technique. The aim of most Delphi techniques is the reliable and creative exploration of ideas or the production of suitable information for decision-making.
The replies to one round of questions are summarized and used to construct the next questionnaire. This reiterative process is continued until consensus or clear disagreement is reached among the participants.
Locating experts One disadvantage of the Delphi method is the definition and selection of experts; that is, whom to regard as an expert and how to create a representative group.
For this survey, experts were defined as those people working on process validation in:

• the pharmaceutical industry
• pharmaceutical authorities
• pharmaceutical schools
• consultant companies.

Representatives of the pharmaceutical industry were chosen from quality assurance, production and product development positions; representatives of the authorities had to either evaluate pharmaceutical and chemical aspects of the marketing authorization applications or work in inspection; and the representatives of pharmaceutical education had to teach process validation. Further details were unspecified; educational background was disregarded and the objective was to obtain the widest possible representation of different organizational levels. The level of experience of pharmaceutical process validation would have been of interest, but because of the limited number of experts in the field, this issue was not used as an exclusion criterion. Given the pharmaceutical industry's sensitivity concerning knowledge sharing and to get both the regulating authorities and the regulated industry involved in the survey, anonymity was regarded as essential.

Figure 3 and Figure 4.

The search for participants took 5 months and was the most challenging part of the survey, particularly contacting industry experts because their e-mail addresses could not be located. To find suitable people from the pharmaceutical industry, a snowball method was used.23 Additionally, addresses for quality assurance, product development and production experts were requested from the representatives of appropriate foreign companies in Finland and from the qualified persons of appropriate domestic companies. However, only a few participants from the foreign companies participated because the representatives did not know who the right people were to ask, or the company refused to participate because of time constraints. The only effective way of obtaining willing participants was finally found to be direct telephone contact; this method also worked well for all three pharmaceutical fields. The size of the expert group is also important to the outcome of a Delphi study, but it depends on the homogeneity of the expert population and whether the study searches for qualitative or quantitative results.23 Other Delphi surveys have varied in size from 10–15 up to 2000–3000.23,24 For this survey, the number of experts was limited and the study mainly searched for qualitative results. Thus, a group of approximately 30–50 participants was considered apposite.
The questionnaires An extremely important part of the Delphi method is the questionnaires, particularly the first round questionnaire (Q1). Q1 needs to be easy and clear, to motivate and encourage the respondents; otherwise they may lose interest.
The design of the questionnaires was carefully discussed by the advisory group before the start. The objective was to form easy-to-use and fast-to-complete questionnaires. It was agreed to keep the number of questions to a minimum and to limit the use of open-ended questions. Not only would these measures avoid making the survey too time consuming, but they would deter those who would use these factors as reasons for abandoning the survey. The use of open-ended questions is, though, often found necessary to eliminate the possible external bias linked to the guiding role of the investigator.7 Instead of open-ended questions, the external bias was eliminated using a mixture of negatively and positively influenced arguments. The questionnaires were also pre-tested with a pilot study among the advisory group and external experts.
Although the aim was to identify the attitude on the usefulness of pharmaceutical process validation, a further aim was to establish whether there are differences in attitudes between European countries or the different parties.
Operationalization of the subject was done under five headings:

• How do you feel about process validation?
• What are the benefits of process validation?
• What are the negative aspects of process validation?
• How can we make process validation easier and more effective to get the most from it?
• What hinders positive thinking on process validation?

The first three questions were designed to measure the overall attitude towards process validation and the final two were mostly determined the reasons underlying the attitudes, and also attempted to find out if some specific tools of process validation were known among the participants.
The initial round started with a background information questionnaire, which also included one final question estimating the overall opinion on process validation. This questionnaire was to be completed before commencing Q1, and thus, the last question served as a control, measuring the attitude at the beginning of the study. The same question was repeated at the end of the second round questionnaire (Q2).

Figure 5: Pharmaceutical participant demography: gender, education and age.

Q1 consisted of 31 questions, most of which were multiple-choice. Only three of the questions were open-ended to increase the inclination and quality of personal expression. Q2 included some new or modified questions, but most were repeated in their original form together with a summary of the answers from Q1. In Q2, the opportunity to add comments was provided after every question and was encouraged by offering participants the option to answer in their native language. Also in this round, the questions were posed in a slightly different order, with the addition of one new heading - "Cost of validation." In Q1, questions concerning the cost of validation had been spread under other headings.
The Internet as an environment for the survey The WebCT (WebCT, Inc., Lynnefield, Massachusetts, USA) learning environment26 was chosen as the platform for the survey because it was already being used in Helsinki University and offered the required tools. Extranet homepages were constructed and the questionnaires, together with supporting communication tools and information pages, were available from the Internet public page. The participants were e-mailed the passwords required to access these pages.
Guidance and other information, including definitions of the critical terms, were offered on the homepages and an online forum was available for anonymous discussion. The discussion area was continuously available and an online forum was organized twice during the survey - before and after Q2. The surveys' Internet public homepage can still be viewed.
Methodological results Response rate and expert demography. Of the total 73 used e-mail addresses, 36 experts' responses to Q1 were received, 28 of whom continued to Q2. Thus, the response rates were 49% and 38% respectively, for Q1 and Q2.

Table I: Visits (hits) on the information pages during the survey.

