Is FDA's Draft Process-Validation Guidance a Mixed Blessing?

By: Erik Greb

The US Food and Drug Administration’s Draft Guidance for Industry—Process Validation: General Principles and Practices provides a life-cycle approach for validating pharmaceutical processes and aims to help pharmaceutical companies achieve consistently high product quality. The document includes several concepts that are familiar to the industry but also contains ambiguities and recommendations that might be difficult for some drugmakers to follow.
The draft guidance suggests manufacturers establish links from their clinical process to their commercial-manufacturing process. This approach is similar to the one FDA has used in its preapproval inspections. If the guidance becomes final as it currently stands, manufacturers may be expected to use the data that they gain during formulation and development to define a product’s critical attributes, which would be the basis for the manufacturing-process parameters.
The agency points out that development and formulation data can improve a company’s understanding of its processes during scale-up and commercial manufacturing. This understanding would help companies control variability and increase product quality, says Chris Ames, director of global validation at Catalent Pharma Solutions (Somerset, NJ). Companies would submit these data to FDA to establish links between clinical and commercial processes.
But the draft guidance does not advise manufacturers about how to identify the most important characteristics of its product or manufacturing process, or about how to demonstrate links from the clinical to commercial process. “They’ve left it completely open to interpretation as to what data you provide and what format you use,” says Jim Agalloco, president of Agalloco and Associates. This ambiguity would suit Big Pharma because it frees companies to use their experience and discretion in deciding how to follow the guidance, says Agalloco. Small and emerging drugmakers, however, would likely be confused because they don’t have the depth of knowledge that would help them define critical attributes.
Some elements of the draft guidance resemble a Six Sigma approach to manufacturing, which is familiar to the pharmaceutical industry. The main similarity is the draft guidance’s recommendation of a statistical link that demonstrates that variability remains constant from the clinical through the commercial manufacturing stages. The statistical link is intended to confirm that processes are the same throughout all phases.
Although the draft guidance suggests statistical analysis, it leaves industry with only a broad understanding of what that means. FDA does not explicitly suggest that manufacturers use particular statistical tools, the agency simply recommends that companies apply good statistics to establish the links, says Agalloco.
The draft guidance suggests manufacturers define a process that can be measured, analyzed, improved, and controlled, and this approach is closely related to Six Sigma. The benefit of the Six Sigma technique is that it provides a mechanism for scientific review of a process, for assessing variability, and for identifying improvements, says Ames.
On the other hand, it is unclear whether the draft guidance recommends a product be refined in the way that a Six Sigma approach would. “To me, Six Sigma implies an acceptance by FDA that you might not have done a sufficient job in development and scale-up and are allowed to improve product and process while it is in operation,” says Agalloco. Patients’ experiences with a product might persuade a manufacturer that it should adjust one of the drug’s parameters to improve it. Six Sigma would allow postcommercialization changes to a product, but the draft guidance may not be compatible with them, Agalloco says.
Before it could submit a regulatory filing, a company would have to spend a great deal of time and money to better understand its ingredients, its product, its manufacturing process, its material handling, and associated variables. Pharmaceutical companies might object to the draft guidance’s approach because it suggests this expensive work be completed before commercialization, but the costs would not be recoverable before commercial-scale manufacturing began.
Although it is based on good science, if the final guidance is approved as drafted, it could easily increase drug-development time by one or two years, thus costing a manufacturer millions of dollars, says Warren Charlton, a consultant at WHC Bio Pharma Technical Services. Manufacturers would need to use smart strategies to shorten development time, but not knowing how much data regulators expect in a submission would make this strategy difficult.
The draft guidance inspired a huge volume of comments that will likely take FDA a long time to review, says Agalloco. Even though the guidance might not be final for at least a year, manufacturers would be wise to study it now and seek advice about interpreting it. In this difficult time for the pharmaceutical industry, no company can afford to ignore regulators’ recommendations, and advance preparation would be to a manufacturer’s benefit.

