T ECHNICAL G UIDE EXPANDING THE GLOBAL KNOWLEDGE BASE FOR COMPLIANCE PROFESSIONALS IN
FDA-REGULA REGULATED TED
INDUSTRIES. Technical Guide
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A Practical Guide
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Change Control Systems Management . . . FDA FDA has ci cited ted a number of manufacturers for lack of comprehensive change control systems.
by Shahid Shahi d T. T. Dara President Compliance Consulting Inc. 2
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hange is accepted as part of everyday manufacturing operations by current good manufacturing practice (cGMPs) and FDA. Pharmaceutical manufacturers have developed excellent quality/compliance systems to minimize unplanned changes in the manufacturing/packaging manufacturing/pac kaging operations. Howev However, er, planned changes also require a stringent set of controls to attain desired results. In recent years, FDA has cited a number of manufacturers for lack of comprehensive change control systems. systems. The Agency expects industry to have quality/compliance systems in place, which should trigger a chain of events event s whenever there is change involving a drug product or medical device intended for consumer use. The ultimate goal is to build quality into a drug product instead of testing a sample for conformance at the end, thereby rigidly controlling any changes and deviant behavior of the systems involved. This paper will provide quality/validation professionals with basic concepts about change control systems, different types
Journal of cGMP Compliance
of changes that might be encountered in a pharmaceutical operation, and the means to control them.
cGMP REGULATIONS AND CHANGE CONTROL Since the end of World War War II, the pharmaceutical industry has experienced tremendous growth and expansion in more than just economic econom ic terms. Starting with with antibiotics, the drug discovery process has introduced hundreds of new remedies along with new and novel drug delivery systems, transforming the art of formulation into a pure science. Technological advances in manufacturing equipment enabled industry to not only increase the speed of manufacturing, but improve the quality of the end productt as well. produc well. All these these changes in pharmaceutical manufacturing happened in a little over 50 years, and the process is continuing. continuing. The new global economic realities and market pressures of the 1990s have forced the entire industry to adopt cost-effective ways of managing every aspect of the
A Practical Guide
to
Change Control Systems Management . . . FDA FDA has ci cited ted a number of manufacturers for lack of comprehensive change control systems.
by Shahid Shahi d T. T. Dara President Compliance Consulting Inc. 2
C
hange is accepted as part of everyday manufacturing operations by current good manufacturing practice (cGMPs) and FDA. Pharmaceutical manufacturers have developed excellent quality/compliance systems to minimize unplanned changes in the manufacturing/packaging manufacturing/pac kaging operations. Howev However, er, planned changes also require a stringent set of controls to attain desired results. In recent years, FDA has cited a number of manufacturers for lack of comprehensive change control systems. systems. The Agency expects industry to have quality/compliance systems in place, which should trigger a chain of events event s whenever there is change involving a drug product or medical device intended for consumer use. The ultimate goal is to build quality into a drug product instead of testing a sample for conformance at the end, thereby rigidly controlling any changes and deviant behavior of the systems involved. This paper will provide quality/validation professionals with basic concepts about change control systems, different types
Journal of cGMP Compliance
of changes that might be encountered in a pharmaceutical operation, and the means to control them.
cGMP REGULATIONS AND CHANGE CONTROL Since the end of World War War II, the pharmaceutical industry has experienced tremendous growth and expansion in more than just economic econom ic terms. Starting with with antibiotics, the drug discovery process has introduced hundreds of new remedies along with new and novel drug delivery systems, transforming the art of formulation into a pure science. Technological advances in manufacturing equipment enabled industry to not only increase the speed of manufacturing, but improve the quality of the end productt as well. produc well. All these these changes in pharmaceutical manufacturing happened in a little over 50 years, and the process is continuing. continuing. The new global economic realities and market pressures of the 1990s have forced the entire industry to adopt cost-effective ways of managing every aspect of the
Shahid Shahi d T. T. Dara business. There are fewer fewer qualified individuals managing multitudes of critical responsibilities within each organization, thereby making it imperative that new techniques of managing quality and compliance be adopted. This constant cycle of change demands effective tools to control all such changes related to drug products. FDA and other regulatory agencies agencies in the world accept the fact that change is part of the pharmaceutical business, but expect industry to have effective effective change control systems in place to assure that the quality, quality, strength, and efficacy of drug products are not compromised.
Evolution of cGMPs On the legal front, the regulatory and quality/compliance expectations for the pharmaceutical industry have steadily increased over the past 90 plus years, since the enactment of the Food and Drug Act of 1906, to the point where it is one of the most regulated industries in the world today.. Drug regulations continued to evolve today evolve over the first half of the 20th century and culminated in 1962 with the introduction of Current Good Manufacturing Practices (cGMPs) regulations. Section 501(a) (2)(B) of the Food, Drug and Cosmetic Act deems a drug to be adulterated if: “…the methods used in, or the facilities or controls used for for,, its manufacture manufacture,, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practices to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.” The cGMP regulations were developed by the Pharmaceutical Manufacturers Association as guidelines for its member companies in the early 1960s and were later adopted by the FDA as part of the Food, Drug and Cosmetic Cosmetic Act of 1962. From FDA’s FDA’ s perspective, these regulations were meant to provide a precise, easily understood set of standards that would help both compliance and enforcement, while encouraging the new innovations to improve the manufacturing and control practices pract ices.. Theref Therefore, ore, the word “current” “current” in these regulations takes on a critical meaning, as it implies that the manufacturers will change their
practices as technological innovations are made in components, machines, or manufacturing practices. Thus cGMPs indirectly ask for for a change control system to manage any new developments regarding manufacture of a drug product or medical device. The cGMP regulations have been criticized as being too vague by industry, but are based on these fundamental principles of quality assurance: “Quality, safety and effectiveness must be designed and built into a finished drug product; Quality cannot be inspected or tested into a finished drug product; product; Each step of the manumanufacturing process must be controlled to assure that the finished drug product will meet its specifications.” With advances in technology and scientific knowledge, the understanding of critical material, equipment, and process variables also increases, thereby resulting in a better definition of the variables that could impact the overall quality of the drug product. Such variables variables should be closely monitored and controlled to assure end product homogeneity and conformance to specifications specifications.. 21CFR – Parts 210 and 211 describe the cGMP regulations for human and animal drug products. Change control is specifically addressed in the following sections of cGMP Regulations and the Quality System Regulation (QSR):
21CFR – Part 211 Subpart F – Production and Process Control 211.100 Written Written Procedures; Procedures; deviatio deviations: ns: (a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. (b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation deviation from the written procedures shall be recorded and justified. Technical Guide
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21CFR – Part 211 Subpart I – Laboratory Control
21CFR – Part 211 Subpart B – Organization and Personnel
211.160: (a) The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any changes, in such specifications,, standards, sampling plans, test specifications procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and revie reviewed wed and approved by the quality control control unit. The requirements in this subpart shall be followed and shall be documented at the time time of performance. performance. Any deviadeviation from the written specifications, standards, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justifie just ified. d.
211.22 Responsibilities of Quality Control Unit (Proposed) The quality control unit shall be responsible for the review and approval of validation protocols and the review of changes in product, process, equipment, or other changes to determine if and when revalidation revalidat ion is warranted. By proposing this revision to the quality control unit, the Agency has clearly stated its position on the subject of change control and its compliance expectations from the pharmaceutical phar maceutical industry. Since the inception of the cGMP regulations in 1962, pharmaceutical manufacturers have variously interpreted them to suit their particular organizational and operational needs. As a result, each company has a unique change control system in place, attempting to assure the quality, strength, and purity of the drug products being manufactured. As the industry is consolidating via mergers and acquisitions, the change control systems of both the individual and the combined companies are stressed to the limit with no relief in sight. Another aspect is the increasing use of third party manufacturing/packaging facilities by major manufacturers, which creates its own set of change control issues. Nonetheless, an effective and comprehensive change control system is essential for every pharmaceutical and medical device manufacturer, manufacturer, with built-in flexibility to deal with all kinds of scenarios.
21CFR – Part 820, which became effective in October 1996, details the Quality System Regulations, which governs the manufacture of medical devices, addresses the subject of change control in the following subparts: 820.30 – Design Controls (i) Design changes ■ 820.40 – Document Controls (b) Document changes ■ 820.70 – Production and Process Controls (c) Production and process changes Validation ■ 820.75 – Process Validation (d) Changes or process deviations Nonconforming ing Product ■ 820.90 – Nonconform ■
As is evident from the above listing, the Agency has put forth these requirements with a clear objective, i.e., to build quality into a medical device being manufactured by adhering to these regulations while controlling every aspect of possible changes. FDA has amended the cGMP regulations many times since their implementation in 1963. Major revisions were made in 1971, 1978, and 1995. A new set of regulations was was issued in 1997 to address the electronic signature and related issues. issues. In 1996, the Agency proposed the latest revisions to these regulations to clarify the subject of process validation, but also addressed other issues, including change control. 4
Journal of cGMP Compliance
CHANGE CONTROL MANAGEMENT Whether it is a small pharmaceutical manufacturmanufacturing operation or a multination multinational al drug house, it makes perfect sense to define the quality/compliance goals of the organization and have top management involved volv ed in defining and designing such a policy policy.. In recent years, FDA has increasingly emphasized the accountability accountabilit y of senior managers within a pharmaceutical company whenever the Agency encountered quality/compliance quality/com pliance issues; therefor therefore, e, the responsibility for cGMP compliance is directly brought to the boardrooms of huge corporations.
Corporate Quality Policy The corporate quality policy is a sensitive sub ject that should be developed with the utmost care, taking into consideration the organization’s
Shahid T. Dara strengths and weaknesses from a quality/compliance point of view. The policy is a general statement which should spell out the quality mission of the company along with broad guidelines on which different quality systems will be part of the quality program. Quality policy is usually part of the Corporate Quality Manual, which delineates the generic quality concepts and systems that all the divisions of a company are supposed to develop, depending on each unit’s individual requirements.
Quality Culture Corporate quality policies and quality manuals can be useful only if the organization as a whole is committed to its principles. Otherwise, these documents would collect dust on bookshelves, while everyone in the company had their own interpretation of quality responsibility and accountability. Therefore it is imperative that the organization strive to develop a quality culture based on mutual understanding of each operational unit’s function within the company, with due recognition for the expertise of different departments and individuals. Such a working environment creates mutual respect among peers while developing a team with a common goal: to produce quality drug product within the cGMPs. This means quality assurance inspectors and auditors are considered part of the team and not the cops with a “got-you” attitude. Also, in such a quality environment, efforts are directed at solving the quality problems by addressing the systems related issues instead of finger pointing to who did it. In other words, the quality issues are freed from the cult of personality conflicts.
Organizational Structure One key aspect of the quality policy and manual is that it should define the quality responsibility and reporting structure of different operational units, assuring that there is no bias when a critical quality decision is to be made. FDA and cGMPs are vague on the organizational and reporting structure within a pharmaceutical manufacturing operation. However, the Agency does expect an independent quality function responsible for deciding all the quality-related issues which could impact a distributed drug product or a clinical study material. With the evolution of quality assurance practices over the past 30 years or so, most pharmaceutical companies now have a separate quality assurance
function, independent of the quality control laboratory, recognizing the fact that even analytical operations need to be monitored for quality and compliance practices.The reporting structure should be such that the quality assurance function should not report to the individual who heads up the manufacturing operations in general. This leads to a conflict of interest, as some quality decisions may not be very pleasant for the operations folks. However, sound management practices and a genuine commitment to quality practices can help the organization overcome such fears. The corporate quality policy and manual can also establish the basic procedures on change control and resolution of any issues that might arise because of any of the critical changes involved.
Quality/Compliance Review Committee As part of the organizational structure, there should be a group of designated individuals from key operational and quality/compliance functions with the responsibility to evaluate all quality/compliancerelated changes/issues, assess their impact on the drug product involved, define any corrective actions needed, and the authority to make critical decisions as to the disposition of the materials or drug products involved. Such a group or committee can be named the Material Review Board or Quality/Compliance Committee and quality assurance should lead the group. However, in some cases, such decisions involve major capital investments or critical compliance decisions. Under such circumstances, the group should make recommendations to upper management, defining the possible course of action to resolve the situation at hand while addressing the long-term solution to the problem as well and thereby forcing the senior managers to get involved in the quality/compliance decision making process.
Change Control Master System and Subsystems Fundamentals of a change control system should be spelled out in the corporate quality manual, if there is one. A typical change control system usually has a master change control system and a number of subsystems, depending on the types of changes encountered. A master change control SOP details the basics of the master change control system, defining the overall responsibility and authority for reporting, investigating, and decision-making for a critical change. The Technical Guide
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Shahid T. Dara master SOP also defines the general classes or types of changes that might be encountered within a given manufacturing operation and which changes are considered critical, major, or minor, based on general guidelines. The master change control system oversees the functioning of subsystems, as each one is established for a unique type of change, for example deviations, nonconforming materials handling, out-of-specifications data investigations, etc. For the change control subsystems, each should have an SOP defining a given change and how to manage it, with its attendant corrective actions, etc. One key element of any corrective action plan is how it is to be implemented and whether it involves additional training for employees. Finally, there should be an effective audit trail to assure that the desired changes are being implemented in a controlled environment, with full documentation of each critical step involved and employee training and retraining whenever necessary.
Enforcement of Change Control Systems Like any other quality practice, a change control system can only be effective if it is implemented as part of everyday operational activities, thereby making everyone aware of the fact that every change has to be documented and reported to appropriate organizational units. Many times machine operators and front line supervisors have a tendency to consider a given change as a minor one, forgetting the fact that an accumulation of these minor changes could lead to major deviations from approved practices. A key factor in successful implementation of any change control system is that it should be implemented consistently, meaning all changes must be documented, reviewed, justified, and approved or rejected by Quality Assurance.
Training Employee training in change control systems and related procedures is essential in enforcing such a system. The training program should be interactive, detailing the impact of changes on the overall quality of the drug product being manufactured and the consequences if these changes are not controlled. For example, little deviations from an approved NDA procedure or SOP, at the time of occurrence, might seem of no consequence, but an accumulation of these changes can result in an adulterated drug product, since the NDA procedure or SOP is no 6
Journal of cGMP Compliance
longer being followed. Thus, the SOPs detailing change control systems should be very clear as to their contents, as ambiguous SOPs lead to ineffective training and, therefore, could cause failure of the change control system itself. The importance of utilizing effective change control systems is evident when employees are trained on revised SOPs. Here is an opportunity to explain why a change was made and how it would impact the quality of the product.
Empowerment and Shared Quality Responsibility Individual employees within the operations group should not only be trained in detecting any changes from approved practices, but they should also be empowered to bring such a situation to the attention of their immediate supervisors and the quality assurance function, without fear of reprisals.This approach can work miracles for the organization as it makes each individual at every level responsible for the quality of the product and, therefore, forces everyone to watch for deviations from approved practices. One way to implement such a system (which can be termed as Shared Quality Responsibility) is to ask the frontline operators to write their own SOPs, thereby minimizing the potential for a conflict between an approved SOP and actual practice on the floor. Also, this approach helps to identify any changes in approved practices/SOPs in a much more organized and timely fashion. Routine audits of batch records indicate if there are any unreported changes in any process. If there are no changes documented in the records, then one has to be concerned about the effectiveness of the change control system. There is a possibility that many changes are considered minor by the operators and therefore are neither documented nor reported to the appropriate authorities, and eventually such minor changes could lead to a total loss of control over a period of time.