Some of the experts' demography can be seen in Figures 1–5, which show a comprehensive variation in their background. There were participants from Finland, Denmark, France, Germany, the UK, Norway, Sweden, Belgium, Iceland and Switzerland; however, the number of participants from each country was not equal. Activity reports Throughout the survey, the level of activity from the participants varied. During Q1, 19% wrote extra comments in their answers, but in Q2, 46% wanted to define their opinions and, therefore, expanded on their answers.
Some participants experienced technical problems and requested an extension of the deadline. At the beginning of the study, it became apparent that entering the Extranet pages was not possible for all participants because of problems with firewalls or browsers. For these individuals, an HTML alternative was provided. Eight respondents used this alternative in Q1 and three in Q2.
At the start of the survey, one participant initiated an Extranet discussion, however, no one replied. Thirty nine per cent had visited the discussion page, but only 8% had read all the comments on that page. No one took part in the two organized online forums.
From the system report, it could be seen that 69% of the participants had visited the Extranet pages not only to fill in the questionnaires, but also to check the other information available on the pages (Figure 6). The average time to fill in the questionnaire was approximately 5 min for background information, 21 min for Q1 and 41 min for Q2.
Respondent feedback At the end of the survey, respondents were offered the chance to provide feedback on the survey through an anonymous evaluation form. Only four participants returned the form, all of whom found the subject of the survey interesting, and three out of the four found the methodology suitable for the survey. No one found the Internet technology difficult to use. All found the instructions clear, and that the survey matched their expectations. Two had participated because of interest in the subject, and three out of four gave lack of time as a reason for not participating in discussion and the online forum.
Discussion Altogether, the methodology worked fairly well for this type of opinion survey. The number of respondents and their written comments indicated that most welcomed the opportunity to express their views. The Delphi method fulfilled the expectations and was the appropriate tool for contacting experts anonymously.
The Extranet homepages of the WebCT functioned satisfactorily for the survey. All the necessary information could be offered in an illustrative format, and the completion and sending of the questionnaires was simple. However, as WebCT is mainly provided for the education market, some unnecessary instructions and numberings could not be deleted or changed, but according to the respondents' feedback, these minor issues did not cause the participants difficulties. The major challenges of the Extranet were the firewall and browser problems, which should, of course, have been eliminated beforehand for all participants. Because these problems arose unexpectedly, the only solution was to offer HTML, which meant missing all of the other information given on the Internet pages. Apparently, many lost interest because of this and the majority of the respondents who used the hyperlink in Q1 discontinued the survey in Q2. The opportunity for discussion and online debate was not utilized even though the availability of these functions was highly underlined.
The biggest problem to overcome was the participants' lack of time. This reason for not participating was given mainly by the representatives from the pharmaceutical industry. The authorities were mostly willing to participate, but, only one or two participants were gathered from each country. The pharmaceutical schools found the subject interesting, although some doubted their suitability.
As previously mentioned, using e-mail to contact potential participants was insufficient. Of course, some of those who did not participate may also have considered themselves not to be experts in the field and, therefore, excluded themselves. Other probable reasons for not participating after receiving the e-mail request may be because not all people are fully familiar with electronic communication, and the explosion of the quantity of information through the Internet and e-mail has caused a need for filtering information. The latter may be one reason for the reported lower response rates for e-mail Delphi surveys compared with the postal versions. However, in this survey, more participants were willing to continue to Q2 than in many comparable surveys in which the response rates normally fall dramatically in the second and subsequent rounds.
A group size of approximately 30 proved satisfactory to gather overall information regarding pharmaceutical process validation opinions. The group cannot be regarded as very homogeneous because it consisted of experts from 10 different European countries from the three different parties. Thus, the group was representative of the expert population despite the limited total number of participants. As can be seen from Figure 2, all the participants, with one exception, reported that they practiced, taught or controlled process validation in their work, and they can, therefore, be regarded as experts. It is important to note that above a certain threshold, the inclusion of more respondents only contributes to marginal statistical and qualitative improvements.
Conclusion The Delphi method was found to be a suitable tool for measuring opinion in the pharmaceutical field. It is particularly useful in the pharma-ceutical manufacturing sector where the discussion between the regulated industry and the regulators is often difficult to achieve on a "neutral" basis in face-to-face-meetings. Because of this gap between the two parties, many regulations are accepted by the industry without official criticism and real assessment, and as a consequence, a lot of unnecessary work is performed. The Delphi method offers a perfect tool for this type of situation - it can be organized anonymously and can bring together geographically dispersed experts.
The use of the Internet and electronic communication gives the method clear advantages - the survey can be organized much faster, the group size can be easily increased and a lot of supporting information can be provided. However, in a climate where the quantity of electronic information is ever increasing, there is a high chance that some may be in part ignored; this is a threat to the use of electronic communication. For this reason, the Internet Delphi demands high motivation of the participants; ideally, the method can then be used in situations where the participants clearly see the advantages of participating, and where they can be entitled to participate without the fear of time constraints. If these prerequisites can be granted, the Internet Delphi can be used for systematic assessment of any kind of new technology or methodology in pharmaceutical manufacturing or pharmaceutical quality assurance. There should, however, always be available at least one independent, neutral person to serve as a reporter between the rounds and after the survey. Furthermore, the possible firewall and browser problems have to be taken into consideration before the start of the survey.

Changes in the Delphi survey
Figure 1 and Figure 2.
Figure 3 and Figure 4.
Figure 5: Pharmaceutical participant demography: gender, education and age.
Table I: Visits (hits) on the information pages during the survey.

Optimizing resources and minimizing risk

By Henrik Johanning

An electronic object-based approach towards validation is forecasted to be the upcoming validation paradigm supported by reliable web-based technology, organizational focus on risk management and overall enterprise effectiveness.

Life science organizations face corporate governance, enterprise risk management, legal, and internal policy mandates that are increasing in frequency and cost. How life science organizations face product and process compliance issues affects not only the risk of noncompliance, but also their operational viability and, ultimately, their competitive advantage.
Commonly acknowledged problems with paper-based compliance procedures commonly used by the life science industry, including Big Pharma, are:

• Lack of compliance, consistency and accountability in processes.
• High resource requirements for quality assurance (QA) in critical and noncritical processes.
• Suspicious audit trails and low reuse of knowledge across the enterprises and industry.
• No electronic signatures or electronic submissions.
• Uncertainties over the correct enterprise, product and process compliancy level. When is it lean?

Figure 1

All pharma manufacturing processes and related IT systems must be validated and documented according to compliance with the FDA cGMP, ISPE GAMP 4 Guidance, ISO 17025, Eudralex Legislation and GxP Guidelines. As most validation processes are paper-based, life science companies spend a lot of skills and resources on preparing, controlling, approving and archiving validation documents and records throughout the entire product life cycle (Figure 1). Business operational risk and regulatory compliance place an increasing burden on life science companies for the following reasons:¹

• Regulations apply across the entire product life cycle in the life sciences. After securing compliance with the previously mentioned regulatory policies and guidelines, new legal compliance issues are constantly being added.
• International operations and markets increase complexity. Life science companies that produce drugs are some of the world's largest and most globally distributed firms. They must control far-ranging operations and navigate a complex set of local restrictions on promotional and sales activities, which vary across markets. Global standards are also becoming an imperative.
• Multifaceted partner relationships dominate. Worldwide drug supply chains include a complex network of manufacturers, wholesalers, secondary distributors and retailers, all with independent risk mitigation issues.
• Mergers and acquisitions complicate business operations. During the past 7 years, the life science industry has seen record merger and acquisition (M&A) activity in both number (650 M&As in 2005) and size. Rapid M&A activity creates broken and inefficient processes as companies struggle to integrate new operations while maintaining regulatory validation. The operational landscape is further complicated by the industry's growing use of outsourced or offshore vendors to supplement internal resources for clinical trial data management, application development and IT system management.

These key business drivers force life sciences to move from paper-based compliance environments towards applying new information and communication technologies; that is, electronic compliance, which ultimately should demonstrate patient safety and product efficacy as demanded by legal authorities. From an enterprise perspective this transformation should also result in:

• Faster clinical trial completion.
• Faster regulatory approval.
• Faster marketplace introduction and, therefore, longer patent utilization. This results in significant financial and competitive advantages, and shorter pathways to patients.²

The overall conclusion is that life science companies need governance, risk and compliance software platforms (GRC) to drive sustainability, efficiency and consistency in managing enterprise risk and compliance. The GRC software platform market has grown from $85 million (€62 million) in 2002 to $590 million (€434 million) in 2006. Forrester projects that the GRC market will expand to $1.3 billion (approximately €0.95 billion) by 2011; that is, an annual average growth on $142 million (approximately €104 million) in this 5-year period (i.e., 24% annual growth rate).^{1, 3, 4} In particular, GRC platforms based on an object-based validation methodology, compared with traditional document-based GRC software platforms, are expected to experience a high growth rate because several immediate advantages and cost-savings are achieved.
In object-based validation, an object should be considered a well-defined entity or collection of records. This could be fields, sections, documents, tests, results, test plans or requirements. Object-based validation defines and uses entities for validation purposes. This provides better traceability (and thus transparancy), learning and reuses previous object validation, making it more efficient and economic. Validating an object using this method eases the validation of that object used elsewhere. What object-oriented programming did for software development, object-based validation will do the same for validation.
GRC platforms enable life science companies to establish a platform that maintains a single and consistent system of objects for enterprise risk and compliance while managing the intricacies and relationships of risk and compliance. They feature four types of capabilities:

• Policy, procedure and control documentation.
• Risk and control assessment.
• Risk analytics.
• Loss, event and investigations management.