Contractee Responsibilities in Outsourced Pharmaceutical Quality Control Testing

aMethod Qualification (Verification and/or Validation)Once a contract testing laboratory has been given “approved” status, the actual methods to be used may be qualified for their purpose. If the contractor has a desired compendial method in place, the contractee is responsible for providing a sample of test material for verification according to compendial requirements. The US Pharmacopeia includes guidance on verification of compendial procedures (16). For noncompendial lot-release methods (e.g., viral and mycoplasma testing, which are driven by US FDA points to consider and ICH guidance documents), the methods will require validation if used for GMP purposes.
Validation is normally performed by a contract testing organization with a generic sample matrix, so it should not be confused with the product-specific qualification described below. Validation of compendial procedures is outlined in the US Pharmacopeia (17) as well as the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) (18). A contractee may wish to confirm the status of a given method by evaluating validation reports during an on-site visit. Contract testing labs may also be willing to provide copies of method validation reports or summary documents describing those results.
Commercial product lot release testing is expected to be performed using methods deemed suitable for a given product. This typically entails product qualification for the analytical method and evaluation of possible matrix interference. The contractee is responsible for commissioning such studies before routine use of any method and should maintain the resulting reports as evidence that the methods being used are suitable for their purpose. Such studies may need to be repeated if the processes involved in manufacturing a commercial product are modified significantly. Quality and Business Agreements Regulators expect that the relationship between a product sponsor and its contract testing partner be formalized by a quality agreement (7,8). Such agreements specify explicitly the responsibilities of each partner and provide the means by which a contractee extends its QC testing standards to a contractor. The agreement should list technical and/or quality contacts (names and phone numbers) at the contract testing organization as well as contact information for appropriate decision makers at the contractee organization.
Among the specifics to be detailed in a quality agreement are

• the types of compliance to be followed in contracted studies
• details on interactions between the contractor's and the contractee's quality systems
• requirements for equipment and assay validation, verification, and/or qualification
• assurance of quality and reporting requirements
• data recording and archiving practices
• conduct of investigations into nonconformances, deviations, unexpected, and OOS results (and timing of client notification)
• notification of regulatory inspection
• requirements for use of subcontracting laboratories
• use of debarred personnel
• availability of the contract testing laboratory for periodic technical and compliance as well as for-cause audits.

Business requirements should be addressed in a separate document and may take the form of a master service agreement, an agreement of scope, a pricing agreement, or a standard terms and conditions agreement supplied by the contractor. Such considerations may include assay pricing (including discount structures), assay initiation and report turn-around times, testing volume and exclusivity, availability of rush service and associated charges, and (in some cases) penalties for late reporting. These business agreements often specify the requirements of a contract testing laboratory with respect to contractee notification of impending sample submission, which are detailed below.

A Path to Quality and Compliance

By: Rory Budihandojo
Compliance with quality regulations that protect patients' safety is a critical requirement for the pharmaceutical industry. Regulatory compliance goes a long way toward proving that a given product's target for quality has been achieved and documented. Pharmaceutical Manufacturing Handbook: Regulations and Quality is intended to help readers understand how to comply with regulations and how to adapt a quality unit's routine activities to facilitate compliance.
In the book's preface, editor Shayne Cox Gad says the book describes "all regulatory aspects and requirements that govern how drugs are produced for evaluation (and, later, sale to and use) in humans." The book's back cover says it contains "everything you need to ensure full compliance and superior quality control."
The book's eight sections cover topics such as good manufacturing practices (GMPs) and other US Food and Drug Administration guidelines, international GMP regulations, quality, process analytical technology (PAT), personnel, contamination and contamination control, drug stability, and validation.
The book benefits from the work of more than 40 authors—respected academics and industry veterans—who contributed their years of expertise in various topics.

