Susan J. Schniepp is a fellow at Regulatory Compliance Associates, Inc. and a member of Pharmaceutical Technology's Editorial Advisory Board.

Susan J. Schniepp

Auditing a firm's complaint and out-of-specification systems have always been favorite areas for regulators to assess to determine the compliance, effectiveness, and adherence of a company's quality system to the regulations.  

In today's regulatory environment, it is important for organizations to know the regulations with the same depth of knowledge and understanding as regulators. If an organization happens to be a contract manufacturer, it might also find itself in the position of providing that in-depth regulatory expertise to customers. In either case, the contract manufacturer and its customers must be able to work with each other and within the regulatory requirements to assure that the product manufactured and released for patients is of the highest quality. The partnership between the contract provider and contract giver must reflect the requirements and time commitments as defined in the regulations.  

Potential out-of-spec and adverse event reports

In situations where more than one organization is involved in the complaint and out-of-specification (OOS) processes for the product, all participating organizations must be harmonized in their approach for handling customer complaints and OOS results. In this author's opinion, it is the responsibility of the license holder (i.e., the NDA holder) to make sure its contract providers have the necessary processes and timelines in place to meet the necessary regulatory expectations. Likewise, it is up to the contract providers to make sure their internal systems meet regulatory expectations for all their clients. 

These systems should have established, agreed-to turnaround times regardless of whether the organization manufactures its own products or contracts the manufacturing and testing to external organizations. Complications can arise when more than one organization is involved in the processes and timelines for handling complaints and OOS results.  

The parties involved therefore must establish internal requirements that are consistent with the regulatory guidelines and give both parties sufficient time to conduct the needed activities required for the investigation into the complaint or OOS. The processes and timelines for handling complaints should be defined in a Quality Agreement and the related SOPs of the respective organizations and should include a clear delineation of which organization is responsible for various aspects related to the investigation.  

Contract organizations should establish timeframes for completing certain investigation activities, which may vary from client to client, but are usually completed within 30 days. The internal SOPs for handling complaints should be robust enough to be able to handle various clients' needs without creating multiple SOPs on the same topic. The process for investigating and handling OOS results should be similarly defined.  

The complaint SOP and the Quality Agreement also should address the turnaround requirements needed to investigate complaints associated with adverse or serious unexpected adverse events. For these complaints, the turnaround time must be able to accommodate tighter regulatory requirements. The license holder (i.e., the client) is required to submit a Field Alert within 3 working days after becoming aware of a reported problem either through a complaint or internal testing. 

In these cases, the complaint must be investigated quickly by the contract manufacturer. The turnaround time for these types of investigations should be defined in the Quality Agreement and subsequent SOPs and must be more expeditious than the timelines for handling routine investigations. OOS reports also require an expedited timeline for communicating confirmed results to the client because of the potential impact to product already distributed for use.  

In some cases, there may be more than two organizations involved in product manufacturing. These relationships can be complicated and communication lines blurred. The license holder must make sure through its various Quality Agreements that compliance to the regulations is met and responsibilities are clearly defined and adhered to.  

Below are few scenarios that demonstrate how complaint handling and OOS reporting can be handled to meet regulatory expectations. 

The license holder receives a complaint from a hospital indicating that a lyophilized product will not completely dissolve. The license holder manufactures and tests the product. It completes its investigation and closes it within 30 days as defined in the SOP. In this scenario, there is little risk of regulatory audit action should the complaint be reviewed during an inspection. 

The license holder receives a complaint from a hospital indicating that a lyophilized product will not completely dissolve. The Quality Agreement indicates the contract manufacturer has 30 days to complete a complaint investigation but restricts them from closing the investigation until the license holder gives approval. The complaint is passed on to the contract manufacturer for investigation within 5 days of receipt. The contract manufacture investigates the complaint and the results of the investigation are provided to the license holder within 20 days from receipt. The license holder reviews the investigation and closes the investigation in its system and notifies the contract manufacturer to close its investigation. The timelines for handling complaints and completing the investigation as defined in the Quality Agreement and SOP have been met.  In this scenario, there is little risk of regulatory audit action should this complaint be reviewed during an inspection. 

The license holder receives a complaint from a customer indicating that a lyophilized product will not completely dissolve. The Quality Agreement indicates that the contract manufacturer has 30 days to complete a complaint investigation but restricts the contract manufacturer from closing the investigation until the license holder gives approval. The complaint is passed on to the contract manufacturer for investigation within 5 days of receipt. The contract manufacture provider investigates the complaint and the results of the investigation are provided to the license holder within 20 days from receipt. The license holder reviews the investigation and closes the investigation in its system but does not notify the contract manufacturer to close its investigation. In this scenario, the typical timelines for handling complaints and completing the investigation as defined in the Quality Agreement and SOP have been met.  

In this scenario, there is a slight risk of regulatory audit action at the contract-manufacturing site because its complaint displays as "open." The contract manufacturer needs to show due diligence that it has requested a statement from the license holder to close the complaint should this complaint be reviewed during an inspection. 