Regulatory Means for Change Control Management For approved application drug products (New Drug Applications [NDA]/Abbreviated New Drug Applications [ANDA]), all changes have to be reported to the FDA. Depending on the nature of the change, these could fall into one of the following categories: Pre-Approval Supplements A major change to manufacturing/packaging pro-
Shahid T. Dara cess, materials, product, or procedures require prior approval by the FDA before it can be implemented. Such a submission to FDA is referred to as a Pre-Approval Supplement. However, there is a minor distinction here that the change under review can be implemented prior to FDA approval, but the drug product so manufactured/packaged cannot be marketed until FDA’s approval of the supplement. Change Being Effective (CBE) Improvements to manufacturing/packaging process, materials, product, or procedures do not require prior approval by the FDA before they can be implemented. The Agency wants to review these, but there is no need to wait as it is classified as an improvement. Such a submission to FDA is referred to as a Changes Being Effective (CBE) supplement. Annual Drug Product Reports Routine or minor changes in manufacturing/packaging process, materials, product, or procedures do not require submission to FDA at the time that the change is made. Such changes are reported as part of the NDA/ANDA annual reports and are usually of little consequence to the quality, safety, or efficacy of the drug product. However, such changes must be reviewed and approved by quality assurance prior to their implementation. Quality Failure Investigation Procedure A quality failure incident is usually caused by an unplanned change in materials or practices, with the possible rejection of the raw material or drug product involved. A thorough investigation of such incidents can be of tremendous value in determining whether the change control systems in place work effectively. If there are a number of rejects because of quality failure, that is a sure sign that the materials or process or both has definitely changed without triggering the change control process to avoid the quality failure. Therefore, it is important that a comprehensive quality failure investigation procedure be in place and strictly followed whenever a quality situation arises. Drug Product Annual Quality Review Reports 21CFR 211.180 (e) requires that an annual quality review report be prepared for each marketed drug product to evaluate all the changes made during the review period and their impact on the overall quality. Such a report can be a useful tool for the quality assurance function to detect
minor changes in manufacturing/packaging processes that might have gone unreported. Internal Audits An effective internal audit program is another practical approach to managing change control, as it enables the entire organization to be proactive for planned changes while ensuring the resolution of unplanned changes, which might have gone unnoticed. Also, the internal audit program can be designed to help promote a team approach to resolving quality/compliance issues; however, it is a huge subject in itself and, therefore, cannot be discussed in any detail here. Product Complaints Product complaints should be thoroughly investigated and quantified where needed. A rash of related complaints could be an indication of a major change in the product, involving the components, the process, or both. Such a situation should be handled as an emergency, and a fullscale investigation should be initiated to pin down the change causing the quality complaints. How to Avoid Surprises? No one likes surprises during an FDA visit, especially it demonstrate that the company does not have an effective change control system. And that could have far reaching consequences. In recent years, FDA has cited a number of manufacturers for a lack of comprehensive change control systems, especially in regard to incomplete failure investigations. The best way to avoid any surprises is to have a vibrant quality function within the organization with a quality culture that promotes selfpolicing by all departments. The change control system should trigger a chain of events that prohibits the use or distribution of suspect quality materials or drug products until the resolution of change. Communication is the key to the success of such a system, as sharing information helps everyone understand the situation in a better way while training individuals for future incidents.
POSSIBLE CHANGES ENCOUNTERED IN PHARMACEUTICAL MANUFACTURING FDA compliance enforcement policies have evolved over the past 30 plus years, as the Agency’s understanding of its own regulations and their impact Technical Guide
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Shahid T. Dara on industry practices grew with time. In recent years, the change control issue has been cited as a major cGMP deficiency by the FDA, while inspecting manufacturing facilities, both for dosage forms and active pharmaceutical ingredients (API), but this discussion is limited to dosage form manufacturers only. A comprehensive change control system should be able to control the impact of any changes encountered within a pharmaceutical company that might have a bearing on product quality/compliance status. Also, the master change control system should have supporting subsystems, which can adequately handle any of the situations possible. The following is an overview of different phases and components involved in drug product development, the manufacturing process, and what changes can occur in different scenarios. This review is meant to address the possible quality impact of the potential changes as well as how to control them without compromising the quality of the drug product and outlining what the procedural considerations should be.
Product Development Phase All drug products involve some level of research and development effort, be it a new chemical entity or generic version of a monograph product. Over the past few years the research and development activities have come under increased scrutiny by the Agency, especially as part of Pre-Approval Inspections for NDA/ANDA drug products and as a result of the generic drug scandal of the late 1980s. The Agency expects the company to have a complete development report that summarizes the entire process of development of a given drug product. This subject is discussed in detail toward the end of this section. With the introduction of the proposed cGMPs for APIs, the change control net has widened its range beyond traditional dosage form manufacturing processes, and the critical decision is determining when the process fall under cGMP regulations. Here, the change control decisions should be made by the development scientists at an earlier stage of development. As the drug product enters the clinical testing phase, the cGMP-based change control systems should take over, with due review and approval of all critical changes by quality assurance. When to Initiate Change Control Practices? When do the cGMP regulations apply during the development process? The industry standard has 8
Journal of cGMP Compliance
been that with the manufacture of the first biobatch, the entire manufacturing process should be performed in compliance with cGMP regulations. Bio-batch is the term used to describe that lot of drug product used for the first clinical studies. That is the reason that companies have a cGMP development area and a non-cGMP development area. This practice has some benefits, but in today’s cost-conscious environment, it is much more beneficial to have one set of rules for the entire company to follow, with far less potential for any major mishaps. If research and development and manufacturing departments are following the same basic procedures as far as documentation practices, change control, and employee training are concerned, then the transition from R&D to manufacturing can be much smoother. Another advantage is that all changes and improvements made during the development phase are properly documented and can be a tremendous source of information for future references. Potential Changes During Development Following are some of the changes that can happen during the research and development phase and should be controlled and documented according to company procedures. Formulation Formulation development is a very controlled process, and initial assessment of a new formulation has a number of variables involved; however, once the basic formulation of a dosage form is finalized, all changes should be carefully controlled, documented, and evaluated. Some of the possible changes are: Composition Percentages of active and inactive ingredients per unit dosage define the composition of a given drug product. Once the pharmacological dose of a drug substance is established, its quantity per unit dose is easy to calculate based on the dosage regimen. It is only changed if the stability profile of the drug product indicates a need for an overage, or there is a substantial loss of active pharmaceutical ingredient during the manufacturing process. In the first case, the overage issue will surface at an early stage of development, while production loss may not be detected until the final scale-up batches are manufactured. In either case, the excess must be justified and require pre-approval by FDA prior to its
Shahid T. Dara implementation and will be submitted to the Agency as a supplement to an NDA/ANDA drug product with pertinent stability and process data. Inactive ingredients or excipients however, are changed more frequently as the dosage form formulation is optimized. Depending on the drug substance and dosage form involved, there are always a couple of excipients in each drug product that are critical for its success, both for drug delivery as well as stability of the dosage. Their percentages in a formulation are finalized based on both scientific knowledge and experimental data. However, any quantitative change in a critical excipient could have a devastating effect on the quality of the drug product, as it can be the bulking agent in tablet, a carrier for a lyophilized injectable, or a key preservative in a liquid. If the change in excipients is considered critical, it requires FDA pre-approval. Active Pharmaceutical Ingredient (API) Changes Active pharmaceutical ingredient/s (API) are welldefined molecular entities with a known impurity profile and should not be changed. However, some of the changes that could occur with an API include: New Manufacturer: Alternate manufacturers are essential to maintaining the reliable supply of a drug product. It is highly unlikely that API from multiple sources will be available for evaluation during the formulation development phase. But whenever this change is made, the formulation has to be reevaluated, and the drug product has to undergo stability testing to assure that the new API has no impact on the purity, safety, efficacy, and quality of the drug product. Also, the impurity profile of the new API and its stability must be established to make it a viable source. Such a change would require pre-approval by FDA prior to its implementation and will be submitted to the Agency as a pre-approval supplement to an NDA/ANDA drug product with pertinent stability and process data. A new manufacturing process or major change in the manufacturing process of an API can have similar consequences. Such a change again requires pre-approval by FDA prior to its implementation and will be submitted to the Agency as a pre-approval supplement to an NDA/ANDA drug product with pertinent stability and process data. However, in some cases, this can be a changes-being-effective (CBE) supplement, if the change in manufacturing process is an improvement in the overall quality of the API. Nonetheless, the drug product manufactured with
new API has to be evaluated for stability. A change in physical characteristics of an API can also have a critical effect on the drug product, for example, particle size, crystal form, isomeric resolution, etc. These can impact the manufacturing process, like mixing times for powders, dissolution rates, drug delivery, and invivo bioavailability. Such potential changes should be carefully monitored and controlled via routine sampling and testing of API. If there is a sudden change in physical characteristics, that is a clear sign of a change or deviation in the manufacturing and purification process of the API. For dosage form manufacturers, such changes can be reported to FDA as part of the Annual Report, if the data shows no adverse effects on the drug product quality, safety, and efficacy. A change in the impurity profile of the API poses an equally serious challenge and could go undetected if the incoming API samples are not routinely checked for impurities. Potentially, this could have fatal consequences for the end user and be a major regulatory nightmare for the drug product manufacturer. To avoid this situation, each shipment of an API should be tested for known impurities of consequence, and if the API fails its specifications for impurities it should be considered for rejection. It gets interesting when unknown impurities are found during testing of the finished drug product while assaying for the API, putting the drug product release in jeopardy. To trace the source of such an impurity is a monumental task, and the culprit could be the API itself or the manufacturing process, like a cleaning agent residue. Such instances should be duly investigated and the drug product disposition decision made after considering all the relevant facts, analytical data, regulatory consequences, and, above all, the consumer’s health and well-being. Excipients Most excipients used in drug product formulation are United States Pharmacopoeia (USP) or National Formulary (NF) grade and therefore are well characterized chemical entities. It is common practice to use more than one manufacturer of an excipient as long as the raw material meets its compendial specifications. Of course, formulations using different sources of excipients have to be evaluated for stability and overall quality of the drug product. However, there is a potential that an unapproved source of an excipient might find its way into a formulation, contending that it is the same official grade material. Chemical distributors have earned a reputation for Technical Guide
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Shahid T. Dara switching raw materials manufacturers without notice. In most cases, such a change should be caught at the time of receiving the material, not during the sampling/inspection process. The material should then be put on hold for latter disposition. Sometimes a source change is inevitable due to natural disaster or other reasons, and that is where the change control system should trigger the mechanisms to protect the safety, efficacy, and purity of the dosage form. Such a change might necessitate a reevaluation of the formulation and could even affect the manufacturing process. In most cases, this leads to additional stability testing of the finished drug product, concurrent at controlled room temperature (CRT) and ambient humidity. Equipment The manufacturing process development starts with lab-scale equipment and moves through midsize equipment in the pilot plant, leading to a biobatch size, which is the base for future scale-up. Throughout this process the equipment changes occur. Sometimes it is not just a bigger piece of equipment, but could be of different mechanical configuration, if so dictated by the process needs. All such changes should be documented and evaluated for future references. During the development process, the equipment needs to evolve as the formulation characteristics are better understood. Also, batch size and the economics of manufacturing efficiencies also impact the selection process. Equipment changes will be discussed in more detail later. Process As the manufacturing process evolves from the development lab through the pilot plant, the process parameters begin to take shape as well. Some of these are as follows: Critical Process Conditions Process conditions include mixing times, machine speed set-ups, processing temperatures, and process time limits. Changes in these conditions should be documented and evaluated for their impact on the drug product. At this stage, change is part of the development process, and it must happen. However, even at this stage, all changes should be documented, evaluated, and kept under control. Scale-Up Factors Change from bio-batch to commercial-size batch is termed scale-up, and the Agency allows a 10 10
Journal of cGMP Compliance
times scale-up without additional testing. However, the manufacturing process should be well qualified before the scale-up factor is applied, as it will help avoid unpleasant surprises. Also, one should consider the capacity of the equipment and the physico-chemical properties of the formulation when deciding on scale-up of batch size. Recent FDA guidelines on scale-up and post-approval changes (SUPAC) are of great help in deciding these issues. Commercially manufactured drug product should be equivalent to the bio-batch product for bio-availability of drug substance as well as dosage form specifications. Controlled Environment Since most drug products are temperature or humidity sensitive, the environmental conditions should be defined as the process is being developed, based on chemical and microbial stability of the formulation in general and end product in particular. Again this information evolves as the process is developed, but any deviant behavior of the manufacturing process should be documented under adverse environmental conditions. In-Process Controls In-process controls and sampling/test points are identified as the manufacturing process is evaluated in detail. For each dosage form there are some standard in-process tests, and then there are others which are formulation specific. These latter tests represent the critical stages during the manufacturing process, which can potentially compromise the integrity of the drug product. The in-process specification evolution should be documented and justified so that any future changes can be correlated without jeopardizing the drug product. Finished Drug Product Specifications Finished drug product specifications are, again, those which are dosage-form specific and then others are formulation specific. Their development history is a reflection of the chemical and microbiological nature of the API(s) and their interaction with excipients during the manufacturing process. The finished drug product specifications include physical characteristics, chemical purity, and acceptable bio-burden for a given dosage form. These specifications do change as the development process progresses and more information becomes available from process evaluation and stability studies. All such changes should be documented and explained for future reference.
Shahid T. Dara Analytical Method Development Whether it is a compendial method or not, each analytical method has to be qualified for a given testing laboratory. Depending on the nature of the formulation, the methodology always undergo changes, which should be fully documented and justified according to method qualification protocols. Stability Testing Stability testing starts at an early stage in the development process, and the only major change is usually in the container/closure system, depending on the stability profile of the drug product. Another change can be the storage conditions for the stability samples, again depending on the temperature, humidity, and sensitivity of the drug product. All changes in the container/closure system and storage conditions should be documented, explaining the reason for every change and its impact on the drug product involved. Product Development Report As the initial development process comes to a close for a drug product, a complete development report should be prepared, detailing the following: Formulation: List of ingredients with quantities per dosage unit and their quality reference, i.e., USP, NF, etc. ■ List of manufacturing equipment: ■ Manufacturing process: Development and scale up process with special emphasis on bio-equivalence of bio-batch versus the commercial drug product ■ Packaging process: Container/closure system and packaging conditions ■ Analytical methods ■ In-process and finished-product specifications ■ Stability studies protocols and data summary ■ Detailed discussion of process deviations and excursions during the development and scaleup process and consequent corrective actions ■ Conclusion and summary ■
Such a report can be a ready reference for a given product for future trouble-shooting. Also, it can be presented to the FDA if needed instead of bringing in stacks of paper for their review.
Facilities Changes Facilities are usually not considered critical when a change control system is devised.
