New Draft Guidance on Process Validation

By: Angie Drakulich ePT--the Electronic Newsletter of Pharmaceutical Technology

Rockville, MD (Nov. 20)—The US Food and Drug Administration issued a draft guidance on Nov. 18, 2008, titled Process Validation: General Principles and Practices for comment. The guidance is meant to serve as a revision to the 1987 Guideline on General Principles of Process Validation.
The new draft guidance, based in part on the agency’s Pharmaceutical CGMPs for the 21st Century initiative, promotes a ‘‘life cycle’’ approach that focuses on scientifically sound design practices, robust qualification, and process verification, according to the Nov. 18, 2008, Federal Register. The life cycle approach breaks down process validation into three stages: process design, process qualification, and continued process verification. The draft guidance is also aligned with International Conference on Harmonization quality guidance documents such as Q8: Pharmaceutical Development, Q9: Quality Risk Management, and Q10: Pharmaceutical Quality System.
The guidance will apply to process validation of human and animal drug and biological products, including active pharmaceutical ingredients.
Comments are due Jan. 20, 2009, and can be sent in writing to the Division of Dockets Management (HFA-305), FDA, 5630 Fishers Ln., Rm. 1061, Rockville, MD 20852 or submitted electronically at www.regulations.gov.
View the full draft guidance here.

New WHO Guidelines On Generics

The World Health Organization (WHO) has released two new quality guidelines for generic pharmaceuticals concerning the preparation of dossiers in Common Technical Document (CTD) format and the data that should be provided.
It is hoped that both guidelines will support the objectives of the Prequalification Programme, a United Nations program managed by the WHO that aims to make priority medicines available to those who need them. The medicines should meet WHO-recommended norms and standards of acceptable quality.
Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): Preparation of Product Dossiers (PDs) in CTD format
This guideline provides recommendations about the format and presentation of a generic pharmaceutical PD, and presents the agreed upon common format of a well-structured CTD.
In the introduction to the guideline, the WHO explains that a common format will “significantly” reduce the time and resources needed to compile such PDs, as well as ease the preparation of electronic submissions. It will also make the exchange of regulatory information between national medicine regulatory authorities and the WHO much simpler.
The guideline will apply to PDs for generic pharmaceutical products containing existing APIs (either synthetic or semi-synthetic in origin) and their corresponding finished pharmaceutical product
Guideline on submission of documentation for a multisource (generic) FPP: Quality Part

This quality guideline is more extensive than previous guidelines; however, the WHO claims this is not indicative of an increase in requirements. The guideline offers recommendations on the quality information for APIs and FPPs that should be submitted to the WHO to support PDs.
According to the WHO, the guideline has been updated to reflect current requirements and how these should be met. In some instances, there has also been a reduction in requirements; for example, there is a reduced requirement for the number of FPP batches required to establish the shelf-life for both complicated FPPs (reduced from a minimum of three pilot batches to two pilot batches) and uncomplicated FPPs (reduced from a minimum of three pilot batches to one pilot batch and a second batch that may be smaller).
Additionally, there are reduced requirements for the development and process validation for “established” generic products that have been marketed by the applicant for at least 5 years, with either 10 batches produced in the past year or 25 batches produced in the past 3 years.
Both guidelines have been provisionally accepted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. They will be implemented on a pilot basis in the Prequalification Programme where they will help the WHO to list pharma products of acceptable safety, efficacy and quality in the interest of public health.

Preparing for FDA Inspections in a Changing Regulatory Environment

By Angie Drakulich,Maribel Rios

Industry and regulatory experts provide advice on inspection preparation and best practices.

Manufacturers and regulatory experts expect major transitions in inspections and enforcement. Contributing to this environment are the US Food and Drug Administration's strong focus on product and process quality (see Figure 1), increasing numbers of global business partnerships, and complex product technologies.

Figure 1: FDA's quality system model.

During an investigation, FDA can review everything "from [the] receipt of raw material through manufacture and any component associated with laboratory testing" as well as "anything required or self-imposed by the firm to move through the manufacturing stages," according to Michael Rogers, director of the Division of Field Investigations in FDA's Office of Regulatory Affairs.

Fast facts (FY 2006)

Although the path to compliance with current good manufacturing practices (CGMPs) was never meant to be a one-size-fits all strategy, there are some compliance issues that year after year continue to plague manufacturers. Cited observations relating to quality control, out-of-specification results, process validation, sterility assurance, and contamination continue to be of top concern (see "Fast facts" sidebar and Figure 2).

Figure 2: Top 10 drug observations used in FDA Turbo Establishment Inspection Report*, as of July 1, 2007.