The license holder receives a complaint from a hospital indicating a patient experienced a serious adverse event (SAE). The Quality Agreement indicates that the contract manufacturer has 30 days to complete a complaint investigation but restricts the contract manufacturer from closing the investigation until the license holder gives approval. The contract manufacturer has an SOP in place that defines the process for handling complaint investigation for SAEs. The complaint is passed on to the contract manufacturer for investigation within 24 hours. The contract manufacturer investigates the complaint and the results of the investigation are provided to the license holder within 24 hours. The license holder accepts the investigation of the contract manufacturer and completes its own investigation within 24 hours. The result of the investigation is satisfactory and no field action is needed.  

In this scenario, the typical timelines are not appropriate. There is a risk that the contract manufacturer could be cited for a regulatory violation because its complaint remains "open." In this case, it is fortunate that the contract manufacturing organization has an SOP that defines its heightened reporting requirements for handling complaints associated with SAEs.  The contract manufacturer needs to show due diligence that it has requested a statement from the license holder to close the complaint should this complaint be reviewed during an inspection. Both parties need to revise the Quality Agreement to define responsibility and timelines associated with investigations associated with SAEs. 

The license holder is informed of an OOS result from the contract-testing laboratory responsible for final product testing. The OOS was for a moisture failure on stability. The license holder has independent Quality Agreements with the contract testing organization and the contract manufacturing organization. The OOS is confirmed by the contract-testing laboratory. The separate Quality Agreements, in this case, may not have been reviewed to ensure consistency regarding timelines, notifications to regulatory agencies and partners, and authorizations to close. These inconsistencies may lead to increased regulatory scrutiny and possible actions if deemed sufficiently serious. 

The above scenarios illustrate how important it is for all parties involved in product manufacturing to understand the regulatory requirements and build requirements into SOPs and agreements so that unnecessary regulatory actions during inspections can be averted. 

In today's environment, all parties must take responsibility for product quality and regulatory compliance through clear delineation and communication of responsibilities through Quality Agreements and internal SOPs. 

 is vice-president of quality at OSO Biopharmaceuticals and a member of the PharmTech Editorial Advisory Board. 

Articles

The contract provider needs to know as much as the NDA holder.

Know the Regulations

The author describes an equation that can be used to define the Quality relationship between a contract manufacturing organization and a client, including how to factor in both party's needs and regulatory commitments. 

Contract manufacturing organizations (CMOs) occupy a special niche in the pharmaceutical industry and therefore face problems not encountered by traditional pharmaceutical manufacturing companies. One particular challenge facing CMOs is how to define the responsibility for Quality in a relationship. Which party, the contract giver or the contract provider, has which responsibilities? Although the answer may be straightforward for companies with their own manufacturing operations, it is quite complicated for a CMO. When defining ownership of "Quality," a CMO must consider the compliance needs and regulatory commitments for multiple clients. The CMO also must look at Quality as a function of product lifecycle—in a similar manner to how their clients would look at Quality if they were manufacturing the product themselves.  

If one views the Quality relationship as a simple mathematical equation, it may look something like this:   

where A is the CMO needs, B is the compliance needs, C is the client's needs, D is regulatory commitments, and E is defined as the elements of the Quality relationship. By analyzing this equation, it is clear that there are no constants, only variables. Each variable is based on the consideration of certain elements from each party in the relationship. 

 A CMO's needs are based on maintaining as much operational consistency as possible when managing internal and subcontracted resources. This approach enables cost management for the CMO and cost savings for the customer. Variable A should take into account the audit, testing, sourcing, and customer-specific requirements needed to manufacture the product. The CMO should make sure these requirements are included as part of the Quality Agreement. When defining auditing responsibilities, consideration must be given to determining the appropriate involvement of the client for internal, external, and regulatory audits and should be somewhat consistent between clients.  

Testing requirements (e.g., final product, raw material, and environmental) should include what is required not only to manufacture the product, but also to maintain the environment in which the product is manufactured. For example, testing requirements might be traditional compendial testing, but may also include product-specific testing as defined by the client. In the case of a raw material, the CMO must consider whether the item is used in multiple products and whether it is available from a single or multiple sources. Consider this example: in some cases, the client may dictate the supplier of the component in question because it has an established relationship. In other cases, the CMO may have the more established relationship with the supplier. In such situations, the CMO, in conjunction with the client, must determine who will be responsible for providing the qualification and follow-up audits of that supplier. This type of scenario should be defined in the Quality Agreement so that there is little confusion between the parties. A well-drafted Quality Agreement can save a lot of confusion and duplication of effort on behalf of the client and contract provider and facilitate productive communication.  

 Multiple customers, regulatory agencies, and standard-setting organizations influence compliance requirements maintained by a CMO. Each requirement needs to be implemented to accommodate the broad spectrum of these influences. Variable B of the equation defines the compliance needs for the manufacture of all products at the given facility. Company standard operating procedures (SOPs), customer SOPs, audit observations, and compendial requirements need to be considered in discussion with the client and the CMO. Clients should make every effort to understand their CMO's SOPs.  