However, the physical condition of manufacturing, packaging, and warehousing facilities has a direct impact on the drug product quality, and unauthorized changes should not be made. Facilities should be monitored in the following areas from a change control perspective: Repair and Maintenance Routine repair and maintenance activities should be monitored within the facility, especially if contractors are employed for a given repair job. If there is a structural modification made to an existing facility, the proposed change must be reviewed and evaluated according to company change control procedures. Due consideration should be given to the material and people flow if the facility is modified in any significant fashion. The validation and quality assurance departments should review all such changes to assure that the facility’s qualified or validated status is not compromised. Physical modifications can also impact the functioning of certain utilities, like HVAC, purified water system, dust collection system, etc. Cross-Contamination Potential Facilities should be constantly monitored for cross-contamination potential, particularly when there is a physical change in the facility itself or procedural changes which might impact the flow of materials and personnel. Of particular concern is the potential for inadequate cleaning by the repair crew after the job is done. Company personnel should be aware of such situations to assure that the areas are properly cleaned and inspected before use. In either case, the changes must be reviewed and approved by the quality assurance function. If such a change has affected any raw materials, packaging components, or in-process/finished drug product, the material involved should be carefully evaluated for the potential impact on its quality and safety before deciding its disposition. The quality failure incident investigation procedure should be followed for investigating all such incidents.
Pest Control 21CFR – Part 211, Subpart C – Buildings and Facilities 211.56 Sanitation This section clearly states that the manufacturer should have written procedures in place to define the responsibility and procedures for cleaning and sanitation of facilities. It also requires that only those rodenTechnical Guide
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Shahid T. Dara ticides, insecticides, and fungicides which are registered and used according to the provisions of the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135) can be used in a pharmaceutical manufacturing facility. Requirements of this section apply to both contractors and company employees. Only approved pest control agents should be used in the facility, and this approval is granted by quality assurance with due consultation with other departments. Pest control is usually performed by outside contractors. Each visit should be fully supervised to ensure that components, container/closures, or drug products are not exposed to any of these agents. If there will be a change in any of the agents, it should be pre-approved by the appropriate organizational units according to the pest control SOP. The contractor should be periodically audited to ensure that only approved chemicals are used and in the right concentration. An unauthorized change of pest control agents could compromise the quality and safety of the drug products involved. Natural Disasters Following a natural disaster, most organizations experience the most profound changes possible, yet companies strive to recover as quickly as humanly possible. A tornado or a flood can devastate manufacturing facilities, destroying inventories of both components and finished drug products. Even under such circumstances, the change control activities should be part of the Disaster Recovery Plan, as it will be necessary to change the quality status of a number of components, packaging/labeling materials, and finished drug products, from acceptable to rejected due to natural cause. Though the investigation will be simple, the activities have to be performed to close out inventory cards, batch records, etc. Another aspect of the Disaster Recovery Plan should address how to recover all the quality/compliance information related to marketed drug products. Equipment could be replaced, but critical documentation recreation is a monumental task. In brief, companies should have a comprehensive Disaster Recovery Plan that addresses not only the financial data, but also scientific, technical information, and documentation, and this could be part of the master change control system.
Utilities Changes Although cGMPs refer only to lighting, the HVAC system, and water supply under utilities, 12
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today’s pharmaceutical manufacturing plant uses a number of utilities to carry out everyday operations. Utilities are the ancillary systems which provide support to the manufacturing/packaging operations. These systems provide essential operational accessories to manufacturing, like conditioned air, purified water, clean steam, oil-free compressed air, etc. In most organizations, engineering and maintenance department usually manage utilities independently once these systems are installed and qualified. Potentially, a number of changes could be made to these systems without due review and approval process, resulting in an out-of-control system. To avoid such a situation, there should be a Utilities Change Control SOP in place to assure that all critical changes to a utility system are reviewed and approved by appropriate organizational units, including quality assurance. One way to keep abreast of changes made to a given utility system is to have each repair and maintenance activity performed reviewed and pre-approved by the quality assurance function. Once the task is completed, the system should be examined and released for use. All activity should be fully documented. An alternate system could be integrated into a validation change control system, requiring review of each critical change in a utility system for its impact on the validation status of that particular system to decide whether a revalidation is needed. Critical Utilities Define the critical utility systems for the operations, ones that could have an impact on drug product quality and include: HVAC system ■ Water purification system ■ Dust collection system ■ Compressed air system ■ Clean steam ■
Any major change in any of these systems could adversely impact the processing conditions, thereby compromising the quality of the drug product being manufactured. Parts Change Control Parts change occurs repeatedly in a manufacturing environment as utility systems wear down with use. Some parts changes are minor and have no
Shahid T. Dara impact on the operation of the system. In other cases, a critical part might have to be replaced, which could have a major effect on the operation of the utility system and the quality of its product and service provided to the operations. In most instances, such part changes are addressed during validation of these systems, clearly defining which part changes could lead to a requalification of the system. This aspect is usually covered under the validation change control SOP that describes the criteria for such an option and the review and approval process. In other words, mechanics and technicians are not allowed to change parts without prior approval from appropriate organizational units, including quality assurance. For each utility system there should be a maintenance SOP in place, defining the parts change control and a list of approved parts or a reference to the utility system equipment manual. Use of unapproved change parts should be strictly prohibited, as it could compromise the performance of the system. Sometimes utility systems are underutilized and, as the operational activities increase, the utility systems are expanded to meet the increased demand or to supply a utility to another part of the operation. It is a common practice to extend the water supply pipelines or to add outlets for compressed air.These are major changes and additional piping and outlets will necessitate extensive cleaning of the pipes, etc., to prevent contamination of the system as a whole. This system extension should be strictly controlled, as it can affect the overall operation of the utility system as well as its validation status. Also, as part of this change control system, the as-built drawings of the system must be changed to reflect these extensions. Operational Parameters Each utility system operates within a predetermined set of conditions or parameters. If these operational parameters are changed, it could impact the functioning of the system as a whole. It could be the rate of feed water supply to a deionizing tank in a water purification system or the operating temperature for a compressed air system. Such a change should be avoided at all costs, as it can physically damage the system. But, if such a change does occur, it should be addressed immediately to control the damage and minimize the impact on the quality of the drug products involved. Every utility system is equipped with controls, alarms, and emergency shutdown mechanisms, which immediately trigger a chain of events to control the situation. However, the operators and
plant personnel should be aware of the general operating conditions for each utility system and be able to recognize any extraordinary circumstances. Inter-Relationship of Utilities Functioning Utility systems usually operate independently of each other, but there are situations where two or more utility systems function as a unit, and a change in one system can impact the performance of others. For example, the dust collection system and HVAC system work in tandem to remove dust from a manufacturing area while providing a given amount of conditioned air and a certain amount of air changes per hour to the particular room. Likewise, humidifiers in HVAC systems help maintain a certain level of humidity in the conditioned air. If the humidifier malfunctions, it will affect the performance of the HVAC system by altering humidity levels in the air supplied to the manufacturing areas and, therefore, impact the quality of the drug product being manufactured. Thus, while approving a change in one utility system, other systems should also be considered, as there might be an operational relationship between these systems. Such relationships should be well defined and known to the engineering and maintenance department along with quality assurance and validation personnel.
Equipment Changes Manufacturing/packaging/analytical equipment is a major capital investment, and each piece is carefully selected considering a company’s immediate and long-term manufacturing needs. Usually, major pieces of equipment are not changed very frequently, as is evident from the fact that some manufacturing operations employ equipment that is 20 – 30 years old. Although cGMPs refer to current technology, there is no regulation barring the use of old equipment if it is in good repair and qualified to perform the job required. Another fact is that a number of old application products were approved with the old equipment available at the time, and many companies find it very costly to upgrade some of that equipment, as it will require a number of regulatory submissions. However, some old pieces of equipment are replaced by newer equipment because of technological innovation or capacity reasons. Such equipment change is usually very well controlled, as it involves the qualification of new equipment, including product specific process validation. The first few lots manufactured with the new equipment are placed on stability, either on concurrent CRT Technical Guide
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Shahid T. Dara or under accelerated conditions, depending on the regulatory status of the drug product and its stability profile. If it is an NDA/ANDA drug product, FDA is notified either through a pre-approval supplement to the application or as a changes being effective (CBE) notice, along with process and stability data. SUPAC (Scale-Up and Post-Approval Changes) guidelines were developed jointly by FDA, industry, and academia in response to the growing number of changes that the pharmaceutical industry had experienced in manufacturing operations in recent years, which resulted in an excessive number of submissions to FDA for application drug products. Another factor that contributed toward this effort was a rash of mergers and acquisitions over the past decade, which led to a considerable consolidation of manufacturing operations and technology transfers from one plant to another. While addressing the questions of process scale-up and how to handle post-approval changes in manufacturing procedures and specifications, these guidelines also provide a definition and listings of what is considered similar equipment, based on the same design and operating principle for immediate release drug products. Examples of similar equipment include replacing a ribbon blender from one manufacturer with a ribbon blender from another manufacturer, as it will not present any change in design or operating principle. Switching from a ribbon blender to a V-blender is a change involving different equipment based on their design and operating principle. However, applicants should review each equipment change case on its own merit and make a judicious decision based on sound scientific data. Switching from a ribbon blender to a fluidized bed dryer and mixer is a major change that affects the manufacturing process parameters. Try not to justify this change as part of the SUPAC Similar Equipment Guideline. These are useful reference guides and can be of tremendous value when replacing equipment or transferring manufacturing from one plant to another. There are some limitations, however, which will be discussed later. Equipment Usage Routine usage of equipment also needs to be managed from a change control perspective. Possible variables, which could impact the quality of the drug product, include: ■ ■ ■
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Machine setups Mixing speeds Timers Journal of cGMP Compliance
Switching between similar equipment ■ Sprayer set up for both powders and liquids ■ Compression machine setup ■
There should be detailed instructions in the master batch record describing what equipment is to be used for a given batch size and what should be the operating parameters for each piece of equipment at every step of the manufacturing process. For a granulation, the batch record should describe which mixer is used, at what speeds, and for how long. A critical review of a completed batch record can easily show if the equipment was used within its prescribed parameters. If there is any deviation, it should be reported immediately to appropriate organizational units and approved by quality assurance according to the deviation SOP. In some cases, however, the deviation is discovered after the fact, like the failure of a chart recorder on a drying oven during a cycle lasting 12 hours or more. Here, the situation warrants a critical review of the failure with special emphasis on its impact on the quality of the product. Test additional samples to gather valuable data to decide the fate of the batch involved, while mechanical failure is addressed separately. The entire investigation, test data, and corrective actions should become part of this unplanned change event and reviewed and approved by quality assurance before the drug product involved is released for distribution. Sometimes, there are planned or intentional deviations from an approved procedure. This usually happens when the procedure has been revised, while going through its routing, review, and approval process, but the change usually involving procedural improvements or corrective actions has to be implemented immediately. In either case, these planned deviations or exceptions should be documented, reviewed, justified, and approved by appropriate organizational units according to the particular change control system. Equipment Cleaning Practices Equipment cleaning is a sensitive subject both for the Agency and industry, and the sky seems to be the limit when it comes to the definition of “clean equipment” and “allowable residues.” There should be detailed procedures available for each piece of equipment or grouping of similar equipment based on extensive cleaning validation data, both equipment and product specific. Also, there should be an SOP on approved cleaning agents for product contact surfaces.
Shahid T. Dara Equipment cleaning procedures should be followed religiously, and cleaned equipment should be inspected and released for use by quality assurance. However, the biggest source of variation in equipment cleaning sometimes is the cleaning procedure itself, as it may be vague. Another variable is uncontrolled use of cleaning agents, as the individual procedures may not describe the dilution factors and how to prepare a solution from concentrate. But most of all, the manufacturing crew responsible for cleaning might cause the biggest problem by not following the cleaning procedures, using incorrect dilutions of agents and causing drug product contamination. Thus, operator training in correctly following the equipment cleaning procedures is as important as knowing how to use the equipment. If a drug product is contaminated due to inadequate cleaning of the equipment, the change control system should immediately trigger the batch to be placed on hold/quarantine until the investigation is complete and a decision is made as to its disposition. Such an investigation will focus on both the quality failure of the product as well as failure of the cleaning procedure itself. If the suspected drug product can be proven to be safe and effective based on analytical data and clinical toxicology of the potential contaminants, then it should be considered for release to distribution. Otherwise, it should be non-conformed and processed according to the non-conforming materials SOP. The cleaning procedures involved might require extensive revision and follow-up training of the operators. All such activities should be documented, reviewed, and approved by quality assurance, and the revised SOPs and training records made part of the change control investigation. Critical Parts Change and Qualification Status Parts change is part of a manufacturing environment as manufacturing and packaging equipment wears down with use. Some parts changes are minor and have no impact on the operation of the equipment. In other cases, a critical part might have to be replaced, which could affect the operation of the equipment and the qualified status of the machinery. In most instances, such part change issues are addressed during validation of the equipment, clearly defining which part changes could lead to a revalidation of the equipment concerned. This aspect is usually covered under the validation change control SOP that describes the criteria for such an option and the review and approval process. In other words, mechanics and technicians are not allowed to change
parts without prior approval from appropriate organizational units, including quality assurance. There should be a maintenance SOP in place for each major piece of equipment, defining the parts change control and a list of approved parts or a reference to the equipment manual. Use of unapproved change parts should be strictly prohibited, as it could compromise the performance of the equipment. All critical part changes should be logged into the individual maintenance log for each piece of equipment to maintain traceability. If the equipment requires too many change parts too often, it might be time to replace it. Maintenance – Preventive and For Cause Equipment maintenance could be preventive or for cause. In either case, there should be preventive maintenance SOPs in place for all key pieces of equipment, detailing the methods, equipment, and schedules of preventive maintenance. Such SOPs should also describe disassembly and reassembly of equipment for proper maintenance. All maintenance orders should be reviewed by quality assurance and the equipment inspected and released by quality assurance before it is put back into service. Also, there should be an SOP in place describing the approved product contact lubricants that can be used for repair and maintenance of manufacturing and packaging equipment. Mechanics should be thoroughly trained in these SOPs to avoid any surprises. It is a common practice to declare each repair a minor item to expedite the repair process, and soon a given piece of equipment might have been totally overhauled, without any consideration for its revalidation or impact on the manufacturing process. The employees, both operators and supervisory staff, should be grilled in following the proper procedures when it comes to equipment repair and maintenance to assure that the equipment used in manufacturing is always maintained in a qualified state. Calibration Status Equipment performance is controlled and monitored by gauges and meters, which are calibrated at regular intervals. Sometimes, the gauges have to be removed from the equipment to perform calibration. In the meantime, the gauge is usually replaced by a similar gauge, which is still within its calibration. This change is performed by the metrology department in association with the maintenance staff, without verification by quality assurance that the replacement gauges are similar to the ones being replaced and Technical Guide
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Shahid T. Dara are within calibration when installed. The change control system should address these changes, as it is a compliance requirement to have all critical equipment and associated controls calibrated which could have an impact on the safety, quality, purity, identity, and strength of a drug product.
the relevant parameters need to be tested to assure that the changes do not compromise the validated status of the software and the performance of the equipment involved.