"It seems like these are the same things I've seen for the past 20 years," says John C. (Jack) Garvey, vice-president of compliance and quality management at The Weinberg Group (Princeton, NJ). "Part of the reason is that investigators, even when they are using systems-based techniques, are still relying on the traditional methods of information gathering through the negative-product experience—looking at product failures, deviations, and product complaints." Regardless of the situation leading to an inspection, industry and regulatory experts agree on several basic factors to take into account during preparation.
Conduct a thorough risk assessment
Although good manufacturing practices (GMPs) have for the most part remained the same since the 1970s, increased computerization and automation since that time means that risk assessment has taken a systems-based approach.
Industry's role. Industry is taking a more proactive look at ensuring well-characterized quality systems—those systems for which the link between process requirements and their influence on product quality is well understood and scientifically sound. Companies still must ensure that their standard documents as well as training and operating procedures are in place, but it is now in the context of control-focused documentation. A company must ensure that an investigator understands the application of the quality system to its product and the link between that documentation and essential product requirements.
"You can't just focus on the details and the particulars of doing something," says Chris Smith, vice-president of regulatory affairs and quality at AAIPharma (Wilmington, NC). "Instead you focus on creating a process that will ensure quality every time."Companies must make the investment to develop the good science, the proper product and process characterizations, the properly derived quality system and product-control frameworks. "Companies are still not getting the essence of good product and process characterization and how it drives into a risk-based control framework to make sure we are really controlling the things that are critical to the product build," says Garvey.
An FDA inspection team will have these concepts in mind. "FDA likes to see risk management or risk assessment introduced in the decision-making process regarding things like change control, product release, and product recall," advises Peter D. Smith, vice-president of pharmaceutical compliance at Parexel Consulting (Lowell, MA). "Inspectors get an impression from a company if they talk about a risk approach in decision-making. It's good for them to hear."
The risk-assessment plan involves getting everyone in the company on the same page. As a former FDA investigator, Carmen Medina performed more than 200 inspections. Now a principal at Tunnell Consulting (King of Prussia, PA), she says it's easy to sense disparities between various operating units, even before walking into an inspection site, based solely on a company's documents. These disparities often are related to quality standards or prevalent risk within the company. In many cases, companies might focus on making sure pivotal batch records and corresponding data are acceptable.
Investigators are trained to perform what's called a top-down assessment. "Twenty years ago, investigators walked in looking at inadequacies in individual documents and manufacturing deviations and how those deficiencies impacted products in the field. Today, we're looking at, 'What is the level of risk in a company that could potentially impact every single product within the entire operation?'" says Medina.
This difference is important because it means each division in a company needs to be on the same page in terms of the level of risk they are facing and how seriously it should be taken. For example, a quality unit may seem to be more stringent when it comes to the release of a batch that underwent a manufacturing deviation than the head of manufacturing might be because they place the deviation in a different perspective than quality assurance. Or a manufacturing unit may be more concerned about limited resources than the company's executive management might be. These conflicting priorities must be recognized and reconciled before an inspection begins.
FDA's role. It is too early to ascertain how FDA's most recent risk-based initiatives such as process analytical technology and quality by design will affect inspection preparation. Two opposing approaches to quality, one solidified in ensuring sameness and the other based on process understanding, are resulting in "a great deal of conceptual, scientific, and regulatory uncertainty," says Garvey. "If the agency is serious about moving these initiatives forward, they are going to have to be highly tolerant of mistakes and missteps of companies along the way."
One of the major issues for the agency is one of follow-through, notes Garvey. "If the agency doesn't provide an extremely consistent, aligned approach between how they actually conduct the inspections and their publicly stated intentions, any progress made to date will be in jeopardy."
Do your research
"Failures don't just come from noncompliance with the regulations, but also out of industry expectations and industry standards," says Medina. Even though industry expectations are not yet codified into law, investigators may inspect against them and against that particular trend.
For this reason, there is an entire body of documentation that any company preparing for an FDA inspection should study beforehand in addition to CGMPs. "Review professional publications and go to conferences," advises Medina. "Obtain all the pertinent CBER [Center for Biologics Evaluation and Research]and CDER [Center for Drug Evaluation and Research] guidances and compliance programs. Get your hands on FDA's investigator inspection manual and read the preapproval inspection (PAI) sections. Obtain any recent 483s issued in situations specific and similar to your industry. If you're a small or big manufacturer, read about those that apply to you so you begin to know what the FDA investigator is scanning for when they walk in. They prepare before heading to your site, so you should as well."
Peter Smith agrees that paying attention to guidances, even if they're not technically enforceable, is crucial to passing an inspection. "Any good investigator can make a tie from a failure to follow a certain guidance to a true GMP deficiency," he says.
Think globally
"It's unprecedented right now what's happening globally from a risk-management perspective," says Medina. "We've had over 10 risk-management guidances or global initiatives in the past three years—that's huge. Risk management is on everyone's minds." In preparation, many companies expect to address risk management according to quality guidelines issued by International Conference on Harmonization (ICH) in addition to those issued by FDA.
Seeking conformance to international regulations is critical when preparing for inspections from other countries' regulatory agencies such as the European Medicines Agency. "Europe, Japan, Brazil, and others are all using similar ICH guidelines, even World Health Organization or PIC/S guidelines, so it's important to pay attention to them," adds P. Smith.
ICH Quality Guidelines (i.e., Q7, Q8, Q9, and Q10) are receiving increased attention. Addressing product development, quality risk management, and quality systems, respectively, these guidelines help to put frameworks around some of the issues important to FDA and to other international regulatory agencies.
"We are hoping companies will read and study these documents and find out how to use the concepts within them as they operate their program of drug discovery, development, assessment, and manufacturing controls," says Nicholas Buhay, deputy director of the Division of Manufacturing and Product Quality in FDA's Division of Manufacturing & Product Quality in the Office of Compliance. "We hope through harmonization to make our operations more efficient for industry while still providing valuable approaches to manufacturing, manufacturing control, and development that will make a more certain and reliable product."
Pay attention to overseas operations
Preparing for an overseas inspection may require more time and, in many instances, extra resources than preparing for a local inspection. In addition to reviewing FDA's international inspection guide, there are several unique points to keep in mind.
For example, for inspections in non-English speaking countries, have an interpreter on site. "Sometimes there are misunderstandings caused because a proper English word is not used or because the question is not clearly understood. Use an interpreter to make sure things are clarified," says P. Smith.
"It's also a good idea to have an English translation of critical documents and standard operating procedures (SOPs)," adds P. Smith. "They don't have to be official, but good translations on items such as change control, deviation investigations, and validation reports are important."
FDA has more stringent standards when it comes to imported goods. "The law doesn't provide us the authority to go to another sovereign jurisdiction and do what we want there," explains Buhay. To remedy this, investigators can use an "appearance standard" rather than "a full conformance standard," he says. "We can refuse a product's entrance if it appears to violate the law."
Overseas inspections are announced and are usually for a shorter, predetermined length of time. "One of the flexibilities you don't have in the foreign arena is to extend the inspection. These trips often involve multiple firms and commitments to inspect other sites the following week," explains Rogers. "We also need to have the data and management available before we arrive."
International inspections are often shorter also due to the additional resource burden, adds Buhay. "We can't go out as frequently as we would like to. On the other hand, we prioritize pretty effectively. We are getting to places that matter according to the conditions that apply, like risk and the impact of drugs on the US market."
Get data in order

Table I: Typical documents requested during FDA preapproval inspections.

Table I outlines the most common documents FDA will request during a PAI, including those that are CGMP requirements and those that are not necessarily required by CGMPs but that will be expected. An inspection team should not be given access to financial documents such as sales or revenue reports or forecasts, internal and supplier audit reports, or personnel files, except for employee education and training information. Have an organizational chart on hand as well, suggests Garvey. "A facility diagram that is coded by environmental control area can help the agency get an idea of where they are when doing plant tours, what the controls in those areas are and how they relate to product manufacturing builds."
Review SOPs

Who is at the door?

Reviewing and updating standard operating procedures will not only help the inspection team understand how things operate but also will provide staff with a refresher course on protocol and procedure. This will enable them to better discuss and explain systems when asked. Carry out a mock inspection
The best way to prepare for an FDA inspection is to carry out a mock inspection ahead of time.
Set a timeframe. It's best to carry out an inspection close enough to the scheduled inspection that all the data and procedures are fresh but far enough ahead of time that one can correct any errors or make any adjustments before the big day, advises P. Smith. This is generally about six to eight months before the scheduled inspection.

Don't forget the basics.

Make staff assignments. Inspections are a mobilization effort, and all personnel must know what his or her role will be and what is required. "It's important to assign a trained, key employee to each subject area to the PAI such as management responsibility, R&D, pilot plant, the water system, validation, production, engineering, laboratories, quality, change control, and regulatory affairs," advises Chinny C. Okparanta, president of Integrated Quality Systems (Edison, NJ). Ideally, an internal readiness team made up of personnel with FDA inspection experience and who have interfaced with FDA investigators or were on the regulatory side of the industry is important. "All strategy should be driven by this core team of people who know how to manage the process," says Medina.
Practice interviewing. Surprisingly, a number of inspection failures have less to do with actual facility management and more to do with simple misunderstandings. Although contract manufacturers are constantly going through customer audits and thereby are accustomed to answering questions and retrieving documents, other companies may have very complex systems to explain that are new to an FDA inspector. Staff must be able to explain everything in basic terms, with flow charts and summaries to demonstrate systems.
"Often times, the staff is so familiar with the subject matter that they don't understand the investigator hasn't been to the plant before and may not understand certain terminology," says P. Smith.
It is also important to be able to explain each employee's responsibilities and how the operations are managed. According to Rogers, "The compliance program serves as a recipe for our inspectional process, but for a PAI and especially for an initial inspection, we go through a complete history of the firm's operations, management, management structure, and responsibilities to get an idea of the firm's general operations as well as an understanding of the products they make." During a company's first inspection, adds Rogers, the team should be prepared to talk about the other products the company manufactures beyond the one under review.
Implement a remediation plan
After the mock inspection, companies should "seize the opportunity to enhance all the critical compliance categories that have been identified as deficient by your mock FDA inspection team and address them," says Medina.
For a PAI, one best practice is to eliminate any disparities that might have arisen since the time the submission was made and the time the PAI is to occur. "Information about the facility, manufacturing processes, QC methods, batch record, corresponding equipment, and anything substantive reported in the submission must be consistent with what the investigator will find and inspect against during the PAI," adds Medina. "The biggest reason for failure is the disparity identified by the investigator between what was reported in the regulatory submission's CMC [chemistry, manufacturing, and controls] section and what is actually found on the manufacturing floor and within laboratories."
Applying these strategies should go a long way toward a successful inspection process. "Overall, be forthright in making the appropriate people and records available to support your data," says FDA's Michael Rogers. "We're just trying to do our job. We have a role in public health to protect people, and so does the industry."

For additional resources and online exclusives on this topic, visit pharmtech.com.


Figure 1: FDA's quality system model.
Fast facts (FY 2006)
Figure 2: Top 10 drug observations used in FDA Turbo Establishment Inspection Report*, as of July 1, 2007.
Table I: Typical documents requested during FDA preapproval inspections.
Who is at the door?
Don't forget the basics.

Packing-Line Improvement Based on a Fault-Tree Analysis Approach

By Arturo Toledo Rivero,Nelson Sierra Prado,Yohann Pérez Molina,Ian Toledo de Zayas

This article focuses on upgrading and improving a packing process to comply with current good manufacturing practices. The authors sought to maintain proper quality assurance for finished products.