It is equally important for the CMO to make sure that its SOPs are robust enough to accommodate multiple clients' needs. It is difficult for a CMO with multiple clients to operate using duplicate SOPs for the same process or procedure. The CMO and the client should therefore spend a sufficient amount of time ensuring that the compliance needs of both parties are defined and met.  

Similar to variable A, variable B also has an audit element to consider. In this case, the effectiveness and appropriateness of a CMO's audit program is considered. The audit program must meet the regulatory expectations for internal and supplier audits while also meeting the client's expectations on these points.  

In addition to these audit requirements, the CMO and the client must discuss the communication expectations for regulatory audits either conducted at the CMO's or the client's place of business. The need for the CMO to communicate with the client when a regulatory audit is being conducted at their facility is evident but it is equally important that the client communicate with the CMO when the positions are reversed. Two-way communication is crucial because each organization could be vulnerable for a regulatory audit based on the outcome of the regulatory audit being conducted at either facility.  

In addition to SOPs and audit requirements, compliance to the compendia must be considered under variable B. The client should confirm that the CMO has a process in place for reviewing and updating test procedures to maintain compliance with the applicable monographs, test chapters, and informational chapters maintained by the United States, Japanese, and European pharmacopeial authorities.  

 Customers bring requirements to the table that may be needed due to factors that are not within the purview of the CMO. These requirements might be influenced by development data, regulatory registration commitments, sourcing strategies, or partnerships. Under variable C, the CMO must consider the needs of the client in order to effectively provide them service. For example, the phase of drug-product development and whether the client is virtual or has in-house capabilities are elements that may affect the allocation of responsibilities within the Quality Agreement. If the product is under a cooperative arrangement with multiple companies, there may be more than one Quality Agreement associated with the manufacturing, packaging, and labeling of the product.  

If this is the case, the client should let the CMO know of these agreements and of the expectations when the product is passed to another responsible party during the manufacturing process. In addition, it is important that the client communicate with the CMO whether another contract provider is having regulatory difficulties. Finally, the client and the CMO need to determine whether any special testing protocols are needed for products in Phase 2 or 3 of the development process. If the testing of excipients used in the product is being performed by another organization other than the CMO client, this fact should be disclosed to ensure that excipient compendial requirements are met. The same situation is important with regard to where the material is sourced—whether it be a single source or multiple sources.  

 Regulatory commitments are an evolving body of knowledge that may necessitate flexibility to adapt to CMO and client interpretations of new or impending regulations. Variable D considers the regulatory commitments of the client and/or the CMO. CMOs can indicate which regulatory authorities have audited their facilities, when they were last audited, and the outcome of these audits. A CMO must also communicate to their clients the changes and commitments made to their Quality Systems based on the responses to the regulatory audits because these changes may affect the regulatory filings of the clients. Each client will have its own interpretation of how to comply with the audit observation and what filing strategy should be used to update their filings, if any.  

The CMO must ensure that its responses to regulatory audits do not jeopardize any of their clients' commitments. On the other hand, clients must communicate with the CMO regarding commitments they have made in their registrations. Among other information, they should disclose to the CMO whether they are using novel excipients as opposed to compendial excipients and whether any special specifications or testing must be performed.  

 The solution to the equation noted above (A+B+C+D) is E, which represents Quality as a function of product lifecycle. The document that contains the information defining the various responsibilities that comprise E is the Quality Agreement. This master document should define the CMO's needs, the client's needs, the compliance needs for the product and both parties, and any pertinent regulatory commitments. The Quality Agreement should be a living document that is reviewed and revised as often as needed to clarify the responsibilities of the client and the CMO as the product progresses through its lifecycle. The Quality Agreement is akin to a marriage license between two parties and should clearly identify the roles and responsibilities needed for a successful partnership.  

In general, Quality Agreements are legally binding agreements between the Quality functions of the contract provider and the contract giver. Many companies use a matrix approach for defining these activities which can include but are not limited to compliance, manufacturing, packaging and labeling, documentation, change control, nonconformance, out of specification (OOS), deviations, complaints, recalls, and auditing. Each document should be tailored to address the expectations of the specific operations to be undertaken by the CMO as well as external actions that may have an impact on those operations. Clients and CMOs should communicate frequently to make sure that the product being manufactured meets the necessary specifications required to meet the minimum Quality requirements. In order for the relationship between the client and the CMO to be effective, the two parties should communicate often. 

Defining the Quality relationship between a CMO and a client is complex and requires extensive discussion and attention to detail. The relationship should be open and communication between the two parties should be as frequent as required to assure that the product being manufactured meets the highest Quality standards for the client and for the patients.  

 is vice-president of Quality at OSO Biopharmaceuticals and a member of the PharmTech Editorial Advisory Board, 

The author describes an equation that can be used to define the Quality relationship between a contract manufacturing organization and a client, including how to factor in both party's needs and regulatory commitments.