Equipment Breakdown Equipment failure in the middle of a manufacturing or packaging run is a critical but unplanned change that needs to be carefully controlled to protect the integrity of the drug product. The product or in-process materials should be quarantined immediately to assess the impact of the breakdown and how long it will take to repair the machine. The process time limit conditions for the given operation should also be considered to assure that these limits are not exceeded. If this is the case, additional sampling and testing might be required before proceeding further with manufacturing or packaging operations. This is more critical for liquid preparations and those with natural ingredients, as these drug products are more prone to supporting microbial growth. For parenteral drug products, if the equipment breakdown exceeds the validated process time limits, then the drug product has to be discarded. There should be an SOP addressing equipment breakdown change control situations, detailing the steps needed to assure the integrity of the product, including review and approval requirements and follow-up actions. There should be a log of equipment breakdown, recording each incident, cause, and how long the equipment was out of commission. Also consider the extent of repair required and its effect on the validated status of the equipment. Frequent breakdown of equipment is a sign of age or poor maintenance practices.
Components, containers, closures, labeling, and packaging materials essentially comprise the building blocks for drug manufacturing. As discussed in the product development phase, any critical change in a component or container/closure system will have far reaching quality implications for the drug product involved. Most of the time, these changes are planned to qualify alternate manufacturers. However, some changes are discovered after the fact, and the manufacturer has to respond accordingly. This section addresses potential changes for chemical raw materials and packaging components that come into direct contact with the drug product and their possible impact on the overall compliance and quality status.
Automated Equipment Automated equipment operation, repair, and maintenance pose a different set of issues from a change control perspective. Whenever there is a change involving the PLC boards or software code upgrades, it should be carefully reviewed by information technology and quality assurance personnel to assure that the equipment will continue to perform within its validation parameters. All such changes should be documented, reviewed, and approved by quality assurance according to the change control SOP. The equipment should be fully tested before it is released for use. Likewise, if there is a software code change, then all 16
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Component Changes
Raw Materials Raw materials include both active pharmaceutical ingredients as well as excipients, and possible changes could include the following: Manufacturer Change Alternate manufacturers are essential to maintaining the reliable supply of a drug product. A manufacturing change is either a planned change to qualify an alternate source or to respond to an emergency caused by a plant shut down due to natural disasters or quality/compliance issues. In either case, the formulation change control procedure should be followed. The formulation has to be re-evaluated, and the drug product has to undergo additional stability testing to assure that the new API has no impact on the purity, safety, efficacy, and quality of the drug product. The stability testing could be concurrent if the API from a new manufacturer proves to be identical to the original source. Also, the impurity profile of the new API and its stability characteristics must be established to make it a viable source. Such a change requires pre-approval by FDA prior to its implementation and will be submitted to the Agency as a preapproval supplement to an NDA/ANDA drug product with pertinent stability and process qualification data. In this case, the API from a new source is proven to be identical to the original and is a com-
Shahid T. Dara pendial material. This change in formulation could be reported to FDA as a Changes Being Effective (CBE) supplement. A new manufacturing process or major change in the manufacturing process of an API can have similar consequences. Such a change would again require pre-approval by FDA prior to its implementation and submitted to the Agency as a supplement to an NDA/ANDA drug product with pertinent stability and process data. However, in some cases, this can be a CBE supplement, if the change in manufacturing process is an improvement in the overall quality of the API. Nonetheless, the drug product manufactured with the new API has to be evaluated for stability. This type of change has to be communicated to the drug manufacturer by the API manufacturer and requires effective communication between the two based on a recognized quality agreement, mandating that any change in the manufacturing process be reviewed and approved by the dosage form manufacturer. A change in physical characteristics of an API can also have a critical effect on the drug product, for example, particle size, crystal form, isomeric resolution, etc. These can impact the manufacturing process, like mixing times for powders, dissolution rates, drug delivery, and in-vivo bio-availability. Such potential changes should be carefully monitored and controlled via routine sampling and testing of the API. A sudden change in physical characteristics is a clear sign of a change or deviation in the manufacturing and purification process of the API. For dosage form manufacturers, such changes can be reported to FDA as part of an Annual Report, if the data shows no adverse effects on the drug product. A change in the impurity profile of the API poses an equally serious challenge and could go undetected if the incoming API samples are not routinely checked for impurities. Potentially, this could have fatal consequences for the end user and be a major regulatory nightmare for the drug product manufacturer. To avoid this situation, each shipment of an API should be tested for known impurities of consequence, and if the API fails its specifications for impurities, it should be considered for rejection. It gets real interesting when unknown impurities are found during testing of the finished drug product while assaying for the API, putting the drug product release in jeopardy. To trace the source of an impurity is a monumental task, and the culprit could be the API itself or the manufacturing process, like a cleaning agent
residue. Such instances should be duly investigated, and the drug product disposition decision should be made after considering all the relevant facts, analytical data, regulatory consequences, and above all, the consumer’s health and wellbeing. Excipients Most excipients used in drug product formulation are USP or NF grade and therefore, are, well characterized chemical entities. It is common practice to use more than one manufacturer of an excipient as long as the raw material meets its compendial specifications. Of course, formulations using different sources of excipients have to be evaluated for stability and overall quality of the drug product. However, there is a potential that an unapproved source of an excipient might find its way into a formulation, contending that it is the same official grade material. Chemical distributors have earned a reputation for switching raw material manufacturers without notice. In most cases, such a change should be caught at the time of receiving the material, and if it goes unnoticed, during the sampling/inspection process, the material should be rejected. Sometimes, a source change is inevitable due to natural disaster or other reasons and that is where the change control system should trigger the mechanisms to protect the safety, efficacy, and purity of the dosage form. A change in a critical excipient would have more impact on the quality of the drug product compared to a minor ingredient, especially if it has any bearing on the dissolution or bio-availability of the dosage form. In such a case, the formulation with the new excipient should be carefully monitored for stability profile as well as dissolution and bio-availability behavior. If the new excipient has impacted any of these features, a pre-approval supplement to the application might be required. If it can be proved that the excipient from the new manufacturer is equivalent to the original, then such a change could be reported as CBE or even as part of the Annual Drug Report. Storage Conditions Storage conditions for raw materials are equally critical in maintaining the quality of a drug product. This is especially true for biological derivatives and those raw materials that are susceptible to heat, humidity, or microbial infestations. Warehousing practices and overall environment monitoring of the facilities should have built-in change control mechanisms whenever the temperature/humidity condiTechnical Guide
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Shahid T. Dara tions drift from the specified ranges. Storage conditions are of critical importance for soft gel capsules both empty and filled. If these are stored at very high temperature or under extreme humidity conditions, the soft gels become brittle and fail to perform during the capsule filling operation. Packaging Components Packaging components describe the immediate container/closure system for the drug product and usually include the following: ■ ■ ■ ■ ■ ■ ■ ■ ■ ■
Bottles Caps Tubes Cans Vials Ampoules Stoppers Filler Desiccants Blister materials (both base and lidding)
The USP is an excellent reference and has detailed specifications and test procedures for all types of container/closure systems used in packaging of dosage forms. The container/closure system is meant to provide adequate protection to the drug product through its shelf life and during its usage by the patient. The container/closure system is selected based on the stability profile of the drug product and is submitted as part of the CMC section of an NDA/ANDA drug product. Any critical change in the container/closure system requires additional stability testing, followed by FDA preapproval or some notification of this change to the Agency. Here are some of the changes that could occur with a container/closure system and how to handle these situations: Container/Closure Materials of Construction For HDPE and other plastic containers, the material of construction quality and grade is of critical importance, as the drug product comes into direct contact with the inner surface of the container. For HDPE resin, for example, there might be multiple grades of resin available from the same manufacturer, with minor qualitative and quantitative differences. For bottle manufacturers, such differences might be of little consequence; however, such changes must be communicated to and preapproved by the drug manufacturer as they could 18
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adversely impact the stability of the drug product. Bottle manufacturers should be required to submit a Certificate of Compliance (COC) with each shipment of bottles with lot traceability for the resin used. Multiple resin manufacturers produce similar grades of HDPE and other plastic materials that meet the compendial requirements, yet HDPE from two different manufacturers could have subtle differences which could become apparent only after a rugged stability testing regime. Bottle manufacturers tend to switch HDPE from one manufacturer to another, depending on supply and price. However, a pharmaceutical manufacturer should have a quality agreement in place dictating the approved sources of resins for a given container, along with additives. Any change must be reviewed and approved by the drug manufacturer. A change in resin manufacturer or grade requires new stability studies for the drug product involved and might also require a pre-approval supplement to FDA, if it is a major change. However, if it can be proved that the resin from the new source or of different grade still meets all compendial requirements and would have little impact on the stability profile of the drug product, then it could be an annual reportable event. Nonetheless, it will require the change control system to kick in, and all the safety features and drug product involved would have to be placed on concurrent stability. The closure material of construction is of equal importance, especially the liner material, which comes into direct contact with the drug product. Any changes in material of construction has serious implications for the stability profile of the drug product involved, and any change should be closely monitored, as it requires new stability studies. Moisture permeation and adhesive abilities of the liner material are of special importance as it forms a protective sealing against environmental elements. Possible changes in construction of liner material include a different manufacturer or a grade of material. In either case, the change should be processed per change control SOP and requires a revision of the closure specifications to reflect the change. Unless the new material is deemed similar to the original, it will require concurrent stability studies, and the change reported to FDA as an annual reportable incident. Storage Conditions Like raw materials, packaging components should be stored under controlled temperature and humidity. Exposure to excessive heat and dry conditions could
Shahid T. Dara make certain plastic bottles brittle and even develop cracks. Such conditions can also adversely affect the liner material on closures, especially the pressure-sensitive type. High humidity can also cause deterioration of cotton, used as filler in packaging operations, by making it soggy or facilitating microbial growth. Storage conditions should be constantly monitored with built-in alarms to trigger corrective actions if the temperature/humidity conditions drift outside the predetermined specifications. Details of such a system should be described in an SOP and be part of the master change control system. Labeling Components Change Control Labeling components refer to the immediate label on a drug product container, physician or patient package insert, cartons, etc. Label development and the approval process is tightly controlled within each pharmaceutical organization. For NDA/ANDA drug products, labeling is approved as part of the application, and any post-approval changes in labeling components usually require FDA approval. Labeling development, revision, and the approval process should be separate from its usage controls. Labels and cartons should be stored in a limited access area, and the storage should be organized to prevent any mix-up of labeling components during storage and issuance. Multiple versions of the same label might be in inventory, especially in a use-up situation where the older version can be used until it is gone. Such a change can be managed only if there are mechanisms in place that provide version control for labeling components at the time of issuance as well as during its usage. Labeling errors are still one of the leading causes for drug product recalls.
Process Changes The manufacturing process generally consists of a number of unit operations, e.g., tablet manufacturing involves blending, wet or dry granulation, milling, drying, and compression as unit operations. Each unit operation has its own set of critical parameters that determine the quality of the overall manufacturing process. To fully understand the complexity of a manufacturing process, all the unit operations should be drawn up as a flow diagram. Based on the sensitivities of the drug substance involved and the dosage form being manufactured, define the critical steps, which need to be monitored against any change. Mapping of the manufacturing process is usually done during the pro-
cess development phase. Most process-related changes are unplanned and are handled as “deviations,” and the resulting in-process material or drug product is evaluated accordingly. Process Parameters Process parameters usually refer to machine set-up, mixing speeds, mixing times, drying temperature, sequence of addition of ingredients, etc. They all usually have a predefined range described in the batch record that is based on the process qualification and validation data. Most of the time these process parameters are followed religiously, and the manufacturing operations go on smoothly. However, once in a while, the granulation might be over-mixed or dried at a temperature that was out of its range for part of the cycle. Worst of all, many of these digressions are not caught when they happen, and they come to surface only when the finished batch record is being reviewed by quality control prior to its release for distribution. Now, the granulation that was dried under the suspect drying cycle has already been compressed, as the inprocess test for moisture content was well within specifications and the finished product also met all its specifications. But this is a deviation nonetheless and a change that must be reviewed by appropriate organizational units to pin down the cause of deviation and its impact on the quality, safety, and efficacy of the drug product and is evaluated according to the deviation SOP. The product disposition should be decided based on the nature of the deviation, product quality history, and the available data. Process Conditions Process conditions refer to the manufacturing environment, and it includes both the facilities as well as the temperature/humidity conditions. Depending on the nature of the drug product, the environmental controls can vary from simple temperature/humidity controls to extensive environment monitoring schemes utilized for aseptic processes. Most manufacturing operations are carried out under controlled temperature and humidity conditions. An occasional deviation from the settings should be considered as part of the system operation and could be caused by extremes of external environment. However, if the drug substance or unit operation involved is temperature or humidity sensitive, then it is a cause for investigation, and such a change should be controlled. Again, such changes Technical Guide
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Shahid T. Dara are usually noticed post-occurrence and, therefore, fall under the category of unplanned deviations and should be processed accordingly. Reprocessing Reprocessing is allowed under cGMP regulations; however, it is a critical change in an otherwise validated manufacturing process. It could be a failure of an in-process material or the bulk finished drug product that could force a company to consider a reprocessing option. There should be a reprocessing SOP in place to address such a situation. First of all, the cause of the failure should be investigated per quality failure investigation SOP. The impact of reprocessing on the safety and efficacy of the drug product involved should be thoroughly studied. If it is an NDA/ANDA drug product, regulatory implications of reprocessing should also be carefully examined. Once all the reviews are done and a decision is made to reprocess the material involved, a reprocessing procedure should be prepared, reviewed, and approved by manufacturing and quality assurance. The reprocessing procedure should also detail any additional sampling and testing to be performed. It should define if the reprocessed batch is to be placed on concurrent stability for long-term monitoring. A detailed investigation report should also be prepared, focusing on the corrective actions, particularly the need for revalidation of the manufacturing process. As the batch in question is being considered for reprocessing, it should be placed under quarantine according to the nonconforming materials SOP, so that it is not processed any further.
CHANGE CONTROL MANAGEMENT TOOLS A master change control system is composed of a number of individual procedures and systems that are meant to control changes in various aspects of the operational activities within a pharmaceutical manufacturing operation. Such a system should be interactive, managed by the quality assurance function with due representation from other functionary disciplines to address different changes. An integral part of any change control system is an effective quality failure investigation procedure. This section details some of the tools and procedures that should be implemented to have an effective change control system. 20
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Deviations 21CFR211.100 Written Procedures; Deviations This section mandates that there will be written procedures for production and process control to assure the identity, strength, quality, and purity of the drug product. However; if there is a deviation from written procedures it shall be documented and justified. The following discussion is a procedural approach on how to handle any deviations. Definitions A deviation is any modification or temporary change in any approved procedure, document, or specification. The deviation request/report is a specific one-time use document that will modify documents contained within or referenced by the batch record. It does not permanently change existing specifications, SOPs, or other batch record documents. These documents could be revised according to document change control procedures, if needed. Types of Deviations Deviations could be process or procedure related, and the following types of deviations can be found in a manufacturing operation. Planned vs. Unplanned A planned deviation is a proposed change to any approved procedure, document, or specification prior to execution. An example is the use of water-for-injection instead of purified water to rinse cleaned equipment. An unplanned/in-process deviation is an unexpected event that requires a change to any approved procedure, document, or specification. It is usually discovered after the fact. An example is a sudden change in temperature/humidity in the manufacturing area, missed sampling points, or temperature digression during a drying cycle outside the specified range. Temporary vs. Permanent A deviation could be temporary or permanent, depending upon its impact. If the deviation is a one-time occurrence, then it should be treated as temporary. Otherwise, if the deviation is going to result in permanent changes in an approved procedure, document, or specification, then it is a permanent change and will require detailed follow-up corrective actions to implement the required changes, including employee training.