Packaging is the final step in obtaining a finished pharmaceutical product. It is important because it ensures product integrity, identification, and presentation, including primary information for the patient (1).
For this reason, the packaging process should be analyzed, and manufacturers should take into account the occurrence of deviations such as equipment and component failures, human error, operational errors, and other deviations that negatively affect the final process result (2–4). Risk analysis (RA) methods are valuable tools for mitigating fault events by focusing on the cause–effect interrelations that create them. RA methods thus facilitate fault elimination or, when faults cannot be eliminated, fault reduction.
In today's pharmaceutical industry, most processes are conceived and designed with a high level of automation to minimize operator intervention. Nevertheless, economic considerations lead companies to retain manual operations in certain situations. The packing process that is the subject of this study is one example. In such a process, a fault-tree analysis (FTA) approach can greatly help determine critical process points. The approach also helps manufacturers introduce barriers against equipment and operator failure and minimize their probability of occurring (5, 6). Following these considerations, the packing line was arranged, bearing in mind the potential failures to which the final result could be exposed. The arrangement was validated by challenging the process to demonstrate its effectiveness.
Packing process description and considerations

Figure 1: The packing process represented in a block diagram. QA is quality assurance.

The packing process in general can be summarized in a block diagram (see Figure 1). According to in-house procedures, the quality assurance (QA) department must verify the information from quarantined product and the corresponding packing material for approval. A product-release document is therefore indispensable to starting any product packaging activity. A packing-order document is created upon product release. This document matches the product vials and packing material that are involved in the process. Refrigerated product vials must pass a room-temperature acclimatization stage to eliminate external moisture on the vials before they are labeled. All other product vials are directly transferred together with label rolls for automatic labeling and imprinting. Printed packing material such as labels for multiple unit boxes (MUBs) and shipping boxes, as well as cartons and leaflets, are semiautomatically imprinted, folded, identified, and prepared as needed. These items are then temporarily stored together with the rest of the materials until vial labeling and manual packaging begins.

Figure 2: Packing area layout. MUB is multiple unit box.

The original packing-area distribution was modified to physically separate the preparation of packing material from the labeling, imprinting, and manual packaging operations of the main packing line (see Figure 2). Note that the contiguous packing line included a Sensitive 350 labeling machine (Libra Pharmaceutical Technologies, Fairfield, CT) followed by a 6.65-m long conveyor with speed control to transport labeled vials to manual packaging operators. According to the original arrangement, one of the operators near the labeling machine (No. 8) acts as a buffer by collecting vials and returning them to the conveyor in groups of five. The other operator next to the labeling machine (No. 1) simultaneously configures and distributes empty MUBs using the same conveyor. The rest of the operators (Nos. 2–7) package product vials in individual cartons, including leaflets, placing the packed units into the MUBs in groups of 10.

Figure 3: Packing-process fault tree showing the main start section and the major unwanted event.

A BP 4100 technical balance (Sartorius, Göttingen, Germany) with a 0–4100-g range and a resolution of ± 0.1 g is located at the end of the line. An operator places each MUB and reads its weight to verify that it has been filled. The MUB is then sealed, and the corresponding label is affixed. Shipping boxes are also checked in the same way using a QC1500NNP scale (Sartorius ) with 0–1500-kg range and ± 200-g resolution. Shipping boxes are then sealed and labeled accordingly.

Figure 4: Packing-process fault tree showing the branch that follows from product temperature-requirement failure.

This arrangement is designed to ensure good coordination among all operators regarding manual performance. The time each packing operator took to complete an MUB, including visual inspection, was measured as 160–170 s, with a margin of 10 s for recovery. The conveyor was therefore set to a linear velocity of 900 cm/min. The labeling machine had an optimum working speed of 45–47 vials/min. Hence, the buffer operator has an important task, which is to control vial distribution through the conveyor at intervals of 12–13 s. The buffer operator avoids bottlenecks by gathering the overflow of labeled vials to operators, and releasing the collected vials when the labeling machine is interrupted. Fault-tree analysis of the packing process

Figure 5: Packing-process fault tree showing the branch following from failure in primary-information imprinting.

An FTA model was specially developed for the packing process by representing failure events with logical operators to form a logical information flow chart (see Figure 3). The special symbols employed in this flow chart are explained in the literature (7). The major unwanted event was defined as "Finished-product quality noncompliance resulting from packing process." All cause–effect fault events flow downward. Any of the following failures can provoke the major unwanted event:

• Failure in product temperature requirements during the packing process (which exclusively applies to products that require refrigeration)
• Failure of packing material to display the corresponding primary product information (e.g., batch manufacturing date, batch number or identification code, and batch expiration date)
• Lack of correspondence between product specifications, printed packing material (e.g., vial labels, cartons, leaflets, MUBs, and shipping labels), and documentation (e.g., QA release authorizations, packing order, and records created during packaging)
• Failure to comply with cleaning and line-clearance requirements for areas involved in the packing process, including labeling machine and all workstations, to avoid product-batch cross contamination.

Figure 6: Packing-process fault tree showing the branch following from correspondence failure. QA is quality assurance. MUB is multiple unit box.

The fault events that cause these four failures were identified, and their cause–effect connections were traced until they reached the basic fault events (see Figures 4–7). Note the use of conditional events, which represent process controls that restrict fault-event occurrence. Neglecting process controls exposes the process to failures stemming from basic events.

Figure 7: Packing-process fault tree showing the branch following from cleaning and line-clearance failure.

Noncompliance with product-temperature requirements is considered the most critical of all possible process failures because it can cause premature product deterioration. Because process history shows that these failures occur with a relatively low frequency, the following actions should be sufficiently effective:

• Ensure cold-chamber qualification on at least a yearly basis to demonstrate consistency in keeping product temperature between 2 and 8 °C. Perform a similar study in the acclimatization room.
• Establish a metrological assurance plan, created by the QA department, to guarantee verification and adjustment of cold-chamber temperature controllers on at least a yearly basis.
• Monitor cold chambers daily. Monitor acclimatization- and packing-room temperatures linked to standby and transfer follow-up of each product batch. Standard operational procedures (SOPs) and supervision must be implemented accordingly.
• Implement an SOP to mitigate possible interruptions during the packaging of refrigerated products, and ensure that the quality of these products is preserved.

Failures in the printing of primary information and in the correspondence between products, printed packing material, and documentation are considered less critical because they have less impact on final product quality. Insufficient workstation cleaning and line clearance are also considered less critical failures. All of these faults occur more frequently, however, because of human error. The authors decided to create barriers in the packing-line configuration illustrated in Figure 2 for detecting and eliminating faults throughout the process. The barriers are as follows:

• A first level to detect and eliminate possible faults in product-vial labeling and primary-information imprinting in which the labeling-machine automatically senses and rejects unlabeled vials or nonimprinted vial labels.
• A second level to detect and eliminate possible faults in product-vial labeling and primary-information imprinting in which a buffer operator visually inspects and rejects unlabeled vials, nonimprinted vials, badly pasted or wrinkled labels, and illegible, misplaced, and erroneous imprints.
• A third level to detect and eliminate possible faults in product-vial labeling and primary-information imprinting (also for previously prepared printed packing material) in which packing operators visually inspect and reject unlabeled vials, nonimprinted vials, badly pasted or wrinkled labels, and labeled vials or cartons with illegible, misplaced, or erroneous imprints.
• A fourth level to check for MUB completion in which the first end-of-line operator looks for missing packed units, leaflets, and vials by weighing. The second end-of-line operator performs visual inspection to verify proper MUB manual sealing and correct primary-information printing on the corresponding label.
• A fifth level to check for shipping-box completion in which a handler operator looks for missing multiple boxes by weighing and performs visual inspection to verify proper shipping-box sealing and correct primary information printing on the corresponding label.
• A documented, in-process control implemented at intervals by a supervisor who visually inspects printed packing materials and their primary information. The supervisor also checks the appearance and completion of packed units by taking MUB samples from the end of the line. A similar in-process control is also implemented for previously printed packing material during the imprinting of cartons, MUBs, and shipping-box labels.
• Documented control performed by the supervisor to ensure the cleaning and line clearance for all involved areas at the beginning and end of each process.