Managing the Quality Relationship for a Contractual Agreement

In the pharmaceutical industry, the most frequently audited facilities are without a doubt contract organizations. These organizations are constantly being audited by prospective clients, existing clients, global and domestic regulatory authorities, and their own staffs. They deal with due diligence, regulatory quality systems, routine GMP inspections, preapproval inspections, and internal audits on a monthly, if not weekly basis. 

Audits can last anywhere from 1 day to 3 weeks depending on the type of audit being performed. In addition to typical audits, such as yearly GMP assessments by clients and regulatory authorities, contract organizations can also be tasked with "for-cause" audits by inspectors due to customer complaints or product recalls. Clients might also decide to perform a "for-cause" audit if the contract organization manufactured a number of lots with associated investigations for deviations during the manufacturing process. 

To stay ahead of the audit game, contract organizations must have a system for handling audits that is efficient, consistent, and flexible. A great deal of experience among the audit team is necessary because the team must be audit ready all the time while also assuring that the company's other departments maintain an audit-ready posture. The group must have the ability to host more than one audit at a time and be able to address questions and provide documents—in a timely manner—for as many as three auditors per group. The team must also be prepared to provide some of the same information to more than one group at the same time. 

Admittedly, handling two separate audit groups with two to three auditors each is an unusual situation. However, let's say that a contract organization has 14 clients and each client requires an annual GMP audit.  To maximize audit time, each client brings two auditors and plans for a 3-day visit. Considering that each audit requires one day of preparation and one day of follow-up activities for the contract organization, each audit ultimately takes up one week of the organization's time.  

Let's also assume that the contract organization is trying to attract new business. It has five potential new clients that wish to perform a quality audit before entering into a contractual agreement. In addition, let's assume that the organization provides sterile injectable products (or a similar product) to the global market, placing it in the high-risk category of manufacturing. This classification would result in annual GMP audits from, at a minimum, the regulatory agencies of the US, Europe, and Japan. Agencies typically spend 1 to 2 weeks conducting cGMP audits. 

Because contract organizations also must perform internal audits, which typically last one week and occur once a quarter, the numbers above equate to approximately 26 weeks or half of a year devoted to handling and conducting audits. This amount of time does not take into account preparation of responses to any potential audit observations or necessary follow-up activities. 

To successfully accommodate all of these audits, a contract organization must maintain a full-time contingent. Organizations must be aware that the time commitment entails more than preparing and hosting audit groups. Each audit could easily take 4 to 5 weeks when considering preparation, hosting functions (both escorting and staging room activities), responses, and followup. 

In addition, the organization must have a unique layer of resources to manage internal cGMP audit programs, which are required by regulators to ensure that each facility has a process for meeting compliance. Typically, these resources are passed on to customers as part of the cost for a contracted operation.  

Given these expectations, there seems to be an opportunity for industry to work with consortiums such as Rx–360 or the International Pharmaceutical Excipients Auditing (IPEA) program to share audits and thereby ease overall costs and time tied to the audits.  Moving in the direction of shared audits, however, requires more consistent interpretations and expectations, general acceptance of responses, and perhaps a certification process.  Companies using contract services must be willing to share their audit programs and compromise on what should be the ideal approach to assessing GMP compliance of contract organizations. They must agree to a set of criterion to be consistently applied for auditing and they must be somewhat consistent in their interpretation of the regulations. This would allow contract organizations to be able to maintain a robust quality system that is suitable for multiple clients.  The use of shared audits has been discussed for quite a while and it seems that Rx–360 and IPEA have started down the road of solving the problem for raw-material suppliers. Let's hope they agree to continue with the process and help out contract organizations in the same manner. 

 is vice-president of quality at OSO Biopharmaceuticals and a member of the Pharmech Editorial Advisory Board, 

Contract organizations must have highly organized teams and plans to accommodate today's audits.

Auditing by the Numbers

(USP) is the oldest continuously revised compendium in the world. Established in 1820, this independent organization has been setting US standards for medicines and pharmaceuticals for more than 185 years. Although FDA recognizes 

 standards, the US Pharmacopeial Convention organization was created to be  independent from the government, making it the only nongovernmental compendium in the world. The original 

 was a collection of recipes to aid pharmacists in formulating medicines for patients. The mission was to produce a book that would allow pharmacists to be able to offer reliable products with consistent names to patients in the United States.  

 debuted, the pharmaceutical industry did not exist and pharmacists used the information in 

 to deliver uniform products to the approximately 7 million residents residing in the 22 states that comprised the US at that time. The original publication contained monograph instructions for 621 items and was updated at approximately 10-year intervals.  

 is updated annually and contains more than 4000 monographs in addition to a myriad of general-test and information chapters. USP has more than 550 full-time employees and uses more than 1000 volunteers to set current compendial standards. In a few short years (9 to be exact) USP will celebrate its 200

However, during the past decade, the organization seems to have decided that the patients and pharmaceutical industry of the US are not a big enough arena for its standard-setting activities. USP has changed its mission statement to indicate that it wishes to "improve the health of people around the world through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods" (1). Its current vision is "...to be a leader in promoting the public health by creating a unique knowledge base—consisting of quality standards and information on proper use—for medicines and related products and practices. USP will ensure that people throughout the world have access to this knowledge base" (1).  