Shahid T. Dara Lot Specific vs. Multiple Lots A deviation is usually lot specific for a given drug product but can also involve multiple lots. Product Specific vs. Multiple Products A deviation is generally product specific, but in some cases, it can involve more than one drug product. An example is a sudden failure of the water system, impacting multiple drug products, which might have used suspect-quality water for equipment cleaning or product manufacture. Potential Areas of Deviations Following is a listing of potential deviation areas and how each could influence the drug product quality attributes. Materials Raw materials as well as labeling and packaging components must meet their quality specifications before their usage in manufacturing. Yet there will be situations when an unreleased material might end up in manufacturing, or an unapproved labeling component might be used in the labeling/packaging operation. In either case, the impact on the quality/compliance status of the drug product should be reviewed in detail before deciding its disposition. Equipment The sudden breakdown or malfunction of equipment is an unplanned deviation that could have an adverse impact on drug product quality. Also, if the equipment is beyond its calibration period and is used in manufacturing, packaging, or testing of the drug product, it will compromise its compliance status. Such deviations may not have any apparent effect on the quality, safety, and efficacy of the drug product but still have compliance implications. Another deviation could be replacing equipment by similar or comparable equipment in the middle of a manufacturing run. Such a change should be documented and justified at the time of occurrence and be pre-approved by the quality assurance function. Process Deviations from both process parameters and process conditions could affect the drug product. Machine setups, mixing speeds, drying temperatures, etc., all should remain within the preset limits. Any digression would be a deviation and would require an investigation, especially if the machine
settings drift too far from the validation data. Likewise, process conditions, like temperature, humidity, and the microbial quality of the environment, should be maintained as any change would be considered a deviation and could impact the drug product quality. Practices If the written procedures are not followed strictly, this will be a deviation as spelled out by the regulations. For example, if sampling procedures are not followed, the samples collected will become suspect, and any data obtained from their testing will not be of value to make any quality decisions. Such a deviation requires resampling and retesting of the materials along with other corrective actions, including retraining of employees. Documentation practices cGMPs require that all quality/compliance related documents be prepared, reviewed, revised, and approved according to written SOPs. Likewise, such documents should be used in a consistent manner; if not, this will be a deviation that has to be explained. Documentation practices are a cause for concern throughout the company, and employees should be trained and retrained on this subject. Test Methods Analytical test methods are qualified relative to a given drug product and set of instruments. Whenever there is a deviation from an approved analytical procedure, it requires a detailed investigation and sound scientific justification before the data is accepted for any quality decision. Some deviations are minor, yet these should be documented, while others could lead to a reevaluation of the analytical method or the instrument used. Sometimes deviation from an approved test method is necessary because of compendial changes, and the written procedure is yet to be reviewed and approved by the organization. Specifications Specifications are based on sound scientific data and are a direct result of drug product behavior during the development process. Raw material and packaging component specifications are either based on the most current USP or supplier specifications. Deviations from approved specifications result in failure and rejection or rework of the materials involved. Technical Guide
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Shahid T. Dara Deviation Management Whether a deviation is planned or unplanned, there should be a change control system in place to handle it. Essential elements of such a system would include the following: SOP There should be a written procedure in place on deviation processing, detailing all the steps necessary in resolving a deviated scenario. Deviation Report A standardized deviation report form should be part of the SOP. Such forms should be prenumbered for control and reference purposes and controlled and issued by the quality assurance function. QA should also be responsible for the appropriate closure of each deviation report. The deviation report form should detail all the steps necessary to complete the investigation and resolution of an incident. Probable Cause The deviation reporter or requester should provide information as to the probable cause of the incident, especially if it is process related. Otherwise, the quality/compliance review committee would have to find the cause of the deviation as part of the investigation.
corrective action is required. If the answer is Yes, then details of the corrective action plan should be finalized and agreed upon with time lines for implementation. As part of the corrective action plan, also determine if the deviation under review has impacted any of the following areas and how that affects the quality/compliance status of the drug product involved: Stability data: Is there a need for additional stability testing? If yes, will it be concurrent or prospective, and under what conditions? Would this impact the current established expiration date for the marketed drug product? ■ Validation: Is the revalidation of a manufacturing process or an analytical method required? If so, what is the justification, and how does it affect the qualified status of the drug product involved? ■ Regulatory status: Will this deviation have an adverse effect on the approval status of the drug product? ■ Change request required: Will this deviation require changes in approved procedures, batch records, or specifications? If so, is the change request initiated and by whom? From a regulatory perspective, is this change a pre-approval supplement, changes being effective notice, or an annual reportable event? ■
Review/Investigation (if needed) Quality assurance and the rest of the quality/compliance review committee should review the deviation to make a determination if an investigation is warranted or not, depending upon the nature of the deviation. Such an investigation should be in-depth and in writing.
Responsible Personnel Whenever a corrective action is required, the corrective action plan should clearly define the responsibilities and accountabilities with quality assurance to oversee the effort. By naming the individuals or departments, it becomes much easier to follow up on the progress of the project.
Rationale for Acceptance/Rejection As part of the deviation investigation, the rationale for acceptance or rejection of raw materials and drug products should be well defined and based on sound scientific justification. If it involves a raw material, the quality history of the material should be considered and referenced in the decision-making process. If the deviation was process related, process qualification data and drug product quality history could be of value in the review process.
Deviation Disposition Once the investigation phase is completed, a decision needs to be made to decide the disposition of the materials or drug products involved. Consider if the deviation is an isolated incident or involves multiple lots of the same drug product or multiple drug products. Due consideration should be given to the stability profile of the product, as most process-related deviations necessitate additional stability testing for the lot under review. Also look into the regulatory/compliance status of the drug product; the regulatory affairs department should agree to the proposed disposition of the product. All deviations should be reviewed periodi-
Corrective Actions The quality assurance function should consult with the affected department(s) to determine if a 22
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Shahid T. Dara cally to determine if there are any trends developing which could be indicative of systemic problems. In other words, what might appear to be an isolated incident could prove to be an ongoing quality issue that requires systemic changes, both procedural and practical. Final Reviews and Approvals The deviation report form should be reviewed and approved by the manufacturing, regulatory affairs, and quality assurance departments. QA has the ultimate responsibility to determine that each deviation is resolved before a suspect lot of a product is released or rejected. Follow-up Actions QA should follow up the resolution of each deviation to determine that the corrective actions, if needed, were implemented. The revised documents should be reviewed and approved and be part of the investigation as it is closed. Also, employee training records should be reviewed to see if the operators were, in fact, trained in revised procedures and practices.
each nonconforming situation and deciding the disposition of the materials involved. This could be part of the quality/compliance review committee. Types of Nonconforming Materials Components Incoming raw materials could fail to meet specifications due to shipping damage, contamination, and infestation or fail upon testing of a sample. Sometimes raw materials can fail upon retesting of an older lot or when an older lot cannot be retested because it’s beyond its retesting protocol. Also expired raw materials should be processed as nonconforming materials and should be destroyed. In any of these situations, the raw material involved should be declared a nonconforming material according to company policies and procedures. Container/Closure Incoming container(s) and closures could fail to meet specifications due to shipping damage, contamination, and infestation or fail upon testing of a sample. In such situations, the container/closure involved should be declared a nonconforming material according to company policies and procedures.
Nonconformance Materials Control 21 CFR Part 211.84, 211.122, 211.188, and 211.192 mandate that only those components and packaging/labeling materials can be used in manufacturing drug products which meet their preapproved specifications. Similarly, each lot of a drug product manufactured must be produced in compliance with cGMPs and meet all its in-process and finished drug product specifications. If any of these materials fail to meet their respective specifications, they should be declared nonconforming and be segregated and placed on hold/quarantine until a disposition decision is made. Definitions Nonconforming material refers to a material that fails to meet quality acceptance criteria or its predefined specifications. A Nonconformance Material Report (NCMR) is a specific onetime use report, which documents the nonconformance material and its disposition. Material Review Board – refers to a group of individuals within an organization representing quality assurance, quality control, regulatory affairs, operations, production planning, and purchasing. This group is responsible for reviewing
Labeling Components Incoming labeling components could fail to meet specifications due to shipping damage, contamination, and, most serious of all, printing errors. Sometimes, labeling changes are mandated by FDA, and the existing stock of labeling components can no longer be used and, therefore, becomes nonconforming. In such situations, the labeling components involved should be declared a nonconforming material according to company policies and procedures. In-Process Materials In-process materials require further processing to complete the manufacturing cycle and are sampled and tested at critical points during the process to assure that the process is functioning within its limits. Sometimes the in-process materials fail to meet specifications upon testing, and the material should be declared nonconforming at this stage. It might be resampled and retested or reprocessed depending on the nature of the failure and its cause. But by declaring it a nonconforming material, it is assured that the material will not be processed further. Also expired in-process materials should be processed as nonconforming and be destroyed. Technical Guide
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Shahid T. Dara Finished Drug Products When a finished drug product fails to meet specifications or alert limits, it should be declared nonconforming at this stage to prevent its distribution unless the deficiency is corrected by reprocessing or repackaging. Also, expired drug products should be processed as non-conforming materials and be destroyed. Nonconforming Materials Management SOP There should be a written procedure in place on “Nonconforming Materials Handling,” detailing all the steps necessary in deciding the disposition of a nonconforming material. Nonconformance Material Report (NCMR) A standardized NCMR form should be part of the SOP. Such forms should be prenumbered for control and reference purposes and be controlled and issued by the quality assurance function. The latter should also be responsible for appropriate closure of each NCMR form and disposition of associated materials. The NCMR form should detail all the steps necessary to resolve a nonconforming situation and document the disposition decision as well as actual disposition of the materials as to when and by whom. Probable Cause The nonconformance reporter should provide information as to what materials are involved and what could be the apparent cause of this nonconformance, such as shipping damage or sampling error, etc. The material review board or Quality/Compliance Review Committee can further investigate the issue to define the most probable cause. Review/Investigation (if needed) Some nonconforming situations are self-explanatory, like material contaminated with oil or grease, while others require more in depth investigation, especially those involving a raw material sample test data, failure of an in-process material, or a finished drug product. Quality assurance should define if there is a need for further investigation in consultation with other departments. The investigation phase could involve resampling and testing of the materials involved in order to gather more information. A review of the process validation history and drug product quality profile might also be required to determine the possible cause of failure and potential corrective actions, if possible. 24
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Rationale for Acceptance/Rejection Most nonconforming materials are usually rejected because of the nature of the quality failure. However, in some instances where a sampling technique could be a potential cause for sample failure, a resampling or expanded sampling and testing of material might be recommended before deciding the eventual disposition. Likewise, for inprocess materials and finished drug products, the reprocessing decision should be made after careful consideration of all regulatory/compliance issues as well as quality/stability attributes of the drug product involved. Whatever the rationale, it must be documented, reviewed, and approved by QA. Corrective Actions The quality assurance function should decide, in consultation with other departments, if there is a need for any corrective action. Based on the nature of the quality failure, the potential corrective actions might include one of the following options: Resample/Retest If sampling technique is a potential cause for the quality failure, the material could be resampled and retested to assure that a quality material is not rejected unnecessarily. This is especially true for inprocess materials and finished drug products. However, if the retest data meets specifications, this should initiate another aspect of the change control system, i.e., the out-of-specifications data investigation. Nonetheless, the rationale for the resampling/retesting decision should be justified and documented in detail with review and approval by QA. Reprocessing/Repackaging In-process materials and finished drug products could be considered for reprocessing or repackaging, depending on the cause of the quality failure. Reprocessing is allowed by cGMP regulations; however, consider the regulatory/compliance status of the drug product when faced with such a decision. The reprocessing must not affect the safety, quality, purity, and efficacy of the drug product. Repackaging might be an option where a packaging error is the cause for quality failure, e.g., incorrect lot number or expiration date on the label. Like reprocessing, a repackaging option should be carefully explored as to its potential impact on the safety, quality, purity, and efficacy of the drug product. In both cases, the reworked batch should be considered for concurrent stability studies, if so decided by the Quality/Compliance Review
Shahid T. Dara Committee. There should be a rework procedure prepared and approved by quality assurance before reprocessing or repackaging is initiated and the rework procedure becomes part of the batch record. The justification for the rework decision should be fully documented and become part of the NCMR file for the drug product involved. Reprocessing/repackaging is an example of a temporary change control system that allows for a one time deviation from the approved manufacturing or packaging procedure to correct a quality deficiency. Here, a normally processed batch has to be reworked or repackaged to correct the problem. Once the situation is resolved, go back to the originally approved manufacturing/packaging procedure or batch record. Responsible Personnel Whether a material is to be rejected or a drug product has to be reworked, the responsibilities should be clearly defined with QA interaction throughout the process to assure proper disposition of the nonconforming materials and closure of the NCMR form. The responsible personnel should be indicated on the NCMR form. NCMR Disposition Once a disposition decision is made for a nonconforming material, QA should be responsible for assuring that the material is disposed of accordingly. Release/Reject If the material is to be released for use, its quality status should be changed accordingly. If the material is rejected, it should be moved immediately to the rejected material storage area and be marked for destruction. Return to Vendor If shipping damage is the cause for nonconformance or the raw material fails to meet specifications on testing, it could be returned to the vendor for credit. For contract manufactured/packaged drug products, a similar approach can be taken. Inventory Adjustments Inventory control and reconciliation of raw materials, container/closure, labeling components, as well as in-process and finished drug products is required by cGMP. Whenever a material is nonconformed, inventory records should be adjusted accordingly, with full explanation for the changes.
Final Reviews and Approvals The completed NCMR form should have review and approval signatures from all appropriate departments. It should clearly indicate the disposition of the material and who was responsible, along with a QA double check. Follow-up Actions Quality assurance should follow up the resolution of each nonconforming incident to see if it is an isolated situation or a symptom of systemic problems. Also review the possible implication of other batches of the same drug product or other drug products as well. This could involve vendor audits to ensure there has been no unapproved changes in their shops. A detailed review of the manufacturing process and other control procedures in place should be performed to determine if the process is still operating within a state of control, if there is a need for process revalidation, or if the change control procedures need revisions with attendant employee training. In any case, quality assurance should follow up with all these activities to control the potential for nonconforming situations.