Pharmaceutical Manufacturing Handbook: Regulations and Quality, Shayne Cox Gad, Ed., Wiley, London, 2008, 856 pp., ISBN: 978-0- 470-25959-7

The book's first two sections are devoted to US and international regulation of GMPs. The first section describes FDA's GMP regulation and provides a good reference to other pertinent regulations and guidelines such as scale-up, postapproval changes, and PAT publications. These sections provide useful advice for complying with regulations. A chapter titled "Enforcement of Current Good Manufacturing Practices" includes a surprising and illuminating discussion about FDA's collaboration with the Federal Bureau of Investigations during certain inspections.
The next section discusses various aspects of quality. Despite offering detailed discussions, chapters about total quality management, the role of quality systems and audits, creating and overseeing quality-management systems, and quality-process improvements are quite easy to read. These chapters also provide materials that can be used in a quality operation (e.g., a checklist for performing a quality audit).
The section dedicated to PAT offers a discussion about chemical imaging and chemometrics. Passages provide details about the background of PAT, its benefits, and the various methods of implementing PAT.
The comprehensive section about drug stability provides readers a scientific understanding of how to determine a product's shelf life. This section discusses alternative accelerated testing methods through variable-parameter kinetics studies.
The section about validation includes considerations of essential matters such as analytical methods, laboratory instruments, and pharmaceutical manufacturing. This portion omits other important types of validation, however, such as computer validation, process validation, and facility validation.
Nevertheless, this book is a valuable reference for anyone interested in drug stability, quality, and PAT. The contributors' expertise ensures that the book shines in its treatment of those topics. It is not far off the mark to say that the book contains "everything you need to ensure full compliance and superior quality control."

Coming to Terms with Compliance1

By: Fredrik Sundberg
Drug manufacturers are under increasing pressure to bring products to the market faster and more cost-effectively while simultaneously meeting stringent quality requirements. Changing regulatory environments make the task of monitoring and adhering to quality standards challenging -- but the costs of non-compliance are high. Failing to comply with and satisfy the demands of regulations can result in heavy fines, product recall and in some cases, plant closure.

VMP programme checklist

Before a drug can be marketed, it must gain approval from regulatory authorities such as the US Food and Drug Administration (FDA) and/or the European Agency for the Evaluation of Medicinal Products (EMEA). A company applying for marketing approval must demonstrate that the drug has been produced according to strictly controlled and validated procedures, so ensuring the safety and consistent quality of the product. According to FDA, process validation is defined as: "Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting the predetermined specifications and quality attributes." Regulatory compliance is necessary at all levels of the drug discovery and development chain, encompassing areas such as good laboratory practice (GLP), good manufacturing practice (GMP), and good clinical practice (GCP). GLP focusses on the in vitro and in vivo evaluation of toxicological safety, with an emphasis on anticipating safety issues for clinical evaluations. GCP requires the evaluation of both product efficacy and safety in a clinical context, whereas GMP focusses on the quality evaluation of the manufactured product.
The areas requiring regulatory compliance cover an extremely broad spectrum. Existing regulations are periodically updated and revised, and are stringently enforced. Drug manufacturers, therefore, must keep abreast of regulatory developments - even unintentional non-compliance can potentially cost millions in fines and disruption to operations. The costs of non-compliance A regulatory authority can impose routine inspections, mandatory alterations in procedures, forced closure and even criminal prosecution on companies failing to comply with regulations. During the past 5 years, there has been an increase in the number of consent decrees (legal agreements to settle disputes with FDA) in the US, which can incur costs of tens of millions of dollars.
A dispute in 1999 involving a high profile company resulted in a $100 million fine for failing to correct defects in its manufacturing processes despite 6 years of warnings (Washington Post 03/11/99).