Traditional GRC software platforms and test management systems with these capabilities exist so that life science companies can cope electronically with some of the business and environmental drivers mentioned previously. However, no tradition GRC software has:

• An object-based validation-approach meaning that specific content 'within' and 'across' validation documents can be linked and re-used in subsequent change requests (CR's) and deviations (e.g., the user requirement specification document [URS]) and all related specifications, designs and reports.
• No traditional GRC software supports the entire life cycle validation process via a single platform.

Figure 2

Object-based systems process information in a database rather than in free-format documents. The user is allowed to produce the same types of documents as in the document-based approach, but the documents are collections of specific data (database reports) rather than traditional documents. Moving from the document-based approach to the respective object-based approach, it is possible to link different records so that a particular URS can be directly linked to functional specifications, risk assessment, design records, commissioning and validation. This allows the documentation to be reused. Also, requirements that in an earlier CR resulted in deviations can be alerted as probable future deviations and handled and modified accordingly. The object-based approach is depicted in Figure 2, illustrating the key difference between traditional document-based GRC systems and a respective object-based system. Figure 2 illustrates how multiple records can simultaneously constitute both documents and records. The "!" symbolizes a deviation, which is related to the respective record and allows for active feedback.
Overall, object-based validation will enable life sciences to:

• Reuse records and benefit from earlier project knowledge.
• Reuse templates and forms, and conveniently reproduce records in printed documents.
• Link and trace records with different, subsequent validation records.
• Have multiple authors and privileged users.
• Improve reliability (transparency and access to earlier project knowledge and deviations).
• Provide a 360-degree view from risk assessment implementation in CRM when receiving and reporting on a customer complaint to back-end life cycle stages.
• Proactively monitor and control projects.

Recommendations
Intelligent use of information communication technology manifesting itself in a web-based thin client/thick server solution, including an object-based validation methodology in GRC applications, will ensure true electronic record compliance with regulations, and full traceability across and within structured documents instead of managing documents in a traditional document management system.
While the advantages of using an electronic object-based validation methodology are obvious, it requires that any company introducing such a system has full control of its own processes. It is impossible to introduce such a system without a specific idea of what processes and procedures it has to follow, the roles of each user, and which templates to follow. Without this, no electronic system will be successful.
An object-based system may, however, be the exact push that the organization needs to succeed with its validation processes, and the only way to ensure true compliance because no paper-documented process can ever be performed without errors in relations, violation of written procedures or basic errors in GMP.
Conclusions
Transformation towards electronic validation using web-based technologies securing global standards, coupled with the benefits of an object-based validation methodology demonstrate performance increases available to life science companies as they continue to use and maintain this new paradigm throughout product life cycles. This is because of extensive reuse of earlier documentation and project knowledge (including deviations), monitoring, project transparency and reporting facilities. A document-based, validation process however, whether paper-based or electronic, is predicted to limit life science companies in their efforts effectively minimizing documentation costs and resources.
References
1. M. Rasmussen, "The Forrester Wave: Governance, Risk, And Compliance Platforms, Q1 2006," Forrester, March 2006.
2. US Department of Health and Human Services, Food and Drug Administration, "Guidance for Industry, Fast Track Drug Development Programs — Designation, Development and Application Review," (January 2006).
3. M. Rasmussen, "Will The Real Risk And Compliance Vendor Please Step Forward? Defining The Risk And Compliance Market Landscape," Forrester, November 2005.
4. IBM Business Consulting Services, "The Metamorphorsis of Manufacturing," IBM (2005).
Henrik Johanning is director and executive advisor at QAtor A/S (Denmark), and a member of Pharmaceutical Technology Europe's editorial advisory board.

Figure 1
Figure 2

Essentials of Validation Project Management Part I

By William Garvey

VECTOR CORPORATION

The qualification and validation of complex pharmaceutical manufacturing facilities requires the careful coordination of multiple activities. Conceptual, preliminary, and detailed designs must be reviewed to ensure compliance with current good manufacturing practices (CGMPs); protocol and standard operating procedure (SOP) formats must be developed; and project resources must be identified and obtained. A validation schedule must be created and integrated with the facility construction schedule. The Quality Assurance and Calibration–Metrology departments must be notified of impending increased workloads. And finally, the manufacturer should alert the local US Food and Drug Administration district office that a new facility is planned. Considering all these activities, careful planning and cautious management will increase the likelihood of a successful project outcome, no matter how difficult or complicated the project. Successful project completion is never guaranteed, but by implementing proven techniques and the programs described in this article, a favorable end-result is much more likely. Parts 1 and 2 of this article will examine seven critical components of a comprehensive validation program for new and renovated manufacturing facilities. The programs and procedures explained are appropriate for all commonly manufactured dosage forms (e.g., tablets and capsules, active pharmaceutical ingredients [APIs], parenterals). Given that the design, construction, and qualification and validation of a major facility are relatively infrequent events in most corporate life cycles, some of these project components are not well known or understood. For this reason, Part 1 of this article examines the following areas:

• facility- and equipment-design review to ensure compliance with CGMP regulations;
• project scope definition, organization, and planning;
• project labor requirements and budget;
• validation master plan development.

Part 2 will continue with a discussion of the following validation-related subjects:

• protocol and SOP development, scheduling, and implementation;
• design- and construction-document collection (turnover package);
• evaluation of deviations and discrepancies.

Facility- and equipment-design review
By definition, the construction of a new or renovated facility and the purchase and installation of mechanical equipment and process systems constitute a project. All projects have basic, common features: a logical start, a logical end, and little or no possibility of recurrence (i.e., the project will not repeat at some future time). In addition, the design process is common to all facility projects. All facilities start with a design, about which engineers, owners, scientists, and other stakeholders confer to determine how the facility will appear and operate and what equipment and systems are needed. The usual sequence starts with the development of a conceptual design by an engineering firm, from which preliminary decisions are made about facility layout and size, utilities required, and equipment capacity and material of construction. The process then continues into the preliminary and detailed engineering stages, in which costs are finalized and designs are completed and approved. It is at this point when the conceptual design transitions to preliminary engineering that formal review to verify GMP compliance begins.
In general, process equipment and utility systems affecting product quality or contacting product are the subject of design review. Typical reviewed utilities include heating, ventilation, and air-conditioning (HVAC), compendial waters (e.g., water-for-injection, purified water, clean steam), and compressed gases such as nitrogen and compressed air. At present, regulatory expectations for other utilities such as chilled water or plant steam are minimal, and these may be omitted. Design review is mandatory for highly customized or unique process equipment, particularly when the unit is custom manufactured. Equipment for critical processes such as aseptic filling and packaging, lyophilization, and final purification also requires rigorous evaluation. Because the GMP regulations are interpretive and nonspecific for equipment design and construction, the design engineer and owner are responsible for assessing compliance (1). During the design review stage, the engineer and owner should evaluate all critical specifications and drawings to ensure that regulatory compliance is achieved. In general, experienced vendors understand the requirements imposed by GMP regulations and design and construct their equipment and systems accordingly. Rarely are serious design and construction errors uncovered because a reputable vendor's knowledge and understanding of GMP-compliant design often exceeds that of the owner and engineer combined (2). Design reviews should be performed using a structured and systematic approach. For mechanical systems such as HVAC, the evaluation of drawing sets takes precedence over most other documents. Vendor submittals always should be reviewed. Although less beneficial, Division 15, 22, and 23 type construction specifications (3) also should be examined, even though these are often standard with little customization. Checklists and other reviewing aids may be valuable because they prove that the designs were evaluated and they may be used again for subsequent projects.
Three critical steps must be taken in a design review:

