IMPROVED EXCIPIENT ANALYSIS AND CONTROL

IMPROVED EXCIPIENT ANALYSIS AND CONTROL is being targeted as a key element in advancing quality by design and quality systems in pharmaceutical manufacturing. Excipient suppliers, users, pharmacopeias and regulatory agencies are searching together for ways to open communication pathways so that better analytical choices can be made and GMP needs clarified and met. A recent Product Quality Research Institute workshop on excipient testing and control strategies assessed the current communication challenges and the efforts under way to address them. [A report on Wyeth's work on excipient QbD under FDA's CMC pilot program is included on pp. 16-20.]

PQRI Workshop Focuses On Rationalizing Excipient Testing, Auditing and Labeling

Rationalizing excipient testing and improving excipient GMP standards are two key aspects of an effort under way to strengthen the communication pathways between suppliers, users, pharmacopeias and regulatory agencies.

There is a growing recognition that better analysis and control of excipients is a lynchpin in advancing the new quality-by-design and quality system objectives for pharmaceutical manufacturing. That recognition is leading the regulatory community to try to overcome the obstacles that have prevented the knowledge needed from flowing freely through the communication system.

On the analytical side, the goal is better use of the arsenal of techniques to assess what is truly critical in how the excipient performs in the dosage form process and product, while avoiding testing that is not value-added.

Enhanced communication - enabling excipient manufacturers to learn more about how their product will be used and users about how it was made - will be a key factor in making the right analytical choices. Shifting the focus onto excipient composition and away from the impurities orientation in the active pharmaceutical ingredient (API) arena is being urged as an important first step ("The Gold Sheet" November 2006).

The role of the US Pharmacopeia and other compendias is being closely examined to see how they can best facilitate more finely tuned interactions between makers and users on excipient performance, while avoiding contributing to the unnecessary testing burden.

To improve communications on the GMP side, vendors, users and the pharmacopeias have been refining voluntary standards. The European Commission, meanwhile, is stepping up the pressure by developing new excipient-specific GMP requirements.

ä In search of ways to improve excipient testing and control, suppliers and users joined with FDA and USP officials at a workshop convened by the Product Quality Research Institute (PQRI) in October in North Bethesda, Maryland.

Setting the stage for the discussions was a PQRI survey of excipient testing and control strategies, which was distributed at the workshop.

The workshop included "roundtable" sessions on five key areas where it was felt survey findings were not definitive: ? interpreting "continuous flow manufacturing" and "skip-lot testing" for excipients in the context of 21 CFR Part 211.84 regulations ? how characterization of excipients helps build quality into drug products ? the advantages of using third-party audits ? strategies for reducing the use of excipients that are not labeled USP-NF, and ? when reduced testing is appropriate.

Based on the workshop discussions, PQRI is developing a joint position paper representing the views of excipient and drug product manufacturers, as well as those of USP.

GMPs Allow Test Skipping, Not Skip-Lot Testing

One of the supplier/user communication issues that came out in the sessions on skip-lot testing was how to define batches and lots, particularly in the context of the continuous flow manufacturing operations that are typical of the chemical industry.

It was noted that batches are defined by 21 CFR 210.3(b)(2), while lots can either be equal to batches or portions thereof.

ä However, there is room for latitude in these definitions, industry consultant Lynn Torbeck, who moderated the sessions, indicated in his wrap-up remarks.

"One of the refinements to that is that if you meet the requirement of the GMP for the definition of lot and batch, you can then further refine the definition of a lot and batch as part of the quality agreement or the contract between the supplier and the customer. And we all agree that the essence here of both the GMPs and actual practicality is that the batch must have uniform characteristics. Regardless of what you agree, the GMPs trump that."

Further, the vagaries of production could lead to variations in batch size. "If there is a change in the manufacturing process, some kind of process upset, that could influence and/or change the definition of a batch size," Torbeck noted. "It was clear that a batch could be defined by a period of time - it is actually in the GMPs under the definition of a lot. So, as one supplier was doing, every 24 hours they declared a new batch at 6 a.m. Another example was that every period of six hours was defined as a batch."

ä Additionally, Torbeck noted that drug manufacturers typically define lots differently than do their excipient suppliers. "Different drug manufacturers have different acceptance criteria for raw material and batch definition," he explained.