USP purchased the Food Chemicals Codex and opened offices in Switzerland, India, China, and Brazil. In its October 2008 mid-cycle convention report, USP indicates that the report is intended to inform "...USP's volunteers—members of the USP Convention; Board of Trustees; Council of Experts, Expert Committees, and Advisory Panels; and Stakeholder Forums and Project Teams—of the strides made to date in the 2005–2010 cycle. It offers a snapshot of significant achievements, milestones, and progress toward the goals articulated at the 2005 USP Convention. And perhaps most importantly, it provides a glimpse of where USP is going in the future..." (1).  

In addition, at the USP 2010 Convention, the organization passed Resolution 4, which deals with supporting and advancing global public-health initiatives." The resolution states, "Working in consultation and collaboration with national, regional and global stakeholders, USP resolves to assess the feasibility and advisability of advancing global public health initiatives. Where advisable and feasible, USP should seek to expand its resources for these initiatives, building on identified needs and existing opportunities, in order to support its international activities while preserving and fulfilling its role under US law" (1). On USP's website, there is an update regarding this resolution which indicates that USP is expanding its role in India and China as well as exploring relationships with the Association of Southeast Nations and Middle East and North African nations.   

Although these initiatives are altruistic, this author wonders whether USP is reaching a little too far from home in its pursuit of global pharmacopeial dominance. Perhaps some of these international resources could be redirected to continue and speed up the harmonization of monographs and testing requirements with the 

a goal that has been on USP's plate for some time. Or better yet, the true altruistic action for this standard-setting body would be to provide the other pharmacopeias assistance, staff, and funding to enhance their national compendia, or to work in a more collaborative manner with the World Health Organization to develop additional monographs for the 

One philosophy that has not seemed to change is USP's reluctance to accept that the 

 is a compilation of the hard work and intellectual input of regulatory filings of US proprietary and generic pharmaceutical companies. Representatives from these companies belong to trade organizations. These trade organizations make up the members of USP's Prescription/Nonprescription Stakeholders Forum (PNP–SF). In the May 19, 2011 PNP–SF meeting, USP announced to the attendees that they were re-evaluating the need and purpose of these meetings.  USP proposed reducing its interaction with the industry trade organizations that make up the PNP to a once-a-year webinar instead of the current two face-to-face meetings. In addition, USP opened the planning committee for these meetings by posting a call for interested parties on its website and asking these volunteers to nominate a chair person.  

If all that wasn't enough, USP summarily dismissed the current PNP–SF industry member's suggestions to form new project teams in an effort to help USP achieve some of its 2010 resolutions and to avoid such issues as the recall of 

 28, the monograph redesign project, the confusing implementation of residual-solvents testing, the number of errors in the 

 and the potential confusing implementation of the revised 

 <231> Heavy Metals General Chapter. These situations have left industry with a sense that USP is losing touch of its responsibility to the US pharmaceutical and medical communities. The only project team that USP intends to keep is the Compendial Process Improvement Team, whose charter is to address how USP can streamline and speed up its process for getting monographs and making information available. What USP fails to recognize is that the majority of the people who are representing the industry at the PNP–SF meetings have scientific backgrounds and can offer constructive and valuable insight regarding technical issues facing the USP.  

In summary, there are two issues that are of concern to this author: the apparent globalization of USP without sufficient harmonization and the dichotomous position of wanting the US industry to provide its technical information for monographs but discouraging input when it comes to assisting in improving the scientific information contained in 

. It seems that USP is trying to find a new identity that focuses beyond US borders, an approach that conflicts with what should be USP's main focus: providing current and accurate monographs for use by the US pharmaceutical industry. Let's hope the pharmacopeia can figure out its true identity before it ends up with no identity at all.  

 is vice-president of quality at OSO Biopharmaceuticals, 

The author served on the PNP–SF and on a USP expert committee from 2000 to 2005. She chaired a USP expert committee from 2005 to 2010. 

 To fulfill its role as developer of official standards for medicines quality in the United States, the US Pharmacopeial Convention (USP) has looked past US borders, as have manufacturers and FDA. Globalization of the pharmaceutical industry has altered the ways industry, regulators, and pharmacopeias interact, and USP is engaging the industry as it exists today. Concerns have been raised about USP’s global operations and possible effects on efforts to harmonize and modernize monographs in the 

US Pharmacopeia–National Formulary (USP–NF)

. Additionally, there are concerns about USP’s engagement with the USP Prescription/Nonprescription Stakeholder Forum (PNP–SF). I will touch on these in order.