• identify and evaluate any potential areas or items of noncompliance;
• ensure that designs are modified to eliminate noncompliant features;
• prepare a brief report that summarizes the design-review process and obtain appropriate approvals, including quality assurance.

Much of the current content in both domestic and foreign GMP regulations is limited and nonspecific. The owner is obligated to review all designs and verify conformance with industry standards and regulatory guidelines. In the absence of standard equipment specifications within the GMPs, logic dictates that process equipment and utilities must be designed to be:

Figure 1: Valve orientation (45° above horizontal) and nonchloride insulation in purified water, USP system.

Nonreactive. Materials of construction must be inert and non-additive. Type 304 and Type 316 stainless steel are commonly used. Hastelloy C frequently is used in reactor systems and condensers. Wood should be avoided, even for utensils, because it can generate unwanted particulates and is porous and difficult to clean. Gaskets must withstand attack by process fluids and be dimensionally stable under expected temperature conditions. Chloride-containing insulation should not be used with stainless steel components (see Figure 1).

Figure 2: Fluidized bed dryer showing mechanical components requiring maintenance located outside the process space (photo courtesy of Vector Corporation).

Cleanable. Equipment surfaces must be smooth and free of voids and crevices in which material can accumulate. Welds must be polished smooth, although mirror polishing is not always recommended where glare is a concern. Short-radius corners are preferred at joined surfaces. Threaded fittings usually are not permitted on sanitary systems. Diaphragm valves must be installed on horizontal lines at 45° angles to ensure complete drainage (see Figure 1). Labeling and packaging equipment must be designed to permit thorough inspection. If cut labels are used, equipment should permit stray labels to fall to the floor unimpeded. Seamless floor coverings should be installed where practical because they prevent the infiltration and exfiltration of water and contaminants from and to sublayers. Valves and flanges should be minimized in concealed-piping runs over critical process areas where leakage or failure could be problematic.

Figure 3: Duplex steam-trap assembly at a critical air-handling unit.

Maintainable. Through-the-wall designs should be used where serviceable mechanical components are located outside process spaces (see Figure 2). Such items include HVAC air-control valves and instrumentation, process filters, and operator workstations. Remote grease fittings should be installed on fan bearings to minimize air handler entry. Adequate clearance should be allowed at heat exchangers to permit coil removal and inspection. Redundancy should always be considered for mission-critical systems, including sanitary pumps, steam traps (see Figure 3), filter assemblies and regulators, and recorders on sterilizers. Ergonomics also should be considered. Reliable and controlled. Control systems such as programmable logic controllers (PLCs) should be used to control equipment. Automation allows processes to be replicated without variability, a fundamental principle on which GMPs are based. Mechanical-type (cam) controllers should be avoided because regulations require that current and modern technology be used. Manual control also should be avoided where possible because replication is inherently difficult. Any system that may alter batch-to-batch uniformity, and ultimately the product therapeutic response, must be very carefully considered.
Correct for application. The correct design criteria must be specified. For example, clean compressed air must have a dewpoint temperature of approximately –40 °F to prevent condensation. Refrigerated air driers cannot meet this requirement. Oil-free compressors should be used to exclude oil contamination unless several levels of filtration are used (4). Industry standards allow no more than 1 ppm (1 mg/m³ ) of oil/hydrocarbon in compressed air.
Besides developing some original standards for process equipment design and construction, the pharmaceutical industry has borrowed standards from industries that produce similar consumer products, most notably the dairy industry. The 3-A Sanitary Standards are voluntary guidelines followed by dairy equipment vendors and dairy operators. The standards provide material specifications, design criteria, and other necessary information for the construction of dairy equipment to satisfy public health concerns. The ultimate objective is to safeguard public health from contaminated dairy products.
To meet this objective, 3-A Sanitary Standards and 3-A Accepted Practices ensure that dairy, food, and other microbial-sensitive products are protected from contamination; that all product contact surfaces can be cleaned in place or easily dismantled for manual cleaning; and that all product contact surfaces can be easily inspected to confirm cleaning effectiveness (5). The purpose of these standards and their application to pharmaceutical manufacturing are readily apparent. The 3A Sanitary Standards should be consulted when equipment such as holding tanks, clean-in-place systems, valves, and pumps are undergoing GMP compliance review. Design errors are uncommon, however, because most equipment vendors already fully understand and comply with these standards.
For high-value projects and facilities intended to manufacture sterile products, it is often required and worthwhile to contact the local FDA district office. This alerts the agency that inspections must be scheduled, often to coincide with critical construction milestones and events. FDA Office of Regulatory Affairs Field Management Directive (FMD) 135 also encourages manufacturers to contact FDA when facility and equipment designs are being prepared (6). The following is a summary of FMD 135, which can be found on FDA's Web site:
Providing [FDA] review and comment is desirable because it may reveal [design] defects early and prevent costly construction errors which could lead to defective operations and products. It also affords FDA the opportunity to become aware of future work load obligations and, in some cases, new technologies. Early field involvement with new or modified facilities will increase efficiency and result in the timely processing of applications (6).
Companies should understand and recognize that partnering with FDA to review proposed designs is beneficial to both parties. Costs and delays associated with rework can be avoided if problems are detected early. Definitive dates for facility inspections can be established, which serve as endpoints that motivate project completion. Current agency inspectional focus also may be apparent, foretold by the types of questions that are asked. Overall, early dialogue and FDA involvement may expedite facility completion, reduce engineering and construction costs, and lead to a smooth transition from start-up to operation. These results are desirable for all manufacturers, regardless of company size or complexity.
Scope definition, organization, and planning
Successfully implemented validation projects all begin with a well-defined scope (i.e., the set of activities and deliverables that must occur to complete the project). Scope definition is critical if contracted validation resources are used because it becomes the basis for cost estimates and assessing job completion.

Figure 4: Typical air-flow diagram for an API facility.

Validation project scope definition usually begins by reviewing the following drawings and documents (7):

• air-flow diagrams (see Figure 4);
• piping and instrumentation diagrams;
• utility-flow diagrams;
• equipment lists.