"In most cases, I think, customers said that they defined every incoming shipment as a different batch. So that they did not use the supplier's or the manufacturer's batch as their batch number, but rather gave their own number to each shipment that came in, even if they were from the same manufacturer's batch." This way, they could take into account anything that might have happened during transportation. "In some cases," Torbeck noted, "they tested all characteristics on every lot."

As breakout session participants attempted to define the various players in the excipient supply chain, including suppliers, vendors, distributors and manufacturers, "it was clear from all the discussion that supply chain and a good knowledge of the supply chain, shipping and distribution was an essential part of dealing with a batch and a lot," Torbeck noted.

ä A consensus emerged, Torbeck related, that skipping lots is not a viable approach for reducing testing because of the GMP requirement in 21 CFR 211.84 for product manufacturers to test every lot, at least to confirm the excipient's identity.

Most noteworthy in this context is the wording of 211.84 (a): "Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit," and of Section 211.84(d)(1): "At least one test shall be conducted to verify the identity of each component of a drug product."

However, roundtable participants indicated many product manufacturers are doing what Torbeck called "skip testing." Under this approach, they would, for example, fully test the first five lots. After that, they would rely on a certificate of analysis (C of A) from the supplier for many of the tests, though not the identity test, while still fully testing one lot every year.

"We felt maybe we needed to make a distinction between skip lot and skip test," Torbeck explained. "So technically, we are not doing skip lot, we are doing skip test, in that some tests are not done for some lots, but every lot is tested for ID."

Under the C of A, the excipient manufacturer may also skip certain tests. However, Torbeck emphasized that in these situations, the drug product manufacturer steps in and does them. "So I think a universal statement was that all tests are done for all lots by somebody - either the [excipient] manufacturer or the customer."

There were indications that some excipient companies perform trend analysis of excipient data. Some are "using control charts and process capability analysis like Cpk to monitor and trend their data, both the manufacturer and the customer - we found examples of that," Torbeck indicated. "One supplier/manufacturer allows the customers to see their control charts."

ä In his summary remarks, Torbeck emphasized that "continuous-flow processes can meet GMP definitions of batches and lots."

He went on to recommend that people "go back to the GMPs, [21 CFR] 210.3, and read very, very carefully the definition of a batch and a lot, and then from that develop an operational definition of how that fits with your application." He further suggested that, "as long as you are operating within those constraints, then the batch and lot can be further defined by the quality agreement or contract between the manufacturer and the company."

Torbeck reiterated the rationale for avoiding the skip-lot testing term. "We are going to say that skip-lot testing is not to be used, from a very, very technical standpoint, in the sense that every lot has to be tested for ID. So we are going to differentiate between 'skip lot' and 'skip test,' where you do not do all the tests on every lot. And many companies are doing skip-test procedures."

ä Finally, he explained that the breakout session participants saw no reason to recommend major changes.

"We were very pleased to see that as far as we could tell, the current activities by the majority of the people that attended our session here do meet the current requirements and we did not find the need to change or modify them."

Excipient PAT Should Lead To Reduced Testing

There are several areas where it could be particularly fruitful to seek clarification, Colorcon Global Regulatory Affairs Director David Schoneker remarked in response to Torbeck's presentation. Schoneker is chair-elect of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas).

ä He suggested that the GMP requirement for "uniform characteristics and quality" in continuous processes "is sorely misunderstood" between the chemical and pharmaceutical industries.

"People think that means content uniformity in the pharmaceutical arena, when in fact what it really means is everything … will meet specifications that the manufacturer of the excipient has committed to. It does not mean it is going to be the same throughout the lot or drug to drug. It simply means that it is going to be within specifications."

Under the current approach, Schoneker stressed, "every test must be performed by someone." This approach persists despite frequent discussions about reevaluating it.

"There is tremendous concern throughout industry that that may not be what is necessary in the current climate." The question, he indicated, is whether there is "a way to find a mechanism that allows the proper assurance of compliance to the non-critical compendial specifications that may include process controls at the excipient manufacturer level, instead of somebody having to run the test even when it is fully under control through process control means."

Confusion persists as to whether "somebody runs the tests regardless of the controls. There have been sometimes mixed messages from the FDA as to what their feelings are. It is taken by many users that if you cannot get the actual test from the supplier, a certification statement that they meet the criteria through periodic testing and process controls is not good enough." Schoneker went on to suggest it would be great if the workshop led to further clarification on that point.