Most of USP’s energies and resources go to its US compendia, particularly to 

. Investments during the past several years have been to advance our laboratories, moving from less-than-adequate space and equipment to state-of-the-art facilities and equipment in our Maryland headquarters, India (where a large new building has just opened), China (expansion under consideration), and Brazil. All of these laboratories support the work of the Council of Experts, USP’s standards-setting body, specifically to make available public reference materials that are critically needed for procedures in 

 monographs. USP has devoted considerable energies to better understanding basic measurement science (metrology) imperatives so that all parties—particularly FDA—have access to modern monographs and reference materials.

Given the global nature of pharmaceutical commerce, pharmacopeial harmonization is indeed important. Yet the outputs of the Pharmacopeial Discussion Group (PDG) have not met expectations. (PDG represents the pharmacopeias of Europe, Japan, and the US, and aims to achieve compendial harmonization.) PDG has focused on a narrow slice of standards: excipient monographs and the International Conference on Harmonization (ICH) Q6A-based General Chapters Q6A on test procedures and acceptance criteria for new drug substances and new drug products. After more than 20 years, only 63 excipient monographs of more than 300 in 

, and about 20 General Chapters have been harmonized. 

 is missing 137 monographs and many of the remaining ones require updating, including those that have moved through PDG harmonization. Of approximately 1200 excipients in global commerce, most have no public standards. PDG excludes major countries and regions, notably China and India, Latin America/Caribbean, and Middle East/North Africa.

Other initiatives are needed, and USP is taking a first step, we hope with other pharmacopeias.  We are working with the World Health Organization (WHO) and national and regional pharmacopeias to conduct summits around the world. China has embraced the concept, and will host its second Global Pharmacopeial Summit in Beijing in mid-November. USP hopes a late-2012 culminating meeting, convened by WHO, will pave the way for new thinking on pharmacopeial harmonization. Additionally, USP’s new Medicines Compendium may model a path to more flexible pharmacopeial monographs using performance-based approaches.

 USP has worked with industry for more than a century to include monographs in 

 that mirror FDA approvals. USP greatly appreciates these donations of time, information, and materials from our industry colleagues. We believe every drug needs a public monograph and reference material the moment it enters the market, allowing FDA and other regulatory authorities to check for adulterated, counterfeit, or substandard medicines and their ingredients. USP wishes to work with all manufacturers to gain needed information and materials to support public standards. 

But we cannot overlook the numbers: monographs in 

 number more than 4000, yet it is missing nearly 1900. Many need updating. Deficiencies in USP’s heparin monographs provided an example of why public health is best served by modern monographs—and USP worked carefully with FDA and industry to update these critically needed standards. FDA has identified monographs in 

 needing improvement; we welcome this input.  We have recently received good support from the Consumer Healthcare Products Association, and welcome similar support from other associations. 

USP values the talented representatives from pharmaceutical manufacturers who have worked to advance topics through the PNP–SF since 2000. This has proved an important venue where issues have been discussed and many resolved. In recent years, opportunities for stakeholder input into USP standards have increased significantly, including new expert panel rules allowing experts to fully participate in deliberations without having to abstain due to conflict. A new “design phase” approach—which emanated directly from the PNP–SF—uses workshops, webinars, etc., for stakeholders to provide early input into USP standards. 

USP spoke about ways to expand the forum’s reach at the May 2011 meeting. We focused on two principles: USP will conduct its standards-setting activities in an open, transparent manner that allows participation by all constituencies; and because USP text and publications may have legal implications in the US and elsewhere, their language must stand on its own and not be interpreted to a few, thereby disadvantaging parties without that interpretation. All stakeholders should have same opportunity to participate in USP’s stakeholder activities, so that a select group does not have disproportionate voice. Thus, we are exploring conducting the PNP–SF in a format that can be open to more stakeholders: web meetings. But at the PNP stakeholders’ request, we may continue to conduct face-to-face meetings while enabling web access. We hope to provide enhanced ability for others to participate, including shaping agendas and participating in project teams. 

As noted, there are crucial issues for consideration. These include the role of the pharmacopeia in a modern, democratic society as a means of advancing modern public standards; the challenge of keeping 

 monographs up-to-date and USP’s reliance on industry support for this; and the need for pharmacopeias to come together so that patients and practitioners everywhere have access to good quality medicines. If industry, FDA, and USP address these issues adequately and together, they can be resolved. 

After a series of structural changes, the author wonders whether USP is undergoing an identity crisis. USP CEO Roger L. Williams responds.

Where in the World is the US Pharmacopeia?

At a recent industry workshop, I heard an FDA speaker clarify the concept of "compliance" into four simple statements: Say what you do. Do what you say. Prove it. Improve it. Companies usually use their standard operating procedures (SOP) to show that they have control over their processes, thereby demonstrating compliance with regulatory expectations. The "say what you do" phrase equates to the written SOP that defines the steps taken to achieve compliance to a regulatory requirement. "Do what you say" equates to following the SOP. This concept seems simple enough to follow. However, for years, FDA has been citing industry for failure to follow SOPs. So, it was no surprise when I read Jeanne Moldenhauer's article in the  April 2011 issue of 

, titled "Review of FDA Warning Letters," and found that many of the 483s and Warning Letter observations issued in 2010 began with the words, "Failure to follow procedures..." Digging a little further, I went to the FDA reading room (

www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

) and started looking at the 2011 Warning Letters issued to date. Once again, the phrase, "Failure to follow procedures..." was prevalent throughout.  