These four types of documents are common and essential to all validation projects, although the level of detail and content may vary. Design-document quality is usually closely associated with cost; the greater the upfront engineering costs, the more detail that can be found in drawings and lists. Because facility construction and protocol preparation require drawings that are detailed, accurate, and thoroughly checked, increased funding for engineering services is usually money well spent. In general, one can expect that the cost of facility-design services will be approximately 10–12% of the facility's total installed cost.
It is useful to identify project activities on a spreadsheet when establishing project scope. Systems and equipment requiring qualification and validation are first determined by reviewing the project documents described previously. Then, the spreadsheet is created and the first column is reserved for each identified system and piece of equipment. Adjacent columns become a matrix of activities necessary to complete system and equipment qualification. Column headings and subheadings usually consist of the following:

• document collection and review (to develop protocols and SOPs);
• calibration and metrology;
• protocol preparation (installation qualification [IQ], operational qualification [OQ], performance qualification [PQ], and cleaning);
• protocol execution (IQ, OQ, PQ, and cleaning);
• final reports;
• turnover packages (contain construction test reports, as-built drawings);
• SOPs (operation, maintenance, cleaning).

Table I: Estimated labor hours for commissioning and qualification.

A checkmark is placed in each cell for which a specific activity is required. This checkmark may be replaced eventually with the name of the individual responsible for the activity. Assigning labor hours to each checkmark is even more useful because this provides an estimate of the labor required for each activity and for the entire project (see Table I). Project labor requirements and budgeting
By revising the spreadsheet to include labor hours, and then totaling each row and column, a project labor estimate per activity and system can be derived (7). Dividing total project hours by 2080 h/year provides an estimate of personnel required to complete all activities. Total project headcount will vary depending on project duration, however. Anticipating the number of labor hours is important because the labor involved may exceed available resources, thus requiring that outside validation services be contracted. Assigning a dollar amount (e.g., $75) to each hour of labor provides an estimate of validation project costs, which often is used to justify requests for financial resources and to support the annual budgeting process.
Industry experience has shown that validation costs (excluding commissioning and process validation) typically range from 2.5–5% of the total installed cost of the facility. Aseptic-filling and biotechnology facilities frequently have the highest validation cost, whereas API facilities tend to be the least expensive. Care must be taken not to apply these guidelines too tightly because the percentage validation cost will vary with project size. As an example, the purchase and installation of a small steam sterilizer might have a total installed cost of $150,000; however, the validation costs may exceed $50,000 (33%), when protocol preparation and implementation, SOP development, and laboratory supplies are considered.
On validation projects, personnel are often subdivided into teams, with one team preparing SOPs, another team preparing protocols, and so forth. Alternately, one person may be assigned to a specific system, taking full responsibility for protocol and SOP preparation, implementation, and final-report development. The spreadsheet described previously helps with this decision. Either method is satisfactory, but the one chosen must account for personnel availability and future operational needs. Often, contractors are employed to prepare protocols and SOPs only, while implementation is reserved for company personnel. This approach has several benefits. First, the contractor travel expenses are minimized because all document development can occur in the contractor's home office. Second, protocol implementation is performed by those who will ultimately operate and maintain the validated equipment and systems. This process may reduce the transition time from start-up to manufacturing, and if properly documented, can satisfy GMP training requirements.
Validation master plan development
The validation master plan complements the project scope. Although master plans are not officially required by some regulatory agencies, these documents may be submitted to FDA as part of the preoperational review program (FMD 135) discussed previously. Master plans typically describe the project scope in detail and include preliminary validation acceptance criteria. They also contain a description of all programs that collectively make the facility GMP compliant. A well-conceived and well-written master plan reduces the likelihood that a critical activity or program will be omitted and provides regulators with a sense that the company is quality-minded and operating in a state of control.
Once the project scope is determined and reduced to spreadsheet format, the spreadsheet may be imported into the draft validation master plan. Master plans usually are focused on project deliverables, not costs. Therefore, estimated costs and labor hours do not need to be presented. There is no standard format for validation master plans, although the concept has evolved so that many features are standard from company to company. Each master plan is an analysis and evaluation of a manufacturing facility's validation and compliance requirements. Typical master plan contents include the following:

• approval page (quality-assurance approval is required);
• introduction and facility description;
• project organizational chart (optional);
• descriptions of component and material storage areas, production areas, quality assurance areas, critical utility systems (HVAC, purified water, water-for-injection, building management system);
• spreadsheet (described previously);
• system and equipment descriptions (in sufficient detail for importation into corresponding protocols);
• preliminary acceptance criteria (for each system and piece of equipment);
• SOP listing;
• other GMP-required activities (document control, training, environmental monitoring, and so forth);
• drawings, particularly facility layouts, piping and instrumentation diagrams, and air-flow diagrams.