For their part, excipient manufacturers generally "do not run every test and see no need in running certain tests," he noted, "because they have process control and periodic testing going on that provides assurance that they will always meet the USP."

Typically, excipient makers include a section in their C of A that says, "'we comply with these tests based on periodic testing and controls,' etc., etc.," Schoneker added. "The problem that is out there right now is that there is a lot of confusion about what that means." Invariably, it leads to conflict between the users and makers of excipients, with the users demanding the makers run the additional tests, and the makers refusing, saying that because their processes are controlled, USP does not require the tests.

ä The approach for excipient manufacturing should be consistent with the new process analytical technology (PAT) paradigm targeting the reduction of low-value tests, such as those of non-critical parameters for compendial compliance, Schoneker maintained.

"Why doesn't" the new PAT paradigm "apply here?" he queried. "In 211.84, the word 'test' is there. And again, maybe there is a need for everybody to reevaluate, is that really the right approach in a PAT environment? Or is there some other way in which an assurance of compliance can be met?"

Without this reevaluation, "everybody is just going to be testing these and testing these and there will be fights between makers and users forever, and what is the value there?" Schoneker said. "That is really a confusion that I hear all the time, and nobody seems to do anything about it and just running the test. And I think this conference ought to be saying, 'no that is not acceptable. We need this resolved. And there has to be some clarification."

FDA Points To QbD As Path To Reduced Testing

FDA has demonstrated flexibility on the question of excipient testing and GMP requirements, with an eye to advancing the quality systems approach in a way that is consistent with regulatory requirements.

In his remarks at the PQRI workshop, Nicholas Buhay, acting director of the Division of Manuufacturing and Product Quality in CDER's Office of Compliance, suggested an approach for reducing the amount of testing excipient manufacturers and users must perform.

As Torbeck suggested, FDA would not be likely to condone skip-lot testing due to GMP requirements, Buhay indicated. "When I look at this idea of periodic skip-lot testing, I look through the filter of the required representative sampling," he explained.

Viewed in this way, "we are going to have to extend the applicability of a test on a discrete amount of material to other discrete amounts of material. We are going to have to be able to take away that adjective, discrete. Without that, it is going to be very difficult I think for us to, certainly in a legal way, simply say the requirement to test every batch does not exist."

ä However, the new quality paradigm offers a more viable approach to reduced testing, Buhay suggested.

"I certainly see possibilities where reduced testing can be accomplished by revamping or revising the review of specifications and critical quality attributes." The idea is to test only the critical attributes, thereby eliminating compendial tests for attributes that are non-critical in the context of a particular product.

In turn, a QbD process control approach can render critical attributes non-critical. "If you get control of the processes such that the critical aspect of an attribute goes away, that the attribute becomes so dependably input into the material, it may not then qualify for a specification," Buhay explained. "If you think the specification is not required, then testing is not required."

He further suggested that it may be possible "to come up with some kind of science that will allow us to expand the uniformity rationale from batch to batch, without that physical process which is connected to it."

In response to a question about the relevance of an ICH Q6A provision on using skip-lot testing with sufficient justification, Buhay noted the GMP allows batch release of excipients or final product without using "the compendial method - that has been long-established policy." Noting, however, that "something must be used in its stead," Buhay pointed to "a lot of potential" for the "application of in-line, on-line, at-line kind of measurements that can be either an adequate substitution or surrogate for the final specification test."

Communication Needed To Understand Changes

Characterizing excipient physical and chemical properties can help build quality into drug products, but only with a heightened degree of communication, participants observed in breakout discussions led by Brian Carlin, global manager of pharmaceutical R&D for FMC Biopolymer.

Carlin, who formerly chaired the IPEC-Europe Excipient Master File Committee, suggested that industry is looking forward to FDA's 21^st Century GMP initiative, "especially if it gives reduced regulatory oversight, with flexibility and continuous improvement."

ä Where this could have a real impact on excipients is with multi-sourcing, Carlin predicted. "Switching between suppliers would be much easier if you have got quality by design and PAT" supported by the 21^st Century initiative.

However, for it to work, such switching would require "informed user/supplier collaboration. Because any design in isolation … could easily be thwarted if the supplier does not know what you are using the material for. Change is something that unbeknownst to them is critical to your design."