Vendor qualification checklist

Warning letters from FDA to companies violating regulations, which are publicly displayed on FDA's website, are another cost that severely damages a company's reputation.The language is unequivocal and plainly states how a company has failed to meet regulatory requirements (www.fda.gov/foi/warning.htm). The ultimate cost, however, to those that fail to meet regulatory requirements is that potential revenue from a product will be lost, jeopardizing returns on investment.
Maintaining compliance Regulatory compliance is not a one-off procedure and should be an integral part of an organization; companies must take into account compliance. This may involve devising an ongoing management process that includes:

• company-specific interpretation of current regulations
• creation of a systems inventory
• identification of systems that do/do not comply
• a detailed assessment of any gaps in compliance
• development of an active implementation plan, describing the necessary corrective actions required to bring systems into compliance
• prioritization of systems that need to be upgraded
• ensuring compliance of systems according to a prioritized list
• ensuring documentation is in place, archived and properly maintained.

Validation master plan. To avoid unnecessary work and obtain a good overview of the entire project, the plan should not repeat any information that is available elsewhere, for example, in SOPs. Rather, it should refer to established documentation. Regularly updating and reviewing template documents is required to make sure that all the latest regulations are incorporated with newly introduced company policies. 

Selecting a freeze dryer 2

Validation and compliance
The most current demands on freeze dryers are validation and the ability to be 21 CFR Part 11compliant. These factors are a significant part of the cost of pharmaceutical processing freeze dryers.
For validation, a full component catalogue must be supplied. An installation qualification, operational qualification (IQOQ) document is generated that outlines the proper validation process, and a factory acceptance test (FAT) and site acceptance test (SAT) are implemented to verify that the system is supplied as ordered and performs within the required specifications.
To be 21 CFR Part 11compliant, the freezedryer software must encrypt all data to prevent tampering, and must log every change and entry on the computer control system using user log ins and password protection. Misconceptions
The most common oversight is the concept that "all freeze dryers are the same". The choice of components, materials, construction and instrumentation create a wide variety in cost versus performance.
Older systems tend to have undersized compressors/condensers, as well as restrictions between the product chamber and the condenser, which limits the rate of freeze drying and often causes the freezedrying process to be extended. Today, freeze dryers are much better designed to accommodate the maximum load that may be placed in the system and the freeze dryer is not the limit to the process. For example, compressor reliability has significantly improved during the last 15 years. In small freeze dryers, the use of scroll compressors has virtually eliminated the failures common with reciprocating compressors.
As there are so many possible variations in size and features, advanced freeze dryers are 'built to order' where the end user works with the manufacturer to obtain a system suitable for their application requirements.
Innovations in freeze dryer technology
Thermal analysis and freeze drying microscopes have helped improve the understanding of the critical temperature — the temperature at which the product may collapse or melt-back — of the product being freeze dried. This knowledge provides the information required to produce a robust and efficient freeze drying cycle.
Classic freeze drying control is open loop, where the shelf temperature and chamber pressure are controlled based on a predetermined profile. It is assumed that the temperature of the product stays below its critical temperature, and the result is a reproducible — but very conservative and long — freezedrying cycle.
Closed loop control of the shelf temperature is required to both prevent collapse and minimise the length of the freezedrying cycle. The latest control systems use critical temperature information to dynamically control shelf temperature, which both protects against collapse and meltback whilst optimising the freezedrying cycle.
Methods that use an average measurement of the product in the chamber, such as calculated via pressure rise testing, adjust the temperature of the shelves a few times throughout the first half of the primary drying process. This process is limited to the first half of primary drying and only provides a conservative protocol. However, it is not optimised and does not take into account variations inside the chamber.
The latest control systems take into account both average and specific measurements to ensure there is no melt back and constantly control the shelf temperature throughout the entire cycle to produce a userselectable conservative or aggressive protocol.
In the future, more advanced closed loop control systems will be available that offer improved process control. Today, most applicable measuring instruments, such as tunable diode laser absorption spectroscopy, near infrared and mass spectrometry, are expensive and provide only marginal process improvement, which means they are not economically feasible for process control. As instrumentation and techniques advance, they will be incorporated into real-time process control systems.