If possible, special or unique features should be emphasized in the master plan, especially those that ensure product uniformity or the elimination of contamination and cross-contamination. These features might include a description of extract booths, personnel showers, and isolators used during toxic materials processing. Room air-change rates, personnel gowning practices, and decontamination with formaldehyde or vaporized hydrogen peroxide also are worth mentioning. It is important to convey quality and attention to detail in the master plan because this document is approved by the Quality Assurance department and often is reviewed by FDA.
Other programs to describe in the validation master plan are the facility revalidation program, turnover package development, and system or equipment commissioning. With the publication of the International Society for Pharmaceutical Engineering's Baseline Pharmaceutical Engineering Guide: Commissioning and Qualification in March 2001, greater emphasis has been placed on system and equipment commissioning (8). Until recently, commissioning was an activity often performed without any involvement of quality assurance or validation personnel. The construction team or an agent hired by the project manager usually performed system commissioning. Commissioning documents were often prepared and executed without any review or oversight by the Quality Assurance department. In many instances, validation often repeated common commissioning tests and verifications, thereby increasing costs and creating inefficiencies. In addition, systems often were commissioned and validated where commissioning would have satisfied operational requirements. It is worthwhile to identify and describe the interaction between commissioning and validation in the master plan. The plan may include a description of required commissioning documents and how they support the validation effort. In general, systems that have no product contact are good candidates for commissioning only, although there are occasional exceptions to this rule.
The facility revalidation program also should be described in the master plan because the validation life cycle continues long after the facility is mechanically complete and handed over for operation. Revalidation usually takes two forms: time or event based (9). Time-based revalidation is the practice in which a system or process is recertified at a specified interval. Time-based assessments also can include a review of historical system performance data. Event-based revalidation is implemented whenever physical or operational changes are made to the system outside the scope of the original validation. All such modifications are the subject of the facility's change control program, which also should be described in detail in the master plan.
Turnover package (TOP) development also can be described in the master plan. Turnover package is a system for organizing all documents related to facility and system design, construction, and start-up relevant to the eventual commissioning and qualification of systems and equipment (10). Turnover packages are usually prepared by the construction manager and turned over to the owner at project completion. TOP documents construction activities and contributes to system IQ, OQ, and PQ and usually is a prospective or concurrent activity (i.e., design, construction and start-up documents are compiled as system construction proceeds). Turnover packages will be discussed in detail in Part 2 of this article.
Summary
This article provides a basic introduction to four components that are fundamental to all successful validation projects. Part 2 will describe three additional programs that should be considered and implemented. Before undertaking any validation project, careful planning to arrive at a logical, uncomplicated approach is required. All projects are labor and capital intensive, and incorrect or inefficient use of either resource ultimately escalates cost and extends the schedule.
All validation projects must begin with a comprehensive design review and include FDA assistance if necessary. Once a compliant design is finalized, validation project scope must be established and properly communicated to all project stakeholders. Concurrent with project-scope definition is the development of a labor estimate, and by extension, a cost estimate. Knowing labor requirements and costs early helps identify potential shortfalls in personnel and permits appropriation of sufficient funding to complete the project. Accurately defining project scope also avoids misunderstandings, errors, and omissions when work is assigned to contractors and company personnel. A comprehensive validation master plan follows design review and scope definition in the project timeline. The master plan identifies critical project activities, communicates expectations, and conveys a quality mindset and state of control to regulators. Each of these project components, in conjunction with the guidelines and programs described in Part 2 that follows, helps assure that the project is completed on time and within budget. More importantly, quality is built into the project from the start, regulatory compliance is realized, and the transition from start-up to operation is optimized. In the current environment of cost control, expedited product introductions, and increased regulatory oversight, the benefits of efficient validation project management should be evident.
William Garvey is a senior advisor at Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, tel. 860.715. 2277, fax 860.715.7806, william.garvey@pfizer.com [william.garvey@pfizer.com]
References
1. US Food and Drug Administration, Code of Federal Regulations, Title 21 (FDA, Washington, DC, April 1, 2005), pp. 120–141.
2. W. Garvey, "Integrated Validation Programs for Solid Dosage Facilities—Part 1," Am. Pharm. Rev. 2 (2), 33–39 (1999).
3. The Construction Specifications Institute (Alexandria, VA).
4. Department of Health, Education and Welfare, "Human Drugs—Current Good Manufacturing Practice in Manufacture, Processing, Packing or Holding of Large Volume Parenterals, and Request for Comments Regarding Small Volume Parenterals," Fed. Regist. 41 (106), 22022–22115 (June 1, 1976).
5. 3-A Sanitary Standards Inc., McClean, VA.
6. FDA, "ORA Field Management Directive 135, Pre-Operational Reviews of Manufacturing Facilities" (FDA, Washington, DC, Dec. 4, 1995).
7. W. Garvey, "Effective Validation Project Management," oral presentation given at Interphex Conference 2005, New York, NY, April 26–28, 2005.
8. ISPE Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engineering Guides for New and Renovated Facilities, Vol. 5, Commissioning and Qualification, (International Society for Pharmaceutical Engineering [ISPE], March 2001), pp. 11–15.
9. ISPE Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engineering Guides for New and Renovated Facilities, Vol. 5, Commissioning and Qualification, (ISPE, March 2001), p. 111.
10. M. Chin, "TOP: A Rational Approach For Ensuring Proper Biopharmaceutical Plant Construction," in proceedings from PharmTech Conference '87 (Aster Publishing Corporation, Eugene, OR, 1987), p. 73.

VECTOR CORPORATION
Figure 1: Valve orientation (45° above horizontal) and nonchloride insulation in purified water, USP system.
Figure 2: Fluidized bed dryer showing mechanical components requiring maintenance located outside the process space (photo courtesy of Vector Corporation).
Figure 3: Duplex steam-trap assembly at a critical air-handling unit.
Figure 4: Typical air-flow diagram for an API facility.
Table I: Estimated labor hours for commissioning and qualification.

The Importance of Equivalence in the Execution and Maintenance of Validation Activities

 By James P. Agalloco
The author explains the idea of equivalence and describes how it can facilitate equipment validation.

It is common in the global healthcare industry to have multiple pieces of identical equipment available for the purposes of added capacity and redundancy. These circumstances provide opportunities to streamline qualification and validation activities. When several pieces of equipment are identical in all respects, the qualification effort should seek to demonstrate their basic interchangeability for all uses to reduce the needless repetition of activities. The qualification protocols should identify essential performance criteria for the equipment that each unit must meet to demonstrate its equivalence. The criteria used for this evaluation should be formal, quantitative, reasonably tight, and realistic (the performance of a single piece of equipment will vary over time).* Once equivalence has been demonstrated during the qualification effort, subsequent performance-qualification efforts should be divided between the pieces of equipment to reduce the number of studies that would otherwise be required.

The principles of equivalence can be adapted to several other instances in processing and analysis (e.g., containers, materials, formulations, analytical instruments, and personnel) where basic similarities in performance can be exploited to simplify the overall effort. The principle of equivalence is relevant to even singular instances. The fundamental precept of the US Food and Drug Administration's draft process-validation guidance requires that firms demonstrate the consistency of the process at various scales from development, through scale-up, and continuing into commercial manufacturing (1). At the core of that guidance is an expectation for process equivalence during the course of the initial effort and recommendations for controls that will ensure consistent production over the product's life cycle. The guidance implies the expectation for equivalent performance over scale and time; however it is unfortunately not explicit.

Other citations in the regulatory arena refer to equivalence in the execution of validation. These citations also are somewhat more implicit. In a 1994 Warning Letter, FDA indicated the basic requirements for equivalence:

It is FDA's position, however, that while it is possible to rely on validation data from one chamber to represent that of another, it is only possible to do so for chambers at the same location which are identical in all respects. That means the chambers are of identical construction and installation (i.e., identical plumbing, characteristics, steam supplies, operating environments, etc.) and the product(s) to be sterilized are equivalent in all respects (2).

This letter serves as perhaps the clearest statement with respect to equivalence ever made by FDA. As the letter applies to a sterilization process, one of the more crucial processes requiring validation, industry has every reason to believe that the agency would take a similar view with respect to less crucial process equipment.

FDA's guidance document on revisions to new drug applications (NDAs) and abbreviated new drug applications (ANDAs) come close to touching on the subject of equivalence as it relates to equipment, but focus on the performance of the drug (3). This document and the individual scale-up and postapproval changes guidance documents clearly imply that when individual machines are identical, the implications for process equivalence are clearer and more certain (4).

The cited NDA–ANDA guidance focuses on the potential effect of process changes on the drug product. The following excerpt provides insight into FDA's general expectations but, unfortunately, does not offer quantitative criteria to be satisfied:

When testing is performed, the applicant should usually assess the extent to which the manufacturing change has affected the identity, strength, quality, purity, and potency of the drug product. Typically this is accomplished by comparing test results from pre- and post-change material and determining if the test results are equivalent. Simply stated: Is the drug product made after the change equivalent to the drug product made before the change? An exception to this general approach is that when bioequivalence is re-documented for certain ANDA post-approval changes, FDA recommends that the comparator be the reference listed drug. Equivalence comparisons frequently have a criterion for comparison with calculation of confidence intervals relative to a predetermined equivalence interval. For this, as well as for other reasons, equivalent does not necessarily mean identical. Equivalence may also relate to maintenance of a quality characteristic (e.g., stability) rather than a single performance of a test (3).

Elsewhere in the NDA guidance, equipment elements are discussed in terms of their influence on bioequivalence. The following passage appears later in the same NDA guidance:

Minor Changes (Annual Report)—The following are examples of changes considered to have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.