Hold for Release Issues 21 CFR 211.22 Responsibilities of the Quality Control Unit dictates that all quality decisions regarding a drug product and its components should be made by an independent quality control unit. The quality function in general is also implied to assure the quality of components and processes at each stage. As part of this responsibility, the quality function must have adequate means to control the materials of questionable quality/compliance status before their disposition for use in manufacturing or release for distribution. Definition “Hold” is a questionable quality status of a drug product or its components, or for any other reason, which prevents further processing until it can be determined whether to quarantine, release, or reject the drug product or its component. In all cases, the “Hold” status should prevent distribution of drug products for marketing. Materials placed on hold typically require further investigation or testing and may result in return to vendor or destruction. Technical Guide
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Shahid T. Dara Types of Hold Hold status could be invoked because of a material’s failure to meet specifications or for regulatory/compliance reasons. Most questionable quality status situations fall into one of the following categories:
Formulation/Packaging Components Change Formulation changes are rare, but once these occur, a number of concurrent activities need to be completed before the drug product could be taken off hold status. Potential changes in formulation include: Active Pharmaceutical Ingredient ■ Major Excipient Change ■ Container/Closure Change ■
Planned vs. Unplanned A planned hold status is when the reason for questionable quality status is known and related to a change in formulation, manufacturing process, or container closure system for the drug product. Such changes require additional process validation and stability testing of the drug product to determine the effect of the change(s) on the safety, quality, and purity of the drug product. Until these studies are completed, the drug product cannot be released for distribution. An unplanned hold status is an unexpected event resulting from a sudden failure of the material to meet its specifications. This could happen to an already released drug product or raw material, e.g., a drug product complaint might force the organization to put on hold its existing released stock of particular drug product until the complaint is investigated and resolved. Temporary vs. Permanent Hold status is usually a temporary situation, and the material or drug product involved is either released or rejected. However, under certain regulatory/compliance circumstances, a company might be forced to put its drug product(s) on permanent hold leading to rejection and destruction. This could happen when FDA finds a lack of cGMP compliance or other serious violations of the Act. Lot Specific vs. Multiple Lots Hold status could involve only one lot of drug product or multiple lots. Product Specific Hold status should always be product specific and, if more than one drug product is involved, each should be placed on hold separately, and documentation should reflect this. Reason for Hold Hold status is a result of a questionable quality status and could be caused by one or more of the following reasons: 26
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Either of these changes requires, at a minimum, additional stability testing to determine the effect of the change on drug product quality and stability. API changes require submission of a pre-approval supplement to FDA if it is a NDA/ANDA product. In either case, the drug product should remain on hold until these issues are resolved. Equipment Change Major equipment change necessitates a revalidation of the manufacturing process, unless it could be proven that the change falls under similar equipment criteria based on SUPAC guidelines. The drug product manufactured with new equipment, however, should be placed on hold until the issue is resolved. Process Change A critical change in the manufacturing process also requires a revalidation of the process and additional stability testing for the drug product produced. Again, the drug product has to be placed on hold until these issues are resolved and the drug product safety, purity, and quality can be proven. Stability Data On-going stability studies might reveal a sudden negative trend in drug product potency, making the expiration dating assigned to the drug product questionable. In this case, the current stock of the drug product should be put on hold and distribution temporarily halted until this stability issue is resolved. Validation Validation batches are completed much before a validation study is completed, i.e., all the documentation is signed off and a summary report is prepared and approved by quality assurance. The validation batches should be placed on hold until the validation is complete and successful. Other valida-
Shahid T. Dara tion-related issues, which would necessitate the use of this procedure, could include the following: Change in process ■ Cleaning validation ■ Test method ■ Packaging configuration ■ Facility/utility changes ■ Quality issues ■
Other quality issues might force a drug product to be placed on hold, e.g., periodic review of the reserve samples might reveal a container/closure defect, or a critical product complaint from the field could make the drug product suspect. As part of the investigation, the first step should be to place the drug product on hold to show due vigilance by the company. Regulatory Issues Regulatory/compliance reasons could also dictate that a drug product should be placed on hold until resolution of these concerns. A change in an API requires a pre-approval supplement to the FDA, and until that is approved, the drug product lots involved cannot be released for marketing. Hold for Release Management Whether a hold status is planned or unplanned, there should be a change control system in place to deal with questionable quality status of raw materials, containers/closures, or drug products. Essential elements of such a system include: SOP There should be a written procedure in place on Hold for Release issues, detailing all the necessary steps in controlling and resolving the situation. Hold for Release Report (HFR) Form A standardized Hold for Release report form should be part of the SOP. These forms should be prenumbered for control and reference purposes and be controlled and issued by the QA function. The latter should also be responsible for appropriate closure of each HFR form. The HFR form should detail all the steps necessary to complete the investigation and resolution of a questionable quality status. It should also refer other change control documents involved, like a deviation report or an NCMR form.
Quantity Placed on Hold For inventory purposes, the quantity placed on hold should be clearly marked and adjustments should be made accordingly. Reason Reason for hold should be clearly defined, referring to any source documents involved, especially for planned hold situations. For unplanned quality failures leading to a hold decision, the probable cause should be defined, as it will be the starting point for the investigation by the Quality/Compliance Review Committee. Review/Investigation (if needed) Quality assurance and other members of the Quality/Compliance Review Committee should review the questionable quality status to make a determination if an investigation is warranted or not. Such an investigation should be in-depth and properly documented. Rationale for Acceptance/Rejection The rationale for an acceptance/rejection decision should be well defined, based on solid scientific data, considering the quality history of the drug product, process qualification data, and stability profile. Corrective Actions Quality assurance should determine if the corrective actions carried out to resolve questionable quality status are sufficient or if there is a need to rectify these deficiencies on a broad systemic basis. Corrective actions could involve the following: ■ ■ ■ ■
Additional stability testing Validation considerations Regulatory considerations Employee training issues
Responsible Personnel Whenever a corrective action is required, the plan should clearly define the responsibilities and accountabilities with QA to oversee the effort. If it is a multidisciplinary effort, then it is even more important to define all the participants roles in carrying out the project. Hold for Release Disposition Based on analytical data or regulatory approval of a supplement, the material or drug product involved can be released for use or distribution; Technical Guide
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Shahid T. Dara otherwise, the material might have to be rejected. Care should be taken that all necessary validation or stability testing is completed, and a final report is written up before the drug product is released. Final Reviews and Approvals The HFR form should be reviewed and approved by the hold requester, regulatory affairs, and QA. QA has the responsibility that each HFR incident is resolved, and the drug product involved is disposed of accordingly. Follow-up Actions Quality assurance should follow up the resolution of each hold incident to determine if additional corrective actions are needed or if the reason for the hold incident is a symptom of systemic problems. If such is the case, then all concerned quality/compliance systems should be reviewed and revised accordingly. This might require revision of documents and additional training for the personnel involved.
Out-of-Specifications Investigations Out-of-specification (OOS) data investigation is at the top of the current list of issues facing industry and FDA. Not that it is a new subject, as it has always been part of the cGMP regulations, 21 CFR 211.194, but the issue has assumed a new significance since the infamous Barr Decision. The old school of testing a product till it passed was supposed to be gone with the introduction of cGMP regulations. However, this monster still lives on in some pharmaceutical manufacturers. Like any other compliance issue, OOS is part of analytical reality in any organization, and how to investigate and resolve a situation involving OOS data should not be the subject of deep philosophy and considered right up there with universal metaphysical forces in action. The simple truth is that every drug manufacturer is responsible for investigating OOS data according to a written procedure, with due review and an approval process in place. The following discussion is a procedural approach on how to handle any OOS investigation. Definitions ■ “GMP data” means data upon which a quality or GMP decision is made and includes data collected in determining the disposition (release or rejection) of a raw material, intermediate or inprocess material, or drug product, as well as data 28
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collected to determine expiration dates or validation of processes. ■ “Out-of-specification” is any GMP data which is outside the boundaries of predetermined specifications. ■ “Laboratory error” occurs when an analyst commits an error while following an analytical method (e.g., incorrect standard preparation, miscalculation of data, incorrect sample preparation, etc.). ■ “Inconclusive laboratory error” occurs when the analytical method is followed correctly, but the data generated is questionable. Upon retest, the results show that the material is within specifications, and a reason for the OOS data cannot be determined. ■ “Process error” happens when the manufacturing process itself is found to be the cause of the OOS data. ■ “Nonprocess related error” occurs when human or mechanical errors cause a failure, resulting in questionable GMP data. ■ “Retest of original sample” means the reanalysis of the material involved from the initial sample taken from the bulk. For stability studies, this means the initial sample that was removed from its proper storage condition. Re-injection of the initial HPLC/GC vial also qualifies as retesting the original samples. A freshly diluted sample prepared from an original tablet grind is also considered valid. ■ “Resample of material for analysis” means physically removing a new sample from the bulk material. Barr Decision In 1992, Judge Wolin made a landmark decision in U.S. vs. Barr Laboratories, clarifying the issues of OOS data and the practice of retesting the drug product until it passes. cGMP regulations imply that the drug manufacturer should conduct a failure investigation when a drug product fails to meet test specifications. The Barr decision made it clear that it is a legal requirement for every manufacturer to address the OOS data investigation in a systemic way, and written procedures should be in place to define the course of action. It also emphasized the fact that quality cannot be tested into a drug product, rejecting the practice of testing till it passes. The OOS data should not be summarily dismissed, and it should be part of the analytical results along with the retest data and justification for the retesting of the original sample or resampling and retesting of this sample. The Barr decision had a far-reaching impact on the pharmaceutical industry, as Judge Wolin’s
Shahid T. Dara opinion was the first established detailed explanation of how an OOS situation should be handled. FDA has incorporated this explanation into its inspection guidelines and expects industry to follow it. Types of Data Involved Analytical data pertaining to raw materials, in-process tests, finished drug product analysis, validation test results, and stability study samples are utilized to make quality decisions about drug products. Whenever these results are outside the predetermined specifications for any of these tests, the OOS investigation must be performed. Even if a raw material or drug product is going to be rejected based upon retest data, the investigation must be carried out, as it could involve more than the quality and purity of the material involved. In a Quality Control Laboratory one can encounter the following types of data which could require an OOS investigation including: Component test data ■ In-Process test data ■ Finished product test data ■ Stability studies test data ■ Validation studies test data ■ Analytical method validation ■ Process validation ■ Cleaning validation ■
Management of OOS Data in the Investigation An OOS incident is never planned; however, there should be a system in place to investigate it. Essential elements of such a system should include the following: SOP There should be a written procedure in place for the OOS investigation, detailing all the steps necessary for completing a timely investigation of GMP data which is considered out-of-specification. Laboratory management should train all analysts in this SOP and make sure that all OOS incidents are investigated and resolved in a timely fashion. The SOP should define the time period allowed for initiation and disposition of an OOS incident. Once an analyst has determined that the GMP data generated does not meet specification, he or she should immediately inform management to start the investigation. At this time, an OOS investigation report should be initiated, and all original samples and solutions prepared should be kept and stored under appropriate conditions for later analysis if needed.
OOS Investigation Report A standardized OOS investigation report should be part of the SOP. Such forms should be prenumbered for control and reference purposes and controlled and issued by quality control. An OOS investigation log should be maintained to record the following information: OOS report number issued ■ Name of the material in question ■ Lot number ■ Initial analyst ■ Investigation initiation date and the conclusion date ■ Disposition of the material ■
The following details should be recorded on the OOS Investigation Report: Material Involved List name and lot number of the material involved. If it is a stability study sample, detail the storage conditions and test interval as well. For validation samples, specify whether the sample is for process, cleaning, or method validation. Sampling Information Sampling information should include the container number from which the particular sample was taken, thereby forcing the company not to composite the samples, as required by the cGMPs. For purified water samples, the sampling outlet designation and time of sampling are also important. Analytical Method The analytical method used should be referenced, along with the analyst’s name and laboratory notebook references, as a measure of traceability and good record-keeping. Initial Results vs. Specifications Record the initial test results vs. the specifications in an unambiguous manner. The author has seen many confusing ways of expressing the OOS data, which immediately raises a red flag for an investigator. Probable Cause Define the probable cause if it is immediately known; otherwise, let the investigation take its course. Avoid speculation without hard evidence. Technical Guide
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Shahid T. Dara Investigation Team Members of the investigation team should include the analyst, his/her supervisor, representatives from regulatory affairs, production, and QA. A quality/compliance review committee might be entrusted to make a final decision based on the recommendations of the investigation team.
determine, with reasonable assurance, if the incident is an isolated event or a systemic problem. If the OOS data is a result of the quality system’s deficiencies, like lack of proper process validation, then the investigation scope takes on a whole new meaning, and the QA function should act accordingly to correct the problems.
Review/Investigation The investigation should focus on the following:
Conclusion Once the investigation is completed, a decision has to be made as to the disposition of the materials involved. The material could be released or rejected, and that should close the investigation for the particular OOS incident. However, sometimes the original and retest data are submitted to experts within the company, along with key members of management, to make a decision. The assistance of outside experts might also be sought. All these activities must be documented to maintain a level of control desired by cGMPs.
■ ■ ■ ■ ■ ■ ■ ■
Analytical method validation status Data/calculations verification Instrument Performance/calibration/maintenance history Instrument output/raw data Reference standards Analyst training records Review of batch records
Define Cause The investigation should result in narrowing down the cause for OOS data, and a brief summary of the reasoning behind this decision should be prepared. Probable causes of OOS data could include: ■ ■ ■ ■ ■
Laboratory error Inconclusive laboratory error Nonprocess related error Process related error Stability degradation
Corrective Actions The corrective action plan should be defined to address the following: Retest plan ■ Retest of original sample ■ Resample of material for analysis ■ Predetermined testing procedure to define the source of retest sample and the number of samples to be retested for statistical significance of data ■ A second analyst to perform the analysis, when necessary, to verify the ruggedness of method ■ Evaluation of retest data ■
Related Batches/Drug Products Related batches of the same raw material or drug product or related drug products should be evaluated to establish an analytical history of the material involved. This review is necessary to 30
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Final Reviews and Approval The OOS investigation report should be reviewed and approved by QC Lab personnel, appropriate manufacturing representative (if needed), regulatory affairs, and QA. Final approval should be obtained from a senior member of management to maintain communication at all levels of the organization.