Carlin found general agreement in his breakout sessions that "functionality transcends the excipient." By the same token, roundtable participants preferred the idea of leaving functionality tests out of monographs, so that the supplier and user would feel free "for a particular application to realize the maximum benefit."

ä When auditing suppliers, excipient users should bring technical staff along, Carlin stressed. "I will always encourage you … to bring your techies along - people who can actually learn what the supplier is doing."

It is important for users to define in writing which excipient changes would be considered "significant," he noted. It is difficult for the supplier to make such a determination if it "does not know what you are doing [with the excipient]. They can quite genuinely say they have not changed anything significant that could derail your process."

The participants challenged the general assumption that "just changing suppliers is viewed as a minor change," the moderator reported. In every session, at least one participant shared problematic experience with switching suppliers. Invariably, they would go into it thinking it was not a significant change, and to their surprise, the drug stability would significantly decline. "It is not critical if you get away with it," Carlin observed. "But if it derails your product it then becomes very critical."

For this reason, drug product manufacturers really need to clarify what types of changes would be significant. "If you are identifying critical attributes above and beyond the monograph, it is the responsibility of the user to make sure that they are communicated back to your suppliers."

Another area requiring improved communication is between purchasing and technical functions. Carlin's breakout sessions "came across a wide range of practices. Some people are purely commercial. Other companies have armed their commercial purchasing groups with technically informed people, with substantial experience as industrial pharmaceutical scientists."

ä As part of the effort to improve communications between users and suppliers, change control that involves notification and definition of significance, "should be a critical element of the quality agreement," participants agreed.

The change control requirement should be specific. "It is rather unhelpful just to have a general 'tell us in writing six months in advance.' It does not work like that because … your suppliers are equally at risk to the vagaries of life. Their suppliers could go out of business or have a catastrophe," Carlin noted.

Often, critical changes occur too quickly for any advance notification, instead requiring immediate response. Carlin stressed that "it is how you manage that crisis collectively that is often the litmus test of the quality of the relationship between the user and the supplier."

The reason technical personnel need to be included in audit teams is that audits should be more than "just a compliance exercise through all the SOPs," the moderator explained. "You should actually take the time right on the site to eyeball what your suppliers are doing."

Third-Party Audits Can Help Suppliers And Buyers

The potential benefits of third-party auditing of excipient manufacturers were explored in sessions led by Irwin Silverstein, a consultant specializing in QA and regulatory compliance for pharmaceutical excipients.

Silverstein is chief operating officer of International Pharmaceutical Excipients Auditing (IPEA), an independent subsidiary of IPEC-Americas established in 2000 to conduct third party audits ("The Gold Sheet" January 2000).

He pointed out that one plus for third-party auditing is that they use auditors who are specially trained for dealing with excipient manufacturers.

Also, it means less time wasted for the excipient manufacturer and consequently more time for the auditors. The supplier can afford to give the third-party auditor more time than it could have given auditors for the individual companies the third-party auditor represents.

"If you are hosting customers, typically you get eight hours to do whatever you can - the point being that if you are sponsoring a third-party audit, we would think that if it results in fewer visits to the site, you can afford to allow the company who is doing the audit, the third party, to spend more time to be more thorough."

Silverstein indicated that excipient manufacturers benefit because their customers have a more comprehensive report than they could get themselves.

The pharmaceutical manufacturer benefits by avoiding the need "to use risk management for deciding who to audit, on the premise that you cannot go in to everybody who supplies you with excipients."

One potential downside is that excipient makers might prepare more for the third-party auditor. But the breakout session participants generally felt such preparation would not make much difference.

ä Silverstein stressed the importance of having a third-party auditor you trust.

Third parties are better suited for some types of audits than others, he indicated. Second-party audits are better if the product manufacturer plans to send technical personnel to learn. But third-party auditing might enable product makers to audit more excipient makers than the second-party approach.

He also recommended reserving second-party auditors for for-cause audits or responses to regulatory actions, where they would be clearly preferable. "If you are coming into a facility to follow up on problems you have had with the manufacturer, a so-called 'for-cause audit,' you probably are going to want to use your own auditors who are armed with the information from either quality, receiving or production that you want them to follow up on."