This trend is disappointing. Numerous webinars, seminars, and workshops designed to train personnel in the art of writing and following SOPs are presented every year. A myriad of articles, books, and manuals discuss the who, what, when, where, and how of SOPs. There are numerous companies, consultants, and experts that a company can hire to write, review, and critique these procedures as well. 

Every company in the pharmaceutical industry has training programs to ensure that employees are provided with—and understand—current SOPs. When considering the various tools available to the industry regarding such procedures, it's unclear why industry still has trouble following its own instructions. 

One reason may be the need for customized SOPs, which are often required by clients of contract manufacturing organizations (CMOs). Contract organizations typically write SOPs to accommodate diverse opinions on how a particular process should be implemented in order to guarantee compliance. These SOPs are presented to prospective customers as a part of due-diligence activities. Occasionally, a customer will insist on supplying the CMO with its own version of the SOP activity and demand that the CMO implement the procedure when manufacturing its product. This approach can be disruptive to the CMO for several reasons. For starters, the CMO's employees need to be trained on two procedures for one activity, and they must understand when and why, and in what situations they should use one SOP over the other. 

Consider the following scenario: CMO A has an established SOP for performing visual inspections on final filled vials before packaging them. The SOP indicates the predicted reject rate associated with various vial defects that might occur as a result of the manufacturing process. Examples of some of the indicated defects are cracked vials, misplaced stoppers, poor crimps, and so forth. Each defect has an established reject rate based on production capabilities. Company A, a new client, has just qualified CMO A as an alternate supplier for their life-saving medicine because its primary supplier is unable to keep up with market demand. Company A would like CMO A to use its inspection SOP for visual inspection purposes. There are major differences between the two SOPs, including the defect categories, the established reject rates for defect categories, and the inspection report forms. Company A's SOP has more defect categories, and the reject rates are tighter than CMO A's SOP, which prompts the use of the different inspection report form.  

As a further example, an experienced, trained employee at the CMO is performing the vial inspection for Company A's product and forgets that there is a custom SOP for this process step.  The employee completes the inspection and turns in the results to the manufacturing quality assurance (MQA), which detects the error and initiates an investigation. The lot in question must be reinspected using Company A's SOP, and the appropriate acceptable quality levels (AQLs) must be applied to the product lot in question. This reinspection delays the release of the product by several weeks, causing a stock-out situation in the field. 

Another problem CMOs face when using customized SOPs is how to handle conflicting SOPs.  Consider the following scenario: CMO B has just been selected by Company B to manufacture its product. CMO B has an SOP for identifying and investigating incoming raw materials for foreign matter. The SOP requires CMO B to characterize foreign matter as either inherent or aberrant. If the foreign matter is deemed inherent to the raw material, a description of the foreign matter is recorded as part of the raw-material release. The foreign matter is then removed and the raw material is used in product formulation. If the foreign material is determined to be aberrant, then the raw material in question is put on hold, and an investigation is initiated to determine the identification of the foreign material in question.  

Most of CMO B's clients are comfortable with the SOP, but when manufacturing Company B's product, CMO B comes across some black particles in sucrose, a raw material used in the manufacture of Company B's product. CMO B uses its foreign material SOP to record the incident. The foreign-material report indicates, under high magnification, that the black material is burnt sucrose. Because burnt sucrose is inherent to sucrose (the raw material), it is deemed suitable for manufacture. CMO B releases the batch record and the associated product to Company B for review, approval, and release. Company B refuses to release the product because its internal SOP, which was not provided to CMO B, specifies that foreign matter found in raw materials must be sent for molecular identification. Until the discrepancies between the SOPs are resolved, product manufactured for Company B is required to be released by exception. 

The practice of using customized SOPs also presents a logistical problem for the CMO: Which SOP should be presented to the regulatory authority during a cGMP inspection? For product-specific inspections, only those SOPs associated with the product should be presented to inspectors. However, when a general inspection is combined with a product-specific preapproval inspection, for instance, two SOPs for the same process must be provided to inspectors. Invariably, inspectors will investigate the areas where the firm may have internal challenges and in all likelihood, will leave the CMO or the company with a  an observation that it "failed to follow written procedures..." 

There are no easy solutions to the situations described. CMOs and their clients, however, can minimize these and similar types of circumstances through open communication. CMOs must seek to understand their clients' needs while clients must seek to understand their CMOs' quality systems. Although we are all in the same industry, we do not always share a common language with respect to describing our internal systems. Establishing a common language between the two parties makes it easier to determine what, if any, changes need to be made to a CMO's quality system to accommodate the client's needs.  If the two parties can effectively communicate and eliminate the need for redundant SOPs, their chances of avoiding unfortunate compliance mishaps will greatly increase." 

 is vice-president of quality at OSO Biopharmaceuticals and a member of the PharmTech editorial advisory board, 

Why SOPs are rarely followed, often cited, and in need of follow-through.