Validation of proposed packing-line configuration and organization

Table I: Technical balance qualification for checking multiple-unit boxes (MUB) completion by weighing.

Qualifications of key process components were carried out. The vial-labeling machine was qualified according to the protocol designed for that purpose (8). The technical balance used to checking MUB completion by weighing was calibrated and verified according to in-house metrological procedures. In addition, the balance's ability to detect missing components was also qualified, taking into account MUB weight variations caused by the weights of individual components. The technical balance's sensitivity for reproducibly detecting single leaflets missing from MUBs leaving the packaging line was tested. The results of the testing are shown in Table I. Six MUBs were taken from the end-of-line at different moments (i.e., the start, middle, and end times) during the packing process. Weight differences were determined by removing a single leaflet from each MUB. When the weight differences were compared statistically with the corresponding leaflet weights, they did not vary significantly (9). The packing line was then validated to determine the buffer and packing operators' ability to detect and correct the failures described previously. Three consecutive runs were performed for this purpose by simulating automatic labeling and manual packaging operations in each run on 1440 placebo vials with printed packing material (i.e., vial labels, cartons, and leaflets for testing). Labels for MUB and shipping boxes were not used. To challenge the operators, vials were introduced during each run that had been deliberately prepared with defects. Among them were 40 unlabeled vials, 40 vials with badly pasted or wrinkled labels, and 45 vials with primary information missing from their labels, making a total of 125 faulty vials to detect.
To establish an acceptance criterion in each run, a single sampling plan for normal inspection was employed based on a general inspection level II and 0.10 acceptance-quality limit index (10). It was established that if any of the deliberately defective vials were not detected during a run, the packing-line performance would be considered unsatisfactory. The test also required the detection of all other faulty vials that resulted from errors in labeling-machine operation.
The packing operators' ability to ensure MUB completion was simultaneously verified by weighing MUBs at the end-of-line workstation. Based on the above qualification, an operational procedure determined weight limits at the beginning of each packing operation by averaging the weight of the first three complete MUBs leaving the line. A tolerance of ±1.8 g (i.e., the weight of the lightest leaflet) was established.
Results and analysis

Table II: Results from packing-line simulation runs: Visual checking of defects by operators.

All runs demonstrated that operator performance was good and that the barriers implemented against failure were effective. All 125 of the faulty vials deliberately prepared and introduced into the packing line as failures were detected (see Table II). The buffer operator rejected 73.6–94.4% of the faulty vials. The packing operators rejected the rest. In the worst case, 33 faulty vials reached them. All of the nonprogrammed faulty vials were also detected and rejected. The vials' defects (e.g., labels with tiny wrinkles and labels slightly out of their intended position) were almost imperceptible to the untrained eye. These defects were evidently difficult for the buffer operator to perceive. This operator had intervals of 13 s maximum to inspect vials between each distribution to the packing operators. The labeling machine functioned at a pace of 46 vials/min. The six packing operators had no problem perceiving and eliminating the faulty vials that the buffer operator had missed.

Table III: Results from packing-line simulation runs: Checking multiple-unit box (MUB) completion by weighing.

The packing operator's performance ensuring MUB completion was verified by reading the weight of all MUBs at the end-of-line station. Only one MUB with a weight equal to the lower limit was detected and set aside during the first run. Further visual inspection by the supervisor showed that no components were missing. No out-of-limit MUBs were found during the other runs (see Table III). This result was corroborated by the in-process control documented by the supervisor using the inspected MUBs taken from the end of the line. All packaging runs, including shipping-box completion for market distribution, were thus considered successful.

Figure 8: Diagram of a workstation fitted out for packing operators.

A further operational improvement of the above results can be achieved by reducing the time invested in manual packaging of vials, based on the principle of economy of operator movement. Economy of movement is increased when operators use both hands to pack two vials simultaneously. The time needed to complete MUBs could be reduced accordingly, thereby improving the balance between the manual processing rate of the overall packing line and the optimal working regime of the labeling machine. The amount of vials gathered and assimilated by the buffer operator could be minimized. For this purpose, packing-operator workstations should be fitted out according to Figure 8. The conditions shown can facilitate the use of both hands for packaging manipulation. Conclusion
The experiment demonstrated that a risk-analysis approach based on a fault-tree analysis model of the packing process achieved upgrades and improvements. Packaging operations were arranged according to the analysis. The new arrangement resulted in a product that was consistently packed and identified according to established requirements and current regulations.
Validation demonstrated the effectiveness of barriers against failures, which were implemented throughout the packing line, in detecting and rejecting faulty vials. The barriers detected faulty vials deliberately included in the tests and also the nonprogrammed faulty vials resulting from labeling-machine operation failures. The barriers did not compromise the correct completion of multiple boxes, which reached 100%. The system therefore ensures an exceptionally low probability of product failure and unacceptable defects at the process outlet.
This level of assurance can, in principle, significantly reduce customer complaints. It can also reduce the need for product recalls in the worst case, which normally cause great losses for each batch withdrawn from the market.
Authors' note
A colleague of the authors suggested a test of the end-of-line weighing station during packing-process validation by moving several MUBs along the line with one leaflet missing from each. The authors stand by the original concept followed in this study. Key process components must be qualified before the packing line is validated as a whole. The process is validated by integrating all qualified components and simulating normal process function as closely as possible without compromising the regular course of the process by adding an extra challenge. The authors believe that the technical balance's sensitivity for detecting missing components should be determined in advance. Then, one can focus on the objective of process validation, which is to evaluate the packing operator's ability to deliver completed MUBs throughout the simulation runs. Nevertheless, the above suggestion could be analyzed in a further revalidation of justified in-process changes.
Arturo Toledo Rivero* is the head of the research and development department, Nelson Sierra Prado is the head of the validation group, and Yohann Pérez Molina is a quality engineering specialist at LIORAD Laboratories, Ave. 27A No. 26402, La Lisa, Havana, Cuba, tel. 1537 2717935, fax 1537 2717899, atliorad@infomed.sld.cu [atliorad@infomed.sld.cu]
Ian Toledo de Zayas is a logistics specialist at DUJO Business Group.
*To whom all correspondence should be addressed.
Submitted: Aug. 8, 2007. Accepted: Nov. 1, 2007.
References
1. European Commission, "Production", in Volume 4—Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice, (European Commission, Brussels, Belgium, 2005), pp. 47–49.
2. ISPE, "ISPE Baseline Guide—Packaging, Labeling, and Warehousing," (ISPE, Tampa, FL, vol. 7, rev. B, 2005).

Figure 1: The packing process represented in a block diagram. QA is quality assurance.
Figure 2: Packing area layout. MUB is multiple unit box.
Figure 3: Packing-process fault tree showing the main start section and the major unwanted event.
Figure 6: Packing-process fault tree showing the branch following from correspondence failure. QA is quality assurance. MUB is multiple unit box.
Figure 4: Packing-process fault tree showing the branch that follows from product temperature-requirement failure.
Figure 5: Packing-process fault tree showing the branch following from failure in primary-information imprinting.
Figure 7: Packing-process fault tree showing the branch following from cleaning and line-clearance failure.
Table I: Technical balance qualification for checking multiple-unit boxes (MUB) completion by weighing.
Table II: Results from packing-line simulation runs: Visual checking of defects by operators.
Table III: Results from packing-line simulation runs: Checking multiple-unit box (MUB) completion by weighing.
Figure 8: Diagram of a workstation fitted out for packing operators.

Quality Systems for Drugs and Biologics

By Andrew G. Edwards
FDA is modernizing and streamlining current good manufacturing practices. The author examines FDA's evolving approach to quality systems and how a manufacturer can implement a quality system framework.


Photos.com/m.mcevoy
In 2002, the US Food and Drug Administration publicly recognized a need for change with its current good manufacturing practices (CGMP) for the 21st century initiative [http://current good manufacturing practices (cgmp) for the 21st century initiative|~www.fda.gov/cder/gmp/gmp2004/gmp_finalreport2004.htm] (1). This new approach to GMP compliance and enforcement recognized that FDA and the drug and biologics industries were not where they needed to be in terms of quality, manufacturing science, and risk management. This changing world of GMP applied to human and veterinary drugs and biological drug products. Key to FDA's approach has been to request a holistic cradle-to-grave management of quality issues.