Validation Change Control Issues Validation is establishing, to a high degree of assurance, thoroughly documented evidence that a given process will consistently produce a product that will meet its predetermined specifications and quality attributes. Validated systems and processes by definition should be maintained and operated within a state of control that assures that any changes will be carefully evaluated and monitored so as not to compromise the validated status of a system or process, thereby assuring the quality of the drug product so produced. The pharmaceutical industry is experiencing rapid changes, the pace of which has increased tremendously over the past few years in response to hard economic realities and market forces. Equipment changes are more frequent than in the past and so are the changes to the manufacturing/packaging processes. Both are being done to improve the economic efficiencies of the operations as well as to achieve better compliance. Part of this trend involves technology
Shahid T. Dara transfer from one plant to another, creating more challenges for the change control systems. Validation change control applies to all validated systems and processes, including facilities, utilities, equipment, and manufacturing/packaging processes. However, routine preventive maintenance should not be confused with a change in the validated status of a system. This discussion is meant to provide an overview of validation change control and how to manage it in day-to-day operations. Definition Validation change control can be defined as the process by which each critical or major change in a validated system or process is evaluated to determine if the proposed change impacts the validated status of the system or process involved. Due consideration should be given to the possibility of the revalidation of the system or process. These potential changes include equipment upgrade, change of critical parts of a utility system, major changes in manufacturing process, etc. Types of Validation Changes Planned vs. Unplanned Planned changes in a validated system are meant to improve operation. Such changes usually have been thoroughly studied and agreed upon by different organizational units. However, distinction should be made for planned routine maintenance activities, as these are extensions of the original validation of the equipment or system. Unplanned changes, on the other hand, are a result of an emergency and have to be made to keep operations going. Many times the review process starts after the fact, and the drug product manufactured has to be evaluated for compliance with all its regulatory and quality specifications. Potential Areas of Validation Change Pharmaceutical manufacturing is conducted in a controlled environment, and, anything that could have an impact on the safety, identity, quality, purity, and strength of a drug product should be validated. This validated status must be maintained throughout the life of the system involved. Any critical or major changes in any of the following systems must be carefully reviewed and evaluated for its impact on the system individually and as part of the manufacturing cycle for the drug products involved. ■ Facilities
■ ■ ■ ■ ■ ■ ■ ■ ■
Utility systems changes Equipment change parts Process parameters Procedural issues Test methods Specifications Computer systems Hardware changes Software changes
Validation Change Control Management Validation change control is meant to manage the proposed changes in a way that a system or process maintains its validated status after implementing the changes and could require a revalidation. As part of an effective master change control system, there should be a subsystem addressing validation change control and, within this subsystem, designated procedures for each set of validated systems and processes within an organization. Essentially, such a system should detail the following: SOP There should be a written procedure in place to assure that any changes in a validated system or process are evaluated for their effect on the validated status of the system or process involved before their implementation. Validation Change Control Report A standardized validation change request/control report form should be part of the validation change control SOP. Such forms should be prenumbered for control and reference purposes and controlled and issued by the quality assurance function. The latter should also be responsible for appropriate closure of each proposed change in a validated system, in cooperation with the validation function. The form should ask for all the pertinent information in order to review and dispose of any proposed changes. The validation change request could be initiated due to one of the following reasons: ■ ■ ■ ■ ■ ■ ■
Procedural changes Utilities modifications Equipment calibration New equipment/replacement of equipment Maintenance frequency Engineering study for process improvement Change in API/major excipient source Technical Guide
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Shahid T. Dara ■ ■ ■
Production/packaging process changes Deviations Nonconformance reports
Reason for Change The sponsor of a validation change request should provide the reason and justification for the proposed change along with any technical information and drawings of current and proposed systems. Review of Proposed Change Operations, engineering, QA and validation should review the change request. The review process should consider the following: ■ ■ ■ ■ ■
Validation status of system/process Drug product(s) Stability issues Regulatory status Isolated vs. systemic issues
Quality assurance and validation must evaluate the impact of the proposed change on the validated system or process, and if the opinion is that the validated status is affected by said change, a decision is made as to revalidation of the system or process involved. All proposed changes do not lead to a revalidation of a system or process, and it is possible that the impact on the validated status is minimal, and therefore, corrective actions might involve additional sampling and testing. There could be situations where a change request might be denied altogether for lack of justification, both technical and financial for the organization. Rationale for Acceptance/Rejection Rationale for acceptance or rejection of a proposed change in a validated system or process should be documented in detail, referring to all the appropriate documents, including initial validation documents for the system involved. A change for the sake of change is not an acceptable practice, as each change costs money. Corrective Actions If a decision is made to revalidate the system or process concerned, define all the documents that are impacted, and would have to be revised or prepared as new. These include: ■ ■
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Validation protocol SOPs Journal of cGMP Compliance
Manufacturing batch master records ■ Preventive maintenance procedures ■
A decision has to be made as to the status of the drug product manufactured utilizing the changed system or process. Should it be placed on hold until the validation study is complete and all documentation is reviewed and approved by the organization. This decision is based on the nature of the change and extent of the sampling and testing performed on the impacted drug product and the test results obtained. Some critical changes in manufacturing equipment or process require additional stability studies for the drug product manufactured before it can be marketed. This is necessary to ascertain the stability profile of the product under a different set of processing conditions. There might be a system or manufacturing process improvement situation which has no impact on the overall quality of the drug product and, therefore, will not have to be placed on hold. Pre-Approval The validation change request should be preapproved by validation and quality assurance, authorizing that the proposed change can be made. Validation Change Execution Once it is decided that the change has to be made and the system/process needs revalidation, the following activities should occur in succession: Protocol preparation, review, and approval ■ Protocol execution ■ Data collection ■ Final report and conclusion preparation ■ Review and approval of final report and conclusion ■ Release of the drug product(s) involved (If placed on hold pending completion of revalidation) ■
The final review and approval should be by the same individuals who conducted the pre-approvals of the protocols. Having a senior VP sign off on a completed validation study does not add any more credibility to it than otherwise. Another important aspect is to review the issues related to the justimplemented change if there is collateral damage to other systems. Although this should have been considered up front when the change was proposed, some effects will only manifest after the fact. Therefore, be prepared for all contingencies.
Shahid T. Dara Follow-up Actions Validation is not an event but an on-going cycle that ends only when a system is retired or the drug product is removed from the market. An astute validation professional understands that the systems and processes qualified at one point in their life have to be monitored periodically to assure that they are still operating within the same validated parameters.
QUALITY FAILURE/INCIDENT INVESTIGATIONS Quality systems and procedures are implemented to minimize quality defects, with the aim to create a zero-defect manufacturing environment. In reality, there is no such thing as a perfect system. Quality defects and failures are part of any manufacturing operation, and pharmaceutical manufacturing is no exception. cGMPs require that all quality failures/incidents be investigated, documented, and corrective actions implemented to prevent recurrence. Most pharmaceutical manufacturers have established detailed procedures on how to investigate out-of-specification data originating in the analytical laboratory following the Barr Decision. However, there is a need to have separate procedures to address other operational quality issues, i.e., quality failure/incidents. The quality failure/incident investigation procedures offer a number of benefits, such as: Standardized investigation format ■ Useful communication and training tool ■ Improved processes and procedures ■ Long-term cost savings ■ Enhanced overall compliance ■ Timely resolution of quality issues ■
This article provides an overview of such an SOP, with special reference to water quality failure investigation, both during validation and routine monitoring of the system.
Quality Failure/Incident Investigation Procedure What is a Quality Failure/Incident? Quality failure refers to a situation where a finished drug product, process, or service does not meet its expected attributes or specifications. A quality incident, on the other hand, is a failure of the quality system practices which may or may not
lead to a quality failure of a product, process, or service. Both cases, however, should be fully investigated and documented. Quality Failure/Incident Investigation Procedure A quality failure/incident investigation procedure should address the following areas as appropriate, (see Figure 1 for a summarized list): Define Quality Failure/Incident It is important that the quality failure/incident be defined in a clear and concise manner, detailing exactly what happened. Define Quality Significance of the Failure/Incident Most quality failure/incidents can be classified as critical, major, minor, or for information only. In some cases, the quality data is also measured against alert and action limits, e.g., total aerobic count for an environmental monitoring sample for a given area. This classification can be a useful tool in determining the extent of the investigation as well as the scope of corrective actions needed, including disposition of the drug product or products involved.
Figure 1
Failure/Incident Investigation Procedure Elements of Quality Failure/Incident Investigation Procedure Define quality failure/incident Define quality significance of the failure/incident Define the cause of the quality failure/incident ■ Facilities ■ Utilities ■ Components ■ Equipment ■ Process ■ Drug Product ■ Analytical ■ Personnel Quality failure/incident investigation ■ Facilities ■ Utilities ■ Components ■ Equipment ■ Process ■ Drug Product ■ Personnel ■ Procedures and documentation practices Corrective action plan Summary, conclusion, and sign off
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Shahid T. Dara Define the Cause of Quality Failure A quality failure/incident could be caused by one or more of the following; however, use the process of elimination to narrow down this list as much as possible; Facilities An example of facilities as a possible cause of quality incident/failure could be improper cleaning/sanitization of manufacturing areas leading to increased bioburden in the environment with the potential for drug product contamination. ■
Utilities A malfunction of any of the following utility systems can cause a quality failure/incident leading to a drug product failure. They include: ■
all possibilities, and attempt to define the most probable cause(s) of the quality failure/incident. Quality Failure Investigation A quality failure/incident investigation should include a review of the following, depending on the most probable cause(s). Concentrate on those areas that may have contributed to a given quality failure/incident. The investigation phase is in fact already underway as the probable cause(s) of a given quality failure/incident are being defined and, therefore, the two cannot be totally separated from each other. Quality assurance must lead the investigation phase in cooperation with other departments, as these findings are the basis of any corrective action plan. Facilities If facilities are a possible cause of the quality failure/incident, review the state of repair of manufacturing and packaging areas as well as the temperature and humidity conditions in the plant. Also, if the microbial environment is monitored, the data for the particular incident should be reviewed along with data for the past four to six weeks to identify any adverse trends. ■
• HVAC system • Water purification system • Compressed air system • Dust collection system Components Both chemical raw materials and packaging/labeling components can cause a quality failure/incident. ■
Utilities If any of the utility systems is a potential cause for a quality failure incident, review the system in question in detail. Items to be checked if one or more of the following utility systems is under suspicion include: ■
Equipment Equipment breakdown as well as improper cleaning can lead to a quality failure/incident. ■
Process The manufacturing process as well as process conditions can contribute to a quality failure/incident. ■
Drug Product Failure to meet drug product specifications is the ultimate quality failure/incident.
HVAC system: Temperature/humidity profile of the area and potential temperature/humidity exposure of the components and drug product(s) involved.
■
Analytical Most analytical laboratory quality issues are related to analytical data and are usually investigated according to an out-of-specification data investigation SOP. An OOS investigation will likely involve some of the aspects discussed here. ■
Personnel Personnel expertise and level of training can also significantly contribute to quality failures. This list should not be considered all inclusive, and there could be other factors involved. Review ■
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Water purification system : Both chemical and microbial quality of purified water and water-forinjection can impact the quality of the finished drug product. The quality failure investigation for a water purification system is discussed later. Compressed air system : Possible presence of oil droplets in an oil-free compressed air system can cause contamination. Dust collection system Malfunction of a dust collection system can cause excessive dust in the area, with potential for cross contamination, especially where conditioned air is recirculated. ■
Shahid T. Dara Components Always review the sampling/inspection and release processes if a component is a potential cause for a quality failure/incident. Sample manipulation can have a potential negative impact on the quality of the material being sampled. Both active and inactive raw materials can have a direct bearing on the drug product quality if these are not of desired quality or their quality is compromised either during sampling process or due to improper storage conditions. Packaging/labeling component quality defects can cause potential stability concerns as well as mislabeling situations. Almost one-third of all drug product recalls in recent years were due to mislabeling of drug products, per FDA enforcement reports. ■
Equipment If manufacturing/packaging equipment is a potential cause for a quality failure/incident, review the following:
Personnel This is a subjective issue that is difficult to measure as it tends to indirectly validate the effectiveness of the employee training program. Ensure that the individuals involved in all phases of a given quality failure/incident have the knowledge, expertise, and training to carry out their assignments, and there is documented evidence to support this claim. If not, an isolated quality failure incident could be an indication of a major systemic quality problem within the organization. ■
Procedures and Documentation Practices A review of the SOPs, batch records, analytical procedures, etc., is also required to complete this investigation. This assures that the procedures are detailed enough and easy to follow for the operators. If not, revisions might be needed.