Selecting a freeze dryer 1

By: T.N. ThompsonPharmaceutical Technology Europe
The most important consideration when choosing a freeze dryer is to ensure the system is fit for both today's applications and future needs. For the sake of this discussion, we will focus on freeze dryers with fluidfilled shelves, which does not include lowend manifold or heatonly shelf freeze dryers.
An understanding of the available features of a freeze dryer can facilitate the choice. The following are some considerations:

• shelf size (m² )
• shelf style (bulk or stoppering)
• condensing rate (L/h)
• condensing capacity (L)
• condenser location (internal versus external)
• material (304 versus 316SS)
• 21 CFR Part 11 compliance.

The freeze dryer manufacturer will also want to know what space is available for the freeze dryer and what utilities, such as electrical, air, chilled water and air conditioning, are available.
The following are a few examples of some of the various options:

• Cylindrical or rectangular product chambers — a cylindrical product chamber is less expensive than a rectangular chamber; however, it may occupy more floor space depending on the configuration of the shelf assembly.
• Internal or external condenser — an internal condenser is cheaper and provides unrestricted vapour flow. An external condenser is supplied with an isolation valve to separate the product from the condenser, which protects the product from reconstitution during power loss, and keeps the condensate out of the clean room environment.
• Pirani or capacitance manometer — piranis, the least expensive vacuum measurement device, read the relative vacuum inside a freeze dryer because they are affected by vapour. The more vapour present, the higher the pressure reading. A capacitance manometer reads the absolute vacuum level and the reading is unaffected by vapour pressure. Most production systems use a capacitance manometer for measurement and control of vacuum level. The best method for determining the 'end of primary drying' is to compare a pirani reading to a capacitance manometer reading. When they read the same, there is no vapour present and the product is dry. A quick test can be conducted by lowering the vacuum level to see if the pirani reading tracks the capacitance manometer. If water is present, the capacitance manometer will drop faster. If no water is present, they will drop at the same rate.
• Proportional vacuum control — the least expensive vacuum control system bleeds gas into the chamber using a solenoid valve, providing ±10 mT stability at 100 mT. For better stability, a proportional vacuum controller can be used that regulates the gas bleed through a proportional valve. The result is ±0.5 mT or better control.

Main freeze drying categories
Freeze dryer selection falls into two main categories: laboratory versus production, and non-sterile versus sterile.
Laboratory freeze dryers are used for a large variety of applications, including removal of solvent from a material, Phase I clinical trials and protocol development for scaleup production. A typical laboratory system will have a shelf area of 0.1–1 m² and a condensing capacity of up to 30 L.
Laboratorystyle systems can be simple freeze dryers with only standard features, such as a pirani gauge for vacuum level measurement and thermocouples for temperature monitoring, or they can incorporate more advanced instrumentation:

• capacitance manometer for vacuum measurement
• proportional vacuum control for fine vacuum control
• isolation valve between the product chamber and condenser for pressure rise testing
• liquid nitrogen traps for organic solvent trapping
• additional product thermocouples for monitoring product temperature.

Pilot and production systems offer shelf areas from 1 m² up to more than 40 m² . Production systems are used for Phases II and III clinical trials, and tend to be used for the same or a limited number of products in high-volume production. Recently, there has been a shift from using 10–50-mL vials, to 2mL and 5mL vials for smaller volume, highpotency biotech and proteinrelated products. The result is smaller freeze dryers with expensive payloads.
The type of processing will determine whether stoppering is required. Bulk applications can have fixedinplace shelves, but vial applications require stoppering where the shelves move and are squeezed together to press the partially inserted stoppers into the vial.
Pharmaceutical and other applications may also need to be sterilised between cycles, which can add significant complications and costs to a freeze dryer. A freeze dryer is normally rated for vacuum and the most common method of sterilisation is pressurized steam, which requires the freezedryer chambers to be certified pressure vessels rated to 2 atm at 131 °C.
An alternative sterilisation technique, which is growing in popularity for laboratory and small production systems, uses hydrogen peroxide (H₂0₂). H₂0₂ does not require a pressurerated vessel, which helps to minimise costs.

Using a Delphi Survey to Assess the Value of Pharmaceutical Process Validation Part 1: Survey Methodology 3

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.