Quality system: What is it?

The quality system should be an integrated framework within which the design, manufacture, packaging, labeling, and distribution take place. Commitment from management is crucial; without it there is no quality system. The underlying principles are:

    * Ensure quality is designed and built into the product
    * Reliance on appropriate and documented processes and procedures
    * Provide documented, objective evidence of what was done during design and manufacture
    * Controlled and documented design
    * Management responsibility and control of the quality system
    * Process—the quality of a product is governed by the quality of the processes used in its manufacturing
    * Validation of designs and processes
    * Feedback loop for corrective and preventive actions. (A feedback loop helps find any flaws that may be in a validated process or product. Validation is not 100%, it is a probability. Corrective and preventive action systems are the feedback loop to continuously improve your products and processes.)


Figure 1: Models of quality.
In the changing, evolving world of GMP regulations, quality concepts are changing. The original GMP regulations started with a product-focus and quality control. Next was a shift to a process-focus and quality assurance. Now drug and biologics manufacturers face an enormous paradigm shift with the new model of quality systems (see Figure 1).

However, this new evolutionary step is not new to FDA because the medical device industry has already adopted the quality-system approach in 1996 (2). Other industries also have adopted this approach (e.g., the automotive industry). Guidance is available from American National Standards Institute and International Organization for Standardization (ISO) on what is required in a quality system that parallels the medical device regulation (3, 4). FDA's approach has been to focus on quality by design and the control and reduction of variability by encouraging the use of sophisticated process analytical technologies (PAT) (5). Following the revised GMP guidance and the adoption of new technological advances, FDA hopes manufacturers will consistently maintain high-quality products and improve their manufacturing efficiency. FDA believes this should help lower costs and prevent shortages of critical medicines owing to failures that can result in product recalls. The estimated potential worldwide cost savings from efficiency improvements in the pharmaceutical industry is as high as $90 billion (6).

In October 2006, FDA issued a final guidance on quality systems intended for use in the manufacturing of human and veterinary drugs, including biological drug products (7). This guidance provides manufacturers with the ability to make technological improvements more readily, with appropriate regulatory oversight, and it offers guidance for defining management responsibilities, allocation of quality resources, dividing manufacturing duties between the quality unit and the production staff, and reviewing records and evaluating data.

The quality systems approach describes the responsibilities of the "quality unit," which combines the duties of quality control and quality assurance, "ensuring that the various operations associated with all systems are appropriately planned, approved, conducted, and monitored." The quality unit also is responsible for ensuring that controls are implemented and used; seeing that procedures and specifications are adhered to (at the manufacturer and at any contractors); approving or rejecting incoming materials, in-process materials, and drug products; and reviewing production records and investigating unexplained discrepancies.

FDA is applying a "six-system inspection model" in which the overarching quality system embodies five overlapping subsystems: production, facilities and equipment; laboratory controls, materials, and packaging-and-labeling (8). FDA will continue to monitor manufacturing plants through its inspection program and will continue to advance the training of its investigators in the latest technologies. FDA will focus the detailed inspection of a system so that the findings reflect the state of control in that system for every product (profile) class. A system is considered out of control based on GMP deficiencies that suggest lack of quality assurance. If one of the six systems is out of control, then the firm is considered out of control.

Design controls


Figure 2: Today's model.
FDA is being much more explicit about the industries' scientific and regulatory responsibilities by making product design and process development part of the quality system and focusing on measurement and control (9). The agency has clearly placed the burden of evaluating and demonstrating adequacy and acceptability on the manufacturer. This shift is going to take a substantial effort and will affect research and development more than in the past. An ongoing dedication of more resources will be needed on the "front end" of process design and development. A huge increase is needed in the early and very detailed understanding of the process and product formulation. This will probably mean more time, effort, people, and money than the 1980s process validation movement and may take years to realize the benefits on the "back end." GMP requirements will have much more impact on pharmaceutical development.


Figure 3: Tomorrow's promise.
With the quality system approach, FDA hopes manufacturers will apply an effective, knowledge-based scientific management of the entire product life cycle, from research to nonclinical (in vitro and GLP) studies to pharmaceutical development, clinical manufacture, clinical development (human trials), approval, commercial manufacture, and the postmarketing life of the product. This GMP paradigm shift will change the basic premise of the manufacturing process, completely shifting the point of regulatory and scientific emphasis by moving the regulatory anchor from the fixed process to fixed (constant) outputs (see Figures 2 and 3).

For the industry to evolve to the new model, companies must be open to change. The change will be more complex than just reengineering manufacturing processes where FDA will play a substantial role in the change. The current product life cycle is very inflexible by the regulatory approach where the process is fixed within the operating ranges established in regulatory filings and approvals, and change is difficult and often requires preapproval. Because of this, companies are reluctant to submit supplemental applications and "reopen" product approvals. This reluctance is a result of substantial delay in implementing changes because of regulatory review. There is usually a limited ability to fully understand the potential clinical impact of changes. Currently, the process is not fully understood when a product is newly developed and standards and expectations change with time (e.g., analytical methods, impurity profiles, limits of detection). Companies have chosen to live with poorly understood, inefficient, low-yield processes instead of going through another round of regulatory review and approval and run the risk that additional clinical trials and/or preapproval inspections might be required.

FDA's vision is for industry to focus on reducing variability through process understanding (e.g., application of knowledge throughout the product life cycle). It is a "cradle-to-grave" systematic approach where product quality and performance are ensured through the following:

    * Design of effective and efficient manufacturing processes
    * Product and process specifications based on a mechanistic understanding of how formulation and process factors affect product performance
    * Application of continuous real-time quality assurance.

FDA encourages a risk-based regulatory approach where relevant regulatory policies and procedures are modified to accommodate the most current level of scientific knowledge. The change would focus on increasing the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance. More focus in the development stage is needed to design the capability of process-control strategies to prevent or mitigate the risk of producing a poor quality product.

This step is much more about a new philosophy and operational culture than it is about new standard operating procedures and a new quality manual. There may be a need to vastly improve and retool cross-functional and cross-departmental communication and coordination. A silo-based approach simply will not work. Every part of the organization that touches on the product life cycle will need to operate in a much more integrated way. Most of the advances that have occurred, and are anticipated to occur, are bringing the development, manufacturing, quality assurance, and information and knowledge-management functions so closely together that these four areas should be coordinated in an integrated manner. There may be a need to also include some of the not-so-obvious players such as regulatory, marketing, product surveillance, senior management, and so forth. Management responsibility and involvement is absolutely critical to the quality system. The current business model based on speed-to-market must strike a different balance and approach with more emphasis on doing it right.

Risk management

Process design, process controls, and resource allocations will need to be based on risk assessment and risk management (10). Long-standing concepts of hazard control that use failure mode and effects analysis (FMEA) as well as hazard analysis and critical control point (HACCP) principles may not be familiar to the drug and biologics industries. FDA believes there will be significant regulatory benefits by improved ability to understand and implement changes with less FDA oversight and preapproval, faster and more predictable FDA review, analysis, and approval of new products and CMC changes, and fewer preapproval and shorter GMP inspections. The real business benefits (in cost, time, and efforts) are:

    * Better science, efficiency, predictability, and control
    * Problem avoidance through knowledge
    * Improved process control and yields
    * Less waste, rejection of materials, and rework
    * Greater ability to identify and correct root causes.

There is a practical relationship between quality and today's business realities (profit and cost-of-goods) where business objectives can be used to drive quality-system improvements. An understanding is also needed of the basic operational and scientific principles behind quality systems, quality by design, and PAT. There are core principles common to them all:

    * Scientific knowledge
    * Design for control
    * Oversight
    * Feedback
    * Adjustment
    * Simple logic.


Table I: Hazard control concepts.
These principles boil down to one common theme: Know what you're doing, why, when, and how. The same core principles drove the development of FDA's GMP regulations as well as the standards by the ISO and International Conference on Harmonization and serve as the fundamental basis for the various operational excellence methods (Six Sigma, lean manufacturing, etc.).