1. For drug products, changes to equipment of the same design and operating principle and/or changes in scale except as otherwise provided for in this guidance (3).*

This reference is actually more flexible, in that it does not use the word "identical," but only mentions shared design and operating principles. Thus, equivalence in equipment may be more accepted than is ordinarily recognized. It may embrace different vendors, and sometimes encompasses different sizes of equipment.

Additional statements about equipment equivalence appear in various sterilization documents from the International Organization for Standardization. These statements are relevant for medical devices, but pharmaceutical and biotechnology firms seem rarely to consider them (5, 6). Nevertheless, the clear consensus is that demonstrating equivalence as it relates to process equipment is acceptable to regulatory authorities. But current guidances or standards that discuss equivalence lack a clear set of expectations for the demonstration of equivalence between multiple equipment units. The NDA and ANDA guidance document cites bioequivalence, but usually in terms of testing product that is many steps removed from where equivalence is being sought. The effect of essential unit operations such as sterilization, cleaning, and early process steps on bioequivalence is difficult, if not impossible, to discern. For these applications, one must consider how equivalence might be demonstrated independently of bioequivalence. Moreover, as stated consistently in the NDA–ANDA guidance document, bioequivalence is unlikely to be influenced meaningfully by equivalent, if not actually identical, equipment.

Real-world examples


Approaches to bracketing in process validation
Based on the clear support that equivalence seems to have, whether explicit or implicit, one might assume that the concept is in widespread use. Regrettably, industry seems to be reluctant to use it to design validation programs. When industry uses equivalence, little public information about its application and utility is available. This article draws extensively on the author's experience because of the paucity of published information about applying equivalence to the execution of validation studies. The following list of projects used the equivalent performance of multiple pieces of identical equipment to reduce the overall validation effort.

Nine identical ovens. One company used nine ovens to depyrogenate vials of 14 sizes. If equivalence were ignored, the number of studies required to fully validate minimum and maximum loads would be 756 runs (9 × 14 × 3 × 2). Equivalence and bracketing (see sidebar, "Approaches to bracketing in process validation") reduced the number of runs to 126 (9 × 2 × 3 + 12 × 2 × 3). The entire effort comprised the largest and smallest vials in all ovens in both load sizes, plus single-minimum and maximum load-size runs of the other 12 vials in one or more of the other ovens. Equivalence reduced the workload by 83%.*

Paired terminal sterilizers. A company planned to use identical units to sterilize 15 vial sizes filled with 32 formulations. A total of 56 possible product–container combinations needed to be validated. The validation was expected to cover minimum, maximum, and intermediate-sized loads. Without equivalence, the number of required validation runs to be completed would be 1008 (2 × 56 × 3 × 3). Extensive sterilizer-qualification, cycle-development, and water-challenge (covering five different vial sizes) runs were used to demonstrate the sterilizers' equivalence and to support load-size variation across the breadth of containers. The initial product validation of the sterilizers consisted of 54 biochallenge runs selected to broadly confirm the acceptability of the process for several of the formulations. None of the product loads were tested in triplicate. These data and those from the water-challenge runs, in conjunction with D-value determinations, was used to obtain initial facility approval. This information was supplemented postapproval with physical monitoring that reaffirmed the physical parameters for the remaining products, containers, and load sizes. The overall reduction in workload achieved through the use of equivalence was approximately 95%.

Other examples. In addition to the applications described above, the author has participated in the following validation projects in which equivalence reduced the overall effort:

    * Terminal sterilization
    * Part sterilization
    * Clean- and steam-in-place of fixed and portable tanks
    * Vial and stopper washers
    * Tablet presses
    * Coating pans and columns
    * Granulation vessels
    * Shelf, fluid-bed, and freeze dryers
    * Compounding of oral and injectable solutions
    * Mills and sieves
    * Blenders
    * Filling, packaging, labeling, and inspection equipment.

The abovementioned items represent the author's experiences and are not intended to be all-inclusive. One might reasonably expect to demonstrate equivalence for other items of equipment not indicated above. The increased use of automated monitoring and control in contemporary equipment makes it easier to demonstrate equivalence.

The keys to equivalence

Central to the use of equivalence is the establishment of criteria for the evaluation of the equipment's operational performance. This evaluation demonstrates that individual units perform identically. Criteria must be chosen with some restraint; adding too many criteria or nonessential criteria is unlikely to add meaningful value and more likely to result in the conclusion that the equipment is not equivalent. Common sense indicates that the criteria should focus on the crucial aspects of the equipment's performance. For sterilization processes, that most important criterion would customarily be F 0.* Other criteria in this determination for a sterilization process would add no meaningful value because these processes are intended to achieve lethal conditions. Criteria for other processes could be defined by their key performance measures (e.g., content uniformity, potency, fill weight, and residue level). Another possibility is to use a defined and calibrated test set as a standard for assessment. Test sets are ideally suited for attribute, foreign-particle, and label-inspection equipment and systems.

Regardless of what criteria are chosen, it is appropriate to establish in advance an acceptable range for equipment performance. In setting this range, one should consider the following factors:

    * The inherent analytical variability or measurement sensitivity used to assess the results
    * The normal variation in the underlying process
    * The limitations of sampling.

These factors should be first evaluated on a single piece of equipment in replicate studies in which these and other factors are assessed for their influence on the results. A single piece of equipment tested in replicate studies during a brief interval must be considered equivalent to itself. The actual variations between multiple items should be somewhat, but not dramatically, larger. In the absence of an independent assessment, the author suggests a range of not more than ±10% of the target value, which itself is an average of multiple preliminary runs.

Should the firm set overly restrictive criteria or the equipment prove not to be equivalent, nothing is lost. The accumulated data must be augmented with whatever added studies are necessary to complete the overall exercise without relying on the simplifying effect that equivalence can afford.

Time equivalence

An aspect of equivalence that has largely been ignored is that of time. It is essential that any process provide consistent results over time, whether the process is performed with a set of equivalent equipment or in a single piece of process equipment. This principle might seem obvious, but FDA codified that expectation in the draft revision of the Guideline on General Principles of Process Validation (1). The expectation that a firm can establish equivalence across multiple items at a single point in time is wholly appropriate for the same firm using a comparable approach to demonstrate the equivalence of the same piece of equipment over several points in time. This is a core expectation of the revised guidance and should raise awareness of equivalence as a regulatory expectation when FDA finalizes that document.

The use of statistics

For several reasons, this article has mentioned statistics only in passing. First, in applications where the author initially endeavored to demonstrate equivalence, he did not apply statistics beyond averages because complex tools were simply unavailable. Second, having demonstrated equivalence successfully without statistics, the author was loath to introduce it later on. Third, statistical requirements proved tighter than the process's capability in at least two instances. The implied direction of FDA's draft process-validation guidance leaves little doubt that statistics likely will play a larger role in future equivalence demonstrations. The author prefers to leave the selection of appropriate statistics to experienced individuals.

Conclusion

Validation is an essential component of operations in the pharmaceutical industry that conform to current good manufacturing practices, and one can expect it to remain a focus of regulatory attention. Validation has often been considered a costly and troublesome activity and one badly in need of improvement. Adherence to future regulatory guidance undoubtedly will mandate new validation studies. Equivalence affords an opportunity to realize a degree of economy in executing those expected new validation studies.