Following our Own Instructions

The pharmaceutical industry has been trying to become more efficient from both manufacturing and regulatory perspectives. The challenge is to improve processes, quality systems, and manufacturing capabilities while operating efficiently and in a manner that ensures safe, effective, and cost-efficient medicines to patients. Many updates to processes and quality systems can be easily and readily implemented with little or no impact on regulatory filings. However, changes to manufacturing equipment do affect submissions.  

Consider the following scenario. A contract manufacturing organization (CMO) making aseptic injectable products is planning to update one of its manufacturing lines where multiple products from various clients are made. The equipment involved includes a vial washer, a depyrogenation tunnel, and a filling machine. In addition, a restricted access barrier system (RABS) will be added around the new filling machine and the automatic tray-off area to increase protection against human intervention.  

These equipment updates will impact the regulatory filings of the CMO's clients. The affected clients are notified approximately six months prior to when the replacement is scheduled. Clients also are informed of the necessary downtime needed to complete the activities required to ensure that the new line is capable of producing the same quality of product as the previous line equipment.  

In this scenario, the question most often posed to the CMO from the client is, "What is the recommended filing strategy for the proposed changes?" To address this question, several points must be considered. One consideration is that the CMO must adjust its production schedule to ensure that the product reamins available in the market during the scheduled downtime. Avoiding a drug shortage is particularly important in situations where the CMO is the sole source of the product. 

Another item to consider is how well the CMO understands the client's filing with respect to equipment details. The goal of the CMO in this situation is to be out of commission for the shortest length of time and to propose the most reasonable and acceptable filing strategy to their clients and the appropriate regulatory agency. 

In the most conservative case, these changes might be filed as a prior approval supplement (PAS). However, this approach requires regulatory agency approval before work can begin and, as a result, could lead to the manufacturing line being down for several months to a year.  

Consider also that the project could take four to six months after approval, including performing the appropriate installation, operational, and performance qualifications and the process validation requirements needed to requalify the new line. In the least conservative case, these changes could be reported to the regulator in the client's annual report filing.  

The most realistic filing strategy is to use the CBE-30 category to notify the agency of changes to the CMC section of the regulatory filing. With this approach, the replacement of the vial washer and the filler should be considered like-for-like replacements. In the 2004 FDA guidance for industry,

for drug products, FDA considers, "changes to equipment of the same design and operating principle and/or changes in scale..." as annual reportable material (see Section VII.D.1 of the guidance) (1).  

It is recommended that the use of a comparability protocol be employed to help prove this correlation. The more recent draft FDA guidance on this subject, the 2010 CMC 

Post approval Manufacturing Changes Reportable in Annual Reports,

 suggests the addition of the RABS to a Class A area be considered as annual reportable as indicated in Appendix A under Manufacturing Sites, section 2.1, which respectively states, "Addition of barriers to prevent routine in-process human intervention in a filling or compounding area that is qualified and validated by established procedures" (2).    

Although many of the changes being made could be considered as annual reportable material, the replacement of the depyrogenation tunnel likely could be filed as either part of an annual report or a CBE-30. Submitting this change as a CBE-30 is supported by the following language taken from the 2004 guidance, "For sterile drug products, drug substances, and components, as appropriate ... Changes in dry-heat depyrogenation process for glass container systems for drug substances and drug products that are produced by terminal sterilization processes or aseptic processing" are considered as CBE-30 (see Section VII.C.1.d of the guidance) (1). The changes being made to the manufacturing line will not change the process or parameters for dehydrogenation, but they do replace the tunnel. Although this change could be considered an annual reportable, it is recommended it be a CBE-30 because of the critical nature of the tunnels function.  

Because the replacement of the depyrogenation tunnel is considered a CBE-30 all the changes being made should be considered a CBE-30 per Section XII of the 2003 Guidance which states, "For multiple related changes where the recommended reporting categories for the individual changes differ, CDER recommends that the submission be in accordance with the most restrictive of the categories recommended for the individual changes" (3).  

There are no easy answers when recommending filing strategies to a client. Regardless of what the CMO says, the client can always chose an alternative. The best way to convince a client of a filing strategy is to become familiar with the regulations, use them to justify the recommendation, use a comparability protocol for proving like-to-like equivalency, and present the recommendation to the client in a documented manner. 

 is vice-president of quality at OSO Biopharmaceuticals and a member of Pharmaceutical Technology's editorial advisory board, 

Guidance for Industry: Changes to an Approved NDA or ANDA, Rev. 1 

Draft Guidance for Industry: CMC Postapproval Manufacturing Changes Reportable in Annual Reports

Guidance for Industry: Comparability Protocols—Chemistry, Manufacturing and Controls Information 

What to do when your CMO changes the manufacturing equipment line.