The overarching context for the core principles are the application of hazard control—an umbrella term that broadly describes the various risk-based concepts that FDA has been discussing (see Figure 4). Hazard control includes:

    * Risk assessment
    * Risk evaluation
    * Risk management
    * Risk mitigation.


Figure 4: Hazard control.
The concepts of hazard control should be applied to the product and the process. These concepts are described in Table I.

It is important to look at these core principles through the lens of PAT. PAT is really another way to describe advanced process control and is better described as "process analytical control technology." There is a need to deal first with the process and then the analytical pieces before the technology can have any meaningful use. Both FDA and the industries are looking at new technologies as the silver bullet to cure all of our quality ills, but it will be more important to build the gun first and know where to point it to be able to fire it and hit the target.

For PAT to be successful, the effort should be applied first to the development of a deep scientific understanding of the process and designing that process and its controls appropriately based on the target of constant output. This requires an understanding and application of the concept of critical control points and a full understanding of how the process works and how the process and its output are affected by variations in materials and control conditions. Next, one must understand how and where the process can be measured. One should only measure and analyze the things that really matter, based on process knowledge. There's no rational point in measuring things simply because we can, so this also must be tied into the concept of critical control points and how the process and its output are affected by variations. Finally, a successful PAT strategy requires a true understanding of how and where the process can be measured and effectively adjusted and controlled during production to constantly ensure consistent output.

Fancy technology doesn't mean a thing without the necessary process and analytical knowledge. FDA is pushing for quality system approaches that have been used for a long time in other industries (i.e., the electronics, defense, oil and gas, and telecommunications industries).

Inefficiency in the pharmaceutical industry could be wasting more than $50 billion per year in manufacturing costs alone—costs that could translate into lower prices or greater research and development—according to findings of the largest empirical study ever performed of pharmaceutical manufacturing and FDA monitoring policies (11).

Quality and compliance are not the same

Quality done right will result in compliance. Compliance, on the other hand, will not necessarily create or ensure the quality of processes or products. An organization must have both to succeed. The quality of a product is based upon the quality of the processes used in its manufacture. If one has poorly developed processes and procedures, continued compliance with the existing quality system will just ensure that one has consistently have poor product quality and integrity.

Use business drivers to change your quality system

Two key drivers of management's behavior and direction are regulatory compliance and operating costs–profit margins. A management team must focus on both. The consequences of noncompliance (business threat) as increased ongoing costs should be emphasized because focusing on the regulatory threat usually is not the most effective way to change management's views and actions. Use the company's own business realities as a driver. Understand how quality is related to business objectives (profits and cost-of-goods) and how they can be used to drive quality system improvements.

Measure and monitor the cost of poor quality

Philip Crosby, an expert in quality concepts, had these reflections on quality: "It is erroneous to think that quality is intangible, and therefore unmeasurable. It is precisely measurable by the oldest and most respected of means—cold, hard cash." It is also called "the price of nonconformance" but this is "an oversimplified definition . . . it is the costs associated with avoiding, finding, making, and repairing defects and errors"(12). The cost of nonconformance is part of the ongoing, day-to-day operating costs and is usually hidden in the operations (not measured). Examples are out-of-specification results, investigations, rejects, rework, expired components, unused labeling, production delays, waste, and so forth. The cost of nonconformance is a powerful tool for quantifying and reducing operating costs based on solid science and improved quality. The concept of "do more with less" can be translated into "make more product and profit with less waste and rework." It can be effective even if narrowly focused on just one part of the process. Very few companies are effectively looking at this. "[F]inancial measurements generally aren't used to validate quality's impact on profitability and costs." Most companies have absolutely no idea how their day-to-day operating costs are affected by poor quality.

Measuring and monitoring the cost of nonconformance is going to be increasingly important for our industries. Profit margins are facing growing global pressures from government price controls, larger purchasing power (both public and private), cross-border pricing, Rx-to-OTC switches, loss of patents, and so forth. It is already important to identify opportunities for improvement and hidden value and convince management to do more. Finding the cost of compliance can stop the debate because the returns on investment can be enormous. According to Crosby, "most organizations spend 25–40% of operating cost in nonvalued activities (the price of nonconformance) because requirements are not clear, communicated and consistently met" (13).

A company's cost of nonconformance can increase because:

    * Processes are not fine-tuned or made robust in development before technology transfer. Development staff are not given adequate time (based on activities being driven by filing deadliness) to do the job properly.
    * Some of the process and specification parameters that are agreed to and established in regulatory filings to obtain approval are difficult to meet in manufacturing.
    * Validation is based on development parameters, before the regulatory filing process.
    * Regulatory affairs does not want to reopen a file by submitting an amendment or supplement (and there is no structure or process for reaching a corporate decision in this regard).

How to establish an appropriate quality system

Existing products and processes must be the focus for implementing the quality system. However, it will be years before we approach the ideal cradle-to-grave quality system model. The industry must do what it can, as a practical matter, to effectively reengineer the moving train while the new tracks are being put in place. Dealing with existing products and processes boils down to dealing with and improving the current reality of our products and manufacturing processes.

To start, apply a hazard-control approach to select an existing product and process for improvement. Define the key practical steps toward improvement while proving value to build management support. Then apply quality-system thinking to problems found during the improvement steps.

A quality system should be appropriate for the degree of risk presented by the product, the complexity of the product in the manufacturing process, the intended use of the product, and the size and complexity of the manufacturer.

Major sections of FDA's quality system model include the following:

    * Management responsibilities
    * Resources
    * Manufacturing operations
    * Evaluation activities.

Management responsibility. The quality system should hold senior management responsible for:

    * The effectiveness and robustness of the quality system
    * Ensuring the quality system is meeting customer needs
    * Demonstrating commitment to developing and maintaining their quality system.
    * Setting implementation priorities and developing action plans
    * Providing leadership by being an active participant in the quality-system design, implementation, and monitoring including ongoing review of the system
    * Being an advocate of continual improvement of the quality system
    * Providing adequate resources to support the objectives of the quality system and there should be measurable goals that are monitored regularly for the operation
    * Structuring the organization to ensure quality system includes the authority to oversee the cause and effect of the manufacturing operation
    * The manufacture and production of quality products
    * Documenting the structure to ensure that interactions are defined and understood
    * Ensuring the quality system is in compliance with CGMP regulations
    * Ensuring the quality system provides organizational guidance, the quality standards to be followed, the policies to implement the quality-system criteria and supporting objectives, and the procedures needed to establish and maintain the quality system
    * communicating the vision of quality to the organization
    * ensuring the quality system is communicated and understood by all personnel and contractors.

Management should review the quality system frequently during implementation and after maturing, as a part of the general management meetings. A periodic review by a qualified outside source could be useful in determining suitability and effectiveness of the quality system. Management's review should include assessments of the process, product, and customer needs. A review should consider the following at minimum:

    * Appropriateness of the quality policy and objectives
    * Results of audits and other assessments
    * Customer feedback (including complaints)
    * Data trending analysis results
    * Preventive action to avoid serious issues or recurrence of issues
    * Follow-up action from previous management reviews
    * Changes to business practices or environment
    * Product characteristics meeting customer needs.

Review outcomes typically include improvements to the quality system and processes, improvements to manufacturing processes and products, and realignment of resources. Results should be recorded, and planned actions should be implemented using an effective corrective and preventive action and change control procedures and process.

Resources. Management must provide adequate resources for the following:

    * Supplying and maintaining facilities and equipment to Product quality product
    * Acquiring and receiving material for their intended use
    * Processing the material to produce the finished product
    * Laboratory analysis of the product
    * Collection, storage, and examination of in-process, stability, and reserve samples.

Management should be held responsible for:

    * Developing personnel to support a problem-solving and communicative organizational culture
    * Creating environment that values employee suggestions and acts on suggestions for improvement
    * Developing cross-functional groups to share ideas to improve procedures and processes
    * Defining qualifications for each quality position
    * Ensuring employees understand the impact of their activities on the product and the customers.

Training is critical to ensure all employees remain proficient in their operational functions and understanding of CGMP regulations. Training should be two-fold: covering the employees' job function, as well as CGMP regulatory requirements. Training programs should include:

    * Evaluation of training needs
    * Provision to satisfy needs
    * Evaluation of effectiveness of training
    * Documentation of training and/or retraining
    * A discussion of how skills from training should be incorporated into day-to-day performance.