James Agalloco is president of Agalloco and Associates, PO Box 899, Belle Mead, NJ 08502-0899, tel. 908.874.7558, jagalloco@aol.com [jagalloco@aol.com]
He also is a member of Pharmaceutical Technology's editorial advisory board.

*Given the material and procedural variation, uncertainties of sampling, and inherent variability in analytical methods, even a nonvarying piece of equipment will demonstrate performance variation because of limitations in the method of measurement.

*Both statements imply that the production of natural protein-drug substances and drug products require additional caution.

*Bracketing is the practice of interpolating between extremes with respect to variables such as size, dimension, and potency under the assumption that intermediate situations will provide conforming results. Bracketing is commonly used and accepted independent of equivalence for the purposes of simplifying validation activities, but is also usable in conjunction with it.

*F 0 is coincidently defined as the equivalent sterilization time related to the temperature of 121 °C and a z value of 10 °C. It thus is uniquely appropriate for equivalence studies for steam-sterilization processes.

References

1. FDA, Draft Guideline on General Principles of Process Validation (Rockville, MD, Nov. 2008).

2. FDA, Warning Letter to Sterile Recoveries, Nov. 4, 1994.

3. FDA, Guidance for Industry: Changes to an Approved NDA or ANDA (Rockville, MD, Sept. 2004).

4. FDA, SUPAC-MR: Modified Release Solid Oral Dosage Forms—Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (Rockville, MD, Sept. 1997).

5. ISO, "ISO 14160—Liquid Sterilant Validation," (ISO, Geneva, 1998).

6. AAMI–ISO, "DS/ST63/2002-05-01—Sterilization of Health Care Products—Requirements for the Development, Validation, and Routine Control of an Industrial Sterilization Process for Medical Devices—Dry Heat" (AAMI, Arlington, VA, 2002).


Approaches to bracketing in process validation

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Validating Single-Use Systems

By Tony Hitchcock,George Saunders

This article is part of a special feature on single-use systems that was published in the October issue of PTE Digital, available at http://www.pharmtech.com/ptedigital1010.

Tony Hitchcock

There are a number of validation approaches that can be adopted — all of which incorporate the established approach of user requirement specification (URS), design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). Validating singleuse systems, however, requires a few changes of emphasis with respect to these specific steps. For singleuse systems in general, validation can be performed in three areas. The first relates to the actual process operation itself. This will be dependent on the intended use, e.g., aseptic operations, short or longterm product hold, levels of process closure, the stage of clinical development and whether or not the product being produced is for commercial supply. A riskbased approach will determine the validation programme based on the end use and process requirements. Secondly, it may be necessary to validate the manufacturing process for the singleuse components and the quality assurance systems applied by the supplier. Finally, the actual supply chain process of the singleuse system and the stability of the supply chain must be evaluated. The validation approaches will also very much depend on whether the system is standard or customised. Suppliers are now developing a range of standard packages for both components and control systems and, in such instances, validation packages can be obtained from the supplier, which offer significant cost and time savings.
Key points to consider
The key consideration for the validation of single-use systems is the recognition that much of the ownership of the quality systems will lie with the selected system's vendor. Additionally, as stated above, if the systems are part of standard packages then this also needs to be factored into the validation approach. Companies are developing increasingly detailed packages on leachables and extractables based on USP Class VI and European Pharmacopoeia requirements, as well as recommendations by user groups, such as the BioProcess Systems Alliance. A casebycase assessment is required to determine, for example, if the proposed process fits within the range of process fluids and operational conditions previously assessed by the vendor.
It should also be recognised that the use of the systems places much greater emphasis on the operators responsible for conducting system assembly procedures. In most cases, there will be a reduced capacity to verify systems ahead of manufacturing operations. Under these circumstances, IQ is required every time a system is used and the validation approach needs to take this into consideration. Assessment of OP and staff training is also required to accommodate the change in process risk.
The risks lie not only in the formation of secure connections between items, such as sterile welds and connectors, but also in connecting the various components correctly to form the intended assemblies. The impact of this is that in the initial design phases, thorough URS generation and DQ emphasis needs to be placed on how the system is to be used and how operations personnel will interface with the system, rather than assessing purely functional aspects. This, in turn, means that the process will require a high level of input from the operational team throughout the design and validation process.
Over and above validating the fixed plant and the process, the programme will involve reviewing operational procedures — many of which will be performed at a remote, third-party site. As such, the validation process will need to be more extensive with respect to vendor audits where the entire operational and QA systems of the selected supplier will be appraised. A much closer relationship between the supplier and end users will need to be established. One approach is to identify a limited number of preferred suppliers — based as much on quality systems and supply chain stability as price — and then to look at the procurement of new systems solely from pre-selected vendors. In addition, detailed assessments of operational procedures, including system assembly and the training of associated procedures will be required. This is where the highest risks are likely to lie in terms of operational errors and failed batches. Vendor selection
The vendor is now being assessed not just on price and quality, but on its whole business process — and on an ongoing basis. As a part of the vendor selection process, suppliers will need to demonstrate that they can establish long-term working relationships with customers. Additionally, the vendor audit process needs to become continuous rather than relying on singular assessments at set time intervals. The expectation of customers and the resulting vendor response to these requirements will have a significant impact on vendor selection, and QA groups will play a greater role in the approval and preselection of vendors. The capability of the vendor to be able to maintain long-term supplies of components will also be critical. Business stability, therefore, becomes even more important, as does the vendors' policies towards product and process change.
With respect to changes in component manufacturing procedures, this is a critical area — particularly in a field where rapid advances in manufacturing procedures are being made. This will also be an issue where designs of equipment are continually changing. In response, suppliers will need to develop agreed redundancy/obsolescence policies for older components.
Case study
At the 2nd Annual Disposable Solutions for Biomanufacturing conference held earlier this year, a case study was presented relating to the production of a monoseptic whole cell bacterial vaccine for Advaxis Inc. (NJ, USA). The requirement was to grow and then purify the cells by washing them with ultrafiltration membranes, and then formulating the product into a selected buffer. The aim was to achieve this as a closed process using singleuse technologies, and the process incorporated the use of Wave reactors, hollow fiber systems and a number of bag manifold systems.
The challenge was firstly in developing the technical platform to perform this operation and to maintain high levels of product viability, as well as achieving the required levels of purity and then to be able to validate the process to demonstrate the retention of monosepsis throughout. As the product was being produced under the EU clinical trials directive, there was the need for full validation of the process with regards to monosepsis, even though the product was only being used for earlystage clinical trials.
To achieve this, standard validation (DQ/IQ and OQ) was performed around the individual components and then three full broth simulations were performed within the facility followed by shipping studies to the site of drug product manufacturing, which was actually within the US. The process also included a significant amount of operator training and water simulation because it was essential to fully train the operators in all the key process steps ahead of these validation studies.
The take-home message was the need to retain and build upon existing validation approaches, and also to involve operators and QA staff in all stages of the development and design processes.
Tony Hitchcock is Head of Manufacturing Technologies at RecipharmCobra Bio.
George Saunders is Validation Manager at RecipharmCobra Bio.