■
Cleaning and sanitization records ■ Calibration status of critical equipment ■ Maintenance records ■ Performance history ■ Equipment qualification records ■
Corrective Action Plan Quality assurance management, in collaboration with other appropriate departments within the organization, should develop a corrective action plan with definite time lines for implementation. Such a plan should clearly define the responsibilities and accountability profile of assignments and should include: Does the incident/failure fall under an OOS investigation? If so, is there a need for a separate investigation? ■ In such cases, the two investigations should complement each other in resolving the issue ■ Identifying procedural changes required ■ Identifying documentation to be revised ■ Identifying additional training requirements ■ Disposition of the drug product(s) involved ■
Process Review the manufacturing process in detail to see if there were any deviations or anomalies. Also, review the process conditions, like temperature, humidity, machine speed setups, order of addition of ingredients, process time limits, etc. A review of process validation records might also be in order, if considered necessary. ■
Drug Product Review other batches of the same drug product to see if this is a product-specific quality issue or an isolated incident. Review batches of related drug products manufactured under similar sets of conditions. This will help determine if other drug products are also involved. This part of the investigation demands extreme diligence on the part of the quality management team, as it can have far-reaching implications. In recent years, FDA has repeatedly cited pharmaceutical manufacturers for failure to perform an in-depth investigation of quality failure/incidents. ■
Summary, Conclusion and Final Sign Off A critical step in the successful conclusion of any investigation is that a summary report and conclusion is written up. Before finalizing such a report, QA should verify that all the corrective actions have been (or are being) implemented per their time lines. The effectiveness of completed corrective actions can be evaluated by verification that the procedures and systems were revised, and the employees were retrained by responsible personnel, the new equipment was purchased, or there was a change in a raw material supplier, etc. Documentation supporting that a given corrective action was completed should be reviewed and refTechnical Guide
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Shahid T. Dara erenced or attached to the investigation report, like employee training records, copies of the purchase order, copy of the approved change control, etc. The report should be reviewed and approved by the appropriate departments within the organization. QA and other pertinent departments should sign off on the report, and sign off responsibilities should be delineated in an SOP. The summary report should be used to inform upper management of any critical quality issues, especially those which would involve capital investments as part of their corrective action plan. Water Quality Failure Investigation Procedure Water purification systems are designed and qualified to assure a consistent supply of purified water of the desired quality. However, despite our best efforts, a water sample may fail to meet its specifications. The water quality failure/incident has far-reaching implications as purified water and waterfor-injection are used widely in drug product manufacturing and facilities and equipment cleaning. This is a detailed overview of a water quality failure investigation procedure, both during validation and routine monitoring of the water purification system and is based on the author’s personal experiences in handling them. In order to accomplish a comprehensive investigation of a water quality failure incident, it is important that different aspects of the investigation be assigned to different departments according to their expertise. This is especially true if the incident happens during validation or major revalidation of a water purification system. The investigation team should include the following: Engineering and maintenance, along with validation, should review the water purification system for physical and functional integrity from an engineering and validation point of view. ■ Quality assurance should review the procedural and training issues, as well as the drug product(s) involved, from a compliance point of view. ■ Quality control should review the chemical and microbiological testing issues as well as the water sampling techniques. ■ Drug safety and information should review the safety concerns to decide the disposition of affected drug product(s). ■ The investigation should be led by quality ■
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assurance and may also involve manufacturing, if needed. ■ The investigation team should discuss all findings of the investigation before designing a corrective action plan and deciding the disposition of the drug product(s) involved. Water Quality Failure Investigation A water quality failure investigation should address the following areas, as appropriate (see Figure 2 for a summarized list): Define Water Quality Failure/Incident A water quality failure/incident could involve one or more of the following scenarios:
Figure 2
Water Quality Failure Investigation Elements of Water Quality Failure/Incident Investigation Define water quality failure/incident ■ System malfunction ■ Chemical ■ Microbiological Define quality significance of the water quality failure/incident Define the cause of the water quality failure/incident ■ Purification system ■ Sampling ■ Analytical issues Quality failure/incident investigation ■ Purification system Source water Pretreatment Purification system Storage and distribution Controls, alarms etc. Sanitization cycle Sampling Sampling procedure Sampling technique Sample container prep ■ Analytical procedures Instruments Analytical procedures Analyst training Sample prep Media prep and tracking ■ Drug product(s) involved ■ Personnel ■ Procedures and documentation practices Corrective action plan Summary, conclusion, and sign off ■
Shahid T. Dara Purification system malfunction ■ Chemical ■ Microbiological ■
In most instances, it is the failure of a water sample for chemical or microbiological specifications which triggers an investigation. Since purified water is constantly being used in production, there is always a chance that the suspect quality water might have been used in equipment cleaning or manufacture of a drug product, thereby putting it at risk. Define Quality Significance of the Water Quality Failure Incident Water quality failure incidents can be classified as critical, major, minor, or for information only, depending on the nature and severity of the incident. For microbiological tests, the quality data is measured against alert and action limits, e.g., total aerobic count for a purified water sample. If the water sample fails pH specification or total organic carbon (TOC), and the purified water was used to manufacture a solid oral dosage, the impact on quality, strength, identity, and safety of the drug product will be much less if the water sample fails for microbiological specifications and is used to manufacture a liquid or sterile drug product. This classification can be a useful tool in determining the extent of the investigation as well as the scope of corrective actions including disposition of the drug product(s) involved. Define the Cause of the Water Quality Quality Failure/Incident A water quality failure/incident could be caused by one or more of the following; however, try to narrow down this list as much as possible: Purification System Each water purification system is designed per individual plant requirements but does have some constants which should be looked into when investigating a water quality failure/incident. ■
Source Water The quality of source water as supplied by local water authorities changes with the time of the year and geographic location of the plant. Microbial quality and the total dissolved solids in source water play a vital role in determining the capability of a given water purification system. Source water test data should be part of the validation file for a given water purification system. Sudden changes in
source water quality can cause purified water failure, especially after natural disasters, like floods. Source water test data from the local water authority and in-house periodic source water test results should be reviewed to determine any sudden change in source water quality. This review should also indicate any trends that might be developing over recent weeks, especially after heavy rains or floods in the area, as they can affect the composition of natural water reservoirs. Pretreatment Source water is pretreated to minimize the level of both organic and inorganic impurities before water is actually processed through the final purification step. If pretreatment steps are not precisely controlled and routinely monitored for performance within preset limits, these could cause quality failure of the water produced. Chlorination Chlorine is added to the source water to decrease its bio-burden. It also helps to minimize microbial growth in pipes and storage equipment. Local water authorities usually add a chlorine gas generating chemical to wate like sodium hypochlorite to produce one to two PPM of chlorine gas. However, there is a downside to the presence of chlorine in water, as it tends to corrode stainless steel surfaces and will deteriorate reverse osmosis membranes. Therefore, it is important that chlorine be removed from water before it actually reaches the purification and storage stage. However, if there is insufficient or no chlorine in the source water, the purification system downstream may not be able to remove all the microbial contaminants, thereby causing a quality failure of the water produced. ■
Depth Filters Source water is passed through a series of coarse filters to remove suspended solids. The filtration media could be different grades of sand. However, such filters tend to harbor microbes and should be periodically back-washed to remove all trapped waste. If left unsanitized, these filters could contaminate the water with microbes, causing failure of the water produced after purification. ■
Water Softeners or Deionizers Water softeners or deionizers are used to remove heavy metal ions from source water to ■
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Shahid T. Dara avoid scaling downstream during the purification process. Deionizing resins need to be regenerated periodically, and the regeneration process should be controlled to ensure that a deionizer tank does not sit idle for long periods of time after regeneration, as it could promote microbial growth. If such a tank is used in water purification, it might overburden the system, and the water produced could fail. Carbon Filter Activated carbon filters are used to remove dissolved chlorine and other gases from source water, along with organic materials, before water is sub jected to the final purification process. However, carbon filters can promote microbial growth and, therefore, foul the downstream components. Frequent monitoring and sanitization of carbon filters should be carried out to prevent this situation. Nonetheless, carbon filters can be a cause of water quality failure. ■
Purification System ■ Deionization Deionization is not considered by FDA to be an acceptable water purification process to produce Water-for-Injection (WFI); however, it is used to produce purified water. Cation, anion, and mixed bed resins are used to remove ionic impurities from source water. The quality of these resin beds can be monitored by determining the conductivity of effluent water. A sudden increase in effluent water conductivity indicates that a resin bed needs to be regenerated. Ion exchange resin tank regeneration should be controlled, and regenerated tanks should not sit idle, as this can promote microbial growth. Also, if there is leakage of sodium ions from a cation exchange resin, the water produced will have a higher pH – greater than 7.0. Reverse Osmosis Reverse osmosis membranes are an efficient water purifier when used in series. However, these can harbor microbial growth, as they are chlorine sensitive and, therefore, can produce water of suspect quality. Also, if the membranes are not periodically backwashed, they become overloaded and enable organic and inorganic impurities to pass through. ■
Distillation Distillation is the method of choice for producing WFI, assuming it is a continuous process. If, for ■
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some reason, the system is idle for a period of time, the feed sections of the still can become dead legs and promote microbial growth. On start up, if used unsanitized, this could produce WFI with high endotoxins. Storage and Distribution Storage tank, distribution piping, and associated controls are critical to maintaining the quality of the water being produced. If there are leaks in the system, these could contaminate the entire system. Likewise, the vent filter on the storage tank should be checked for integrity and to see that it is not harboring any microbes in the condensate, as both could compromise the quality of water. There should be a procedure in place for changing the sterile vent filter on the storage tank. Many times water quality is compromised by the addition of foreign material during filter change over. Typically, filter change is followed by a complete sanitization cycle. The heating and cooling system is another critical part of this puzzle, as the water quality is totally dependent on its storage temperature before it is used. Sanitization process Water purification systems are periodically sanitized to remove any biofilm and organic build up on different water contact surfaces. If a chemical sanitizing agent is used, there is potential for residual chemicals in the purified water, unless the system is thoroughly flushed and drained. Sampling Water samples are drawn during validation and routine monitoring of a water purification system. This step is critical and can cause water quality failure if sampling procedure(s) are not strictly adhered to. Details are discussed under the investigation section of this document. ■
Analytical issues Both chemical and microbiological testing have their own set of variables which could cause a water sample to fail. It could be the instrument, sample prep, or the procedure. Details are discussed under the investigation section of this article. ■
Water Quality Failure Investigation A water quality failure/incident investigation should include a review of the following, depending upon the probable cause. Concentrate on those
Shahid T. Dara areas believed to have contributed most to a given quality failure incident. Source water Source water test data from the local water authority and in-house periodic source water test results should be reviewed to determine any sudden changes in source water quality. This review should also indicate any trends that might be developing over recent weeks, especially after heavy rains or floods in the area, as they can affect the composition of natural water reservoirs. Pretreatment Review all the pretreatment steps to see if the quality of source water was compromised at any stage. Also check for leaks or malfunction of any alarms, controls, or autoregeneration of deionizing tanks, etc. Chlorination Review the source water data to see if there was sufficient chlorine in the water. Also, review the residual chlorine level of pretreated water processed downstream, especially in case of a reverse osmosis water purification system. Depth Filters Check the backwash records to see if the depth filters were backwashed and sanitized per requirements, as these can cause both microbial and chemical contamination of the water being purified. Water Softeners or Deionizers Review the regeneration procedure and schedule for water softener and deionizing tanks to detect any deviation, especially if the tanks were sitting idle for a long period of time after regeneration, promoting microbial growth, thereby causing contamination of water. Carbon Filter Review the monitoring data for the post-carbon bed to determine if there was any proliferation of microbes which could have contaminated the system downstream. Purification System ■ Deionization Review the regeneration procedure and schedule for cation, anion, and mixed bed resin tanks to detect any deviation, especially if the tanks were
sitting idle for a long period of time after regeneration, thereby causing microbial contamination of water. Also, the conductivity data for effluent water should be reviewed to determine if the tanks were changed as per schedule and are not totally exhausted before replacement. Reverse Osmosis The reverse osmosis membranes should be checked for integrity if these were exposed to high chlorine source water. Also, the membrane backflushing procedure should be reviewed to determine if it is effective in removing all the build-up. The reverse osmosis system sanitization procedure and frequency should be checked to determine if they need any revisions, both in procedure and frequency. ■
Distillation Ensure that the system was in operation per approved specifications. If there was a shutdown, was the system sanitized before start up? Check to determine if all alarms and controls are functioning and are within calibration. Look for any dead legs in the system as potential breeding grounds for microbes. ■
Storage and Distribution Check the storage tank, distribution piping, and all points of use for leaks or other physical defects. Examine the vent filter on storage tanks for integrity and to see if it is harboring any microbes in the condensate. Check the heat exchanger and chiller controls for proper function to assure the water is maintained at its desired storage and circulation temperature. If plastic pipes are used, like PVDF etc., these should be checked, as they tend to sag over time, leading to potential deadlegs and, therefore, could promote microbial growth. The drain pipe from the storage tank should have at least a two-inch gap or twice the pipe’s diameter, whichever is greater, between pipe and floor drain to prevent “back siphon” of the floor drain. Controls, Alarms Today’s water purification systems have a number of controls and alarms to operate the system within specifications while controlling costs. Review all the controls and alarms in case of a water quality failure/ incident to determine if these were functioning properly and are within calibration, where applicable. Technical Guide
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Shahid T. Dara Sanitization Process Review the water purification system sanitization procedure and frequency to determine if they could be contributing factors in water quality failure, especially when residual chemicals or high/low pH values are detected. Sampling Multiple water samples are drawn on a daily basis during validation and routine monitoring of a water purification system. The sampling procedure and the individual sampler’s technique are key to obtaining uncompromised water samples. While investigating a water quality failure/incident, the sampling process should be scrutinized in detail. Review the following to determine if there is any chance to compromise the integrity of the sample. Sampling Procedure The sampling procedure should be reviewed to determine the level of detail and clarity of statement for a nontechnical person to understand it. Also, review the training requirements spelled out in the SOP and audit training records. Sampling Technique If sampling is a potential cause for water quality failure, QA should review the sampling technique and perhaps have a microbiologist watch the individual sampler do the actual sampling under real time conditions. This provides a wealth of information as to the effectiveness of the sampling technique as described in the sampling procedure and how people are trained. The sampling procedure should simulate actual practice when the system is used to draw water for manufacturing or cleaning activities, i.e., flush the system for 10 seconds before withdrawing water, etc. Sample Container Preparation Water sample containers are specially prepared. Microbiological samples are taken in sterile containers, while chemical samples are taken in containers which have been specially cleaned and rinsed with WFI to minimize contamination. While investigating a water quality failure/incident, also review the sample container prep practices. This could involve reviewing cleaning procedures and any studies done on these containers after cleaning to determine the effectiveness of the cleaning procedure. If presterilized containers are obtained from an outside vendor, have access to 40
Journal of cGMP Compliance
the vendor’s sterilization procedure and supporting validation documents. Nonsterile sample containers have been blamed for false failures of water samples. Analytical Issues Chemical and microbiological tests are usually performed by the quality control laboratory, and this phase of the investigation is best accomplished if a chemist and a microbiologist are asked to review different aspects of the analytical work. In particular, the following should be closely examined: Analytical Instruments Review analytical instruments to determine if they are within calibration and performance limits. Also, check for any unusual repair or maintenance activity that might have affected the performance of the instrument. Analytical Procedures Analytical procedures should be reviewed for both chemical and microbiological testing to determine if there are any issues and if the procedures adequately guide the analyst in a step-by-step process to execute the test. Analyst Training Review training records for the analyst to make sure they were qualified to perform the test under review. Sample Storage and Preparation Water samples are usually transported to the quality control laboratory where they might sit for awhile before testing is conducted. Review sample storage conditions as well as the time elapsed before testing was performed. Some companies refrigerate water samples upon receipt and may test them after 24 hours or so. This practice should be discouraged, as it could result in suspect data. Also, review the sample preparation techniques in the laboratory to assure that they do not compromise the integrity of the sample. Testing Time Limits Water samples should be tested as soon as they are received by the quality control laboratory. However, if the company has a practice that allows the samples to be stored for a limited time before analysis, review the records to determine if the samples were tested within the time limit.
Shahid T. Dara Media Preparation and Storage For microbiological testing, media preparation, storage, and expiration dating issues are critical in defining the success or failure of a test. Review media preparation procedures as well as the expiration date assigned to a given lot of in-house prepared media to assure that media is used within its expiration date. Other issues to be considered when reviewing microbiological testing should include: Incubation conditions ■ Qualification status of incubator ■ Use of positive/negative controls ■ Isolation and speciation of the microbial contaminants ■
Drug Product(s) Involved As part of the investigation, the drug product(s) manufactured with suspect water should be reviewed to determine if the safety, quality, and efficacy of the drug product has been compromised. The following points should be considered in this review: Dosage form of the drug product involved ■ Route of administration ■ Therapeutic class ■ Presence or absence of a preservative system in the drug product ■ Safety history of the drug product(s) ■
Personnel This part of the investigation should define if there are any deficiencies in the training program and also, if the people are qualified to perform their assignments. Procedures and Documentation Practices All the procedures and documentation involved should be reviewed to determine if there is a need for revisions or if new procedures should be prepared to supplement ones already in existence. Also, a determination should be made to assess whether all critical data is being reviewed by the appropriate people to make critical decisions (if needed). Corrective Action Plan Once all the facts are known, QA should develop a corrective action plan in consultation with other departments, as appropriate. The corrective action plan could involve one or more of the
following, depending upon the cause of the water quality failure/incident: If the water purification system is operating within specifications, additional water samples should be taken from source water, storage tank, and all points of use for three to five days and the system released if all samples meet specifications. ■ If part(s) of the water purification system need to be replaced, a determination should be made if this change is covered under a system parts change program or if it necessitates a requalification of the system. ■ Revise water sampling procedures and retrain employees. ■ Revise the analytical procedures. ■ Recalibrate the instruments, etc. ■
Summary, Conclusion and Sign Off A summary report should be prepared detailing the water quality failure/incident, probable or definite cause, corrective action plan, and disposition of the drug product(s) involved. Such a report should be prepared by quality assurance and reviewed and approved by appropriate members of management. The investigation report along with a summary should become part of the water purification system file. However, a brief management summary might be prepared to inform upper management, if the situation so warrants.
Last Word The management of change is an on-going battle and, like perpetual motion, we have yet to develop a perfect change control system that foresees all possible changes. There will always be unforeseen circumstances that will force one to rethink their approach to maintaining a level of control. Document change control and contract manufacturer/packager-related change control issues have been deliberately omitted from this discussion because of the enormity of the two subjects. ❏
About the Author Shahid T. Dara is the president of Compliance Consulting, Inc. He has over 17 years of experi- ence in the areas of product development, manu- Technical Guide
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