Technical experts who understand pharmaceutical science, risk factors, and manufacturing processes related to the product should be responsible for specific facility and equipment requirements. It is important to note that FDA feels that the CGMP regulations require a higher standard for calibration and maintenance than most nonpharmaceutical quality-system models.

Outsourced resources used in operations must be controlled and qualified. Contracts should clearly describe the materials or service, quality specifications, responsibilities, and communication mechanisms. The quality unit is responsible for approving or rejecting products or services provided under a contract.

It is important to qualify the contractor before signing a contract with that firm. Otherwise, the ability to help the contractor become more FDA compliant or choosing another contractor is impaired by a signed contract before audit.

Manufacturing operations. The manufactured product and process should be defined, from design to delivery. Control must be exercised over all changes. Documenting processes, associated controls, and changes to processes will ensure that sources of variability are identified. Documentation should include:

    * Resources and facilities used
    * Procedures to carry out the process
    * Process owner who maintains and updates process as needed
    * Identification and control of important variables
    * Quality control measures, necessary data collection, monitoring, and appropriate controls for product and process
    * Validation activities, including operating ranges and acceptance criteria
    * Effects on related process, functions or personnel.

From a regulatory perspective, it is important to have experts in a pharmaceutical environment who understand pharmaceutical science, equipment, facilities, and process types and how variations in materials and processes can ultimately affect the finished product.

As part of design, controls for all processes within the packaging and labeling systems should have written procedures. As part of the design process, before commercial production, the controls for all processes within the packaging and labeling system should be planned and documented.

All inputs (i.e., materials, purchased or manufactured, that go into a final product) to the manufacturing operations must be examined. Materials are components, containers, or closures. Quality systems should ensure quality controls are established prior to the receipt, production, storage and use of all inputs. Suppliers of input materials must be audited on a periodic basis. An essential element of purchasing controls is the data trending for acceptance and rejection of materials for information on supplier performance. The auditing of suppliers should be based on a risk assessment. An audit should determine the reliability of a supplier's certificate of analysis (COA). A quality-system approach ensures the procedures are established to verify that materials are from qualified sources. Equally important is to have a system in place to respond to changes in materials from suppliers to avoid unintended consequences.

Design concepts established during product development typically matures into commercial design after process experimentation and progressive modification where areas of weakness are identified, corrected, and monitored. Critical quality attributes should receive increased scrutiny. Risk management should help identify areas of process weakness or higher risk and factors that may influence critical quality attributes.

A robust manufacturing process should be in place before commercial production. FDA recommends that scale-up studies be used to help demonstrate that a fundamentally sound design has been fully realized. Proper design and reliable technology transfer processes should ensure the ability to validate the manufacturing process. Validation provides initial proof the design produces intended product quality. Validation is not a one-time event.

The quality-system approach calls for manufacturers to develop procedures that monitor, measure, and analyze the operations, including analytical methods and statistical techniques. The quality-system approach indicators that change control is warranted when data analysis or information reveals an area needing improvement. Changes must be controlled and documented. In other words, the entire product life cycle should be addressed by the establishment of continual improvement mechanisms in the quality system.

Under a quality system, there will be a process in place to handle nonconforming material and product so that it is not placed into distribution. This process must be documented and must define responsibilities for halting and resuming operations, investigating discrepancies, recording nonconformity, and taking remedial action. Investigation, conclusion, and follow-up of nonconformities or deviations must be documented. Remedial action may include correction of the nonconformity, thereby allowing the product to proceed with proper authorization and justification of the conclusion regarding the problem's impact and use of the product for another application where the deficiency does not affect the products' quality or reject the product.

Evaluation activities. It is important to analyze manufacturing data on a regular time interval for trends as a means to control the operation. This analysis will detect potential problems early and enable the planning of corrective and preventive actions.

Internal audits should be conducted according to planned intervals for evaluation of implementation, maintenance of the quality system, and determination of whether processes and products meet established parameters and specifications. Although the CGMP regulations require product review on at least an annual basis, a quality-system approach calls for trending on a more frequent basis as determined by risk. Trending analysis can help focus internal audits.

An internal audit procedure should be established. It should call for a planned audit schedule that takes into account the relative risks of the various quality-system activities, the results of previous audits, and corrective actions. There is an obvious need to audit the complete system. Be sure to include a section on how auditors are trained in evidence gathering, their responsibilities, and auditing procedures. It is critical to maintain records of audit findings and assign responsibility for follow up to prevent problems from recurring.

Quality risk management is a reiterative evaluation process and a tool in development of product specifications and critical process parameters. It also helps manage and control change.

Corrective action is a reactive tool to ensure problems do not recur. Effective decision making in a quality system environment is based on an informed understanding of quality issues. The corrective action procedure should be developed and documented to ensure that the need for action is evaluated, the root cause investigated, actions determined, selected action is taken within a defined timeframe and the effectiveness of the action taken is evaluated.

A preventive action process is an essential tool in quality system management. The selected preventative action should be evaluated, recorded, and monitored. Improvement should be promoted, and senior management should be involved. Being proactive is an essential tool in quality system management. Examples are succession planning, training, capturing institutional knowledge, and so forth.

Conclusion

It will take a long time and a lot of work to complete the change. However, companies simply can't afford to sit on the sideline and wait for the new paradigm to be better defined before taking action. FDA's Quality Systems train has left the station and the effects are already being seen in enforcement actions.

References

1. FDA, CGMP for the 21st Century, available at www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm , accessed Jan. 7, 2008.

2. FDA, Quality System Regulation for Devices, 21 CFR Part 820 (1996).

3. ANSI/ISO/ASQ Q9001-2000, Quality Management Systems—Requirements (American Society for Quality, 2000).

4. ISO/DIS 13485 (April 1996).

5. FDA, Process Analytical Technology (PAT) Initiative (2002), available at www.fda.gov/Cder/OPS/PAT.htm, accessed Jan. 7, 2008.

6. I. Maes and B. Van Liederkerke, "The Need for a Broader Perspective if Process Analytical Technology Implementation Is to be Successful in the Pharmaceutical Sector," J. Pharm. Innovation, (Sept./Oct., 2006).

7. FDA, Quality Systems Approaches to Pharmaceutical Current Good Manufacturing Practice (CGMP) Regulations (Sept. 2006), available at www.fda.gov/cder/guidance/7260fnl.htm, accessed Jan. 7, 2008.

8. CPGM 7356.002 Compliance Program—Drug Manufacturing Inspections, available at www.fda.gov/cder/dmpq/compliance_guide.htm.

9. FDA, Q8 Pharmaceutical Development (May 2006), available at www.fda.gov/cder/guidance/6746fnl.htm.

10. FDA, Q9 Quality Risk Management (June 2006), www.fda.gov/cder/guidance/7153fnl.htm.

11. Pharmaceutical Manufacturing Research Project—Final Benchmarking Report (Sept. 2006), available at www.olin.wustl.edu/faculty/nickerson/results/.

12. G. Cokins, Quality Progress (Sept. 2006), definition is from the article entitled "Measuring the Cost of Quality For Management", available at www.asq.org/qualityprogress/past-issues/index.html?fromYYYY=2006&fromMM=09&index=1, accessed Jan. 22, 2008.

13. P.B. Crosby, Quality is Free: The Art of Making Quality Certain (McGraw-Hill, New York, NY, 1979 and Mentor Books, Denver, CO, 1992).

Andrew G. Edwards is a senior consultant at EduQuest, 1896 Urbana Pike, Suite 14, Hyattstown, MD 20871, tel. 301.874.6031, fax: 310.874.6033, AndyEdwards@EduQuest.net [andyedwards@eduquest.net]



What would you do differently? Email your thoughts about this paper to ptweb@advanstar.com [ptweb@advanstar.com]
and we may post them on pharmtech.com.

For more on this topic, see:
FDA Moves to Implement New GMP Policies [http://fda moves to implement new gmp policies|~www.pharmtech.com/pharmtech/data/articlestandard/pharmtech/452004/132382/article.pdf]Nov. 2004
Out of Specification Results and the Quality System Approach to GMPs [http://out of specification results and the quality system approach to gmps|~pharmtech.findpharma.com/pharmtech/article/articledetail.jsp?id=371493]Sept. 2006
ICH-Q10: A Recipe for the Product Lifecycle [http://ich-q10: a recipe for the product lifecycle|~pharmtech.findpharma.com/pharmtech/article/articledetail.jsp?id=452944]Sept. 2007

Submitted: Aug. 6, 2007. Accepted: Nov. 26, 2007

Photos.com/m.mcevoy
Figure 1: Models of quality.
Figure 4: Hazard control.
Figure 2: Today's model.
Figure 3: Tomorrow's promise.
Table I: Hazard control concepts.
Photos.com/m.mcevoy
Figure 1: Models of quality.
Figure 4: Hazard control.

Should you implement single-use systems?

Using single-use systems for investigational medicinal product (IMP) manufacturing has its advantages and disadvantages. Some key advantages are that process implementation is straight forward, particularly if you stay with a supplier’s standard offering, and there can be a reduced facility footprint as well as significant implementation time savings compared with multiple‑use systems. Single‑use systems can increase flexibility and productivity, make it easier to avoid cross contamination and also negate the need for costly steam‑in‑place or clean‑in‑place validation. The disadvantages are that technology assessment and the choice of systems for implementation can be complex, and implementation time can be particularly long for personalised systems. Additionally, depending on scale, single‑use systems can sometimes be expensive to implement. Connector and bag integrity is also sometimes a worry and, finally, waste disposal can be more or less complex depending on your location and needs.
Cost and waste management
With regards to cost management, the implications of implementing single‑use systems depends on many things, such as your company size, your product, the process knowledge to implement and the process validation status. Is your company a large established firm, a biotech start‑up or a CMO? What are your user requirements? Who are the stakeholders? Are you taking a QbD approach from the outset? Depending on circumstances, if you have an existing facility and qualified installations and equipment, for example, you may not see an immediate requirement for single‑use systems in the same way as a company that is just setting up. A more established company might be cost conscious and seek to lever existing installations, or may apply a mixed single‑use/multiple‑use implementation strategy. A new company, on the other hand, may see single-use systems as a faster, more cost‑effective route to arrival in the clinic. Implementation can be faster and the investment outlay for renovation and/or greenfield setup should be less using single‑use systems. There have been some interesting case studies presented that illustrate these points.^1,2 Acknowledging these points, I nevertheless draw the reader’s attention to my personal experience that some single-use suppliers can be expensive for this material.Waste management is an important part of single-use systems implementation — such systems generate more solid waste than multiple‑use systems (which inversely use more process water). Your single-use system implementation plan should lever multiple points here regarding biosafety concerns (product containment); environmental issues (how is your carbon footprint?); collection and storage of wastes and their inactivation before leaving the facility or site; transport and final elimination; and regulatory requirements — although this last point can be somewhat variable depending on your economic area location. The Bioprocess Systems Alliance has published a guideline on this and other subjects related to Single-Use Systems.³
Choosing the best systems and suppliers
Some people believe that clients seeking to outsource IMP manufacture look more favourably upon companies that use single‑use systems. Is this true? Well, maybe, maybe not.
It’s the old argument about quality, time and money; it depends on the user requirements and where you are in the process validation lifecycle. Think of it from the aspect of it being your money and not that of the outsourcing provider in question. You’re not sure what the future holds or what results you will get and so you will want to move ahead cautiously. You will be looking for the best deal in terms of time and money, and having the appropriate level of quality. In that context, you might be satisfied with a deal from an outsourcing provider with established installations based on multiple-use systems. On the other hand, for some companies, single‑use systems may be seen as being or thinking smarter as they are faster to implement (less to worry about) and less risky from a process perspective.
Single-use systems are of interest to producers of monoclonal antibodies because of the flexibility they bring to manufacturing operations (just to give one example). However, the size limitation for a plastic vessel (1–3 m³) can imply a change of process strategy away from fewer, larger steel bioreactors towards "farms" of single use bioreactors (multiple single use bioreactors of 1 M³). Single-use systems may be particularly attractive, for example, for a company implementing a project handling infectious agents, such as live vaccines or Advanced Therapy Medicinal Products (gene vectors or Cell-Based Medicinal Products) or potent compounds because of the flexibility, easier control of cross contamination and the more efficient use of available facility space. However, where are you in the process validation lifecycle? I just gave a perspective from an early clinical development viewpoint. If you are further along the process validation lifecycle and want to outsource your IMP manufacturing then other issues will have greater weight, such as the level of GMP compliance and the final production scale or process strategy.
The key factors that will influence a small company’s decision as to whether to use single‑use systems or not will be:

• company circumstances and needs - what is the business case and added value to the company?
• scope, process requirements and technology survey results
• on-site testing to confirm applicability, compatibility with facilities and to define other issues such as HSE
• planning, paying attention to project planning versus company strategic planning
• materials management
• process validation
• training requirements
• risk assessment applied as appropriate during this process.

When evaluating suppliers and making the correct choice of systems, ‘local’ factors will also play an important role. For instance, supplier strategy; depending on your supplier and technical choice you may be locked into certain technologies and perhaps just one supplier, which means you will not be able to execute a dual supplier strategy. Supplier capacity assessment and the warehousing space required is also important to consider when using single-use systems, as well as a supplier’s after‑sales service and support. Equally, be ready to decide what to do if, as a small company with a critical eye on strategic planning and business opportunities, you have to change your implementation planning. How will your supplier react? Make sure you have read the general terms and conditions of your supplier(s) and be prepared to negotiate on this point and modify it if necessary. These are often old, generic texts, but it can be very inconvenient if the first time you check them out is when there’s a problem!
Depending on the size and value of the project, a technical agreement can clarify the functional aspects of a business relationship. This should not be confused with a commercial agreement (if applicable). The technical agreement will detail the responsibilities (production, quality and regulatory etc.) of personnel within each company as appropriate, and should improve communication and prevent ambiguous situations. You may choose not to implement this type of agreement if the project is minor; however, on the other hand, I recommend this for scenarios with large repeated supplies such as bioreactor bags because of the value of the agreement and quality issues involved.
The application of the above factors can be seen as a risk management strategy,⁴ indeed, the industry recognises this as the most cost‑effective route to use today and it will also most likely save you time too. This is what many companies have been doing for years, but which has become more formalised with the general adoption and roll-out of Quality Risk Management (QRM) by regulatory authorities. Implementing an appropriate QRM programme during single-use system implementation offers benefits as a means of assessing, controlling, communicating and reviewing risk. The risk assessment process should be applied over the lifecycle of the project. The approach can range from a simple ad-hoc or stand alone application to more robust applications involving qualitative and quantitative methods such as failure modes and effects analysis.
Although in my opinion there are no hard and fast rules, it’s definitely worth small companies implementing single‑use systems. During this process, the company should decide who its stakeholders are and define user requirements, set in place a Project Implementation Plan and as mentioned apply an appropriate level of risk assessment to the whole process.
I’ve given my own personal opinions here based on experience and I advise you to look out for a future technical report from the Parenteral Drug Association on single‑use systems. Prepared by a task force lead by Bob Repetto from Pfizer and Morten Munk from CMC Biologics, this document will definitely help potential new and existing users formulate their ideas coherently and provide the best approach to implementing single use systems.
References
1. T. Nemes (Novavax), Implementation of Disposables in Biologics Manufacturing (PDA/EBE conference on Biopharmaceutical Development and Manufacturing, Ireland, June 2008).
2. A. Sinclair (Biopharm Services), Sustainability Single-Use Technologies – Environmental Impact and waste Management, (Pharma IQ conference on Disposable Solutions for Biomanufacturing, UK, February 2010).
3. Bioprcess Systems Alliance, Guide to Disposal of Single-Use Bioprocess Systems, http://www.bpsalliance.org/guides.html.
4. S. Brown (Vivalis), A Risk Management Approach to Single Use Systems Selection and Implementation (ISPE conference on Disposable and Containment Technology in Biomanufacturing, France, September 2009).