However, when conducting surveillance audits, "just to confirm continuing conformance to excipient GMPs, maybe it is preferable to rely on a third party, so you can focus your attention on those for-cause or initial qualification audits," Silverstein suggested.

Third parties also can be ideal for non-manufacturing-related "audits of warehouse operations or distributors who merely pass along the excipient without repackaging," he added.

ä Silverstein questioned why there is so much resistance to using third-party auditors, noting that pharmaceutical manufacturers already use third parties for more sensitive activities such as packaging, testing and manufacturing.

He acknowledged one reason may be that companies would have to change their SOPs. "We think one of the obstacles might be supplier audit SOPs of the pharmaceutical firms [that] preclude the use of third-party audit," he explained. "They are geared toward second party. And we all know that if you are operating in the pharmaceutical industry, the last thing you do is violate your procedures."

Silverstein went into the issue of auditor training, emphasizing the importance of knowing the differences between Part 211 (dosage form GMPs), ICH Q7A (API GMPs) and USP's general chapter <1078> covering excipient GMPs.

Third-party auditing would be a big benefit for small drug product manufacturers who currently must rely on sending out questionnaires to their excipient suppliers - a much less reliable method for ensuring quality, according to Silverstein.

Asked how third-party auditors would handle confidentiality, he said they could agree to limit release of user-sponsored audits.

ä Silverstein encouraged drug product manufacturers who are resistant to letting others handle their audits to buy a few third-party audit reports so they can make an informed judgment about them.

He noted that during the roundtable sessions, makers and users of excipients both expressed reluctance to sponsor third-party audits. Excipient manufacturers "are reluctant to spend the money, because they do not know if the reports would be purchased by their customers in lieu of coming in to do a audit." Pharmaceutical manufacturers, in turn, "are reluctant to pay the money to sponsor an audit report of an excipient manufacturer, because they do not know the quality of what they would receive."

Noting that IPEA's audit program has been up and running for several years and that USP "is looking to do the same thing," Silverstein stressed that "the benefit to the industry is the sharing of the reports." He pointed out that "if you go to the IPEA web site [www.ipeainc.com], you will find some very commonly used excipients for which we have reports available."

He went on to suggest that, "for a very nominal charge relative to your own audit, you will be able to purchase a copy of a report as an excipient user and determine for yourself if it is suitable as a replacement for your own site visit. If we do not start purchasing these reports, we are never going to get the benefits that we hope from the workshop."

USP-NF Grade Labeling At Issue

Brainstorming sessions at the PQRI conference did not resolve the problem of how to turn around the decrease in the number of excipients produced to meet USP-NF grade and labeled as such.

In the late 1990s, "I saw a huge trend of excipient suppliers that would start sending us letters with regard to moving from USP-NF grade to non-USP-NF grade," recalled Barbara Ferguson, associate director and compendial liaison in global regulatory affairs for Schering-Plough, who led the sessions. "A lot of that came from a misunderstanding" that has abated somewhat over the ensuing years, she noted.

She pointed out that excipient manufacturers may be dropping USP-NF grade labeling in a misguided effort to avoid having to comply with compendial and GMP requirements. The problem is the FD&C Act Section 501(b) drug ingredient requirements extend to excipients, mandating compliance for products marketed to the pharmaceutical industry regardless of labeling.

Schoneker shared the legal advice that it is not enough for a supplier to simply warn pharmaceutical customers that its product is not supported as a pharmaceutical excipient due to lack of USP-NF labeling. To avoid liability, he stressed, "you also have to stop selling it to them."

Some 40% of drug makers have difficulty finding at least one USP-NF grade excipient, according to the PQRI survey. Typically, they use the best grade available, test it per the USP-NF monograph, but do not contact FDA about it.

Ferguson cautioned excipient users to be skeptical when suppliers stop labeling their excipients USP-NF but assert that their production process remains unchanged.

ä She indicated that there have been problems with product manufacturers relying on auditors who are not familiar with excipients. For example, auditors have "mistakenly applied drug GMPs to excipients, which is not appropriate."

Similarly, these auditors tend to use "terms for drug GMPs that are not pertinent to excipient control. They may ask for validation where the excipient manufacturer is looking for control and quality of that excipient."

Another important concern is the drug product maker's purchasing organization, which tends to seek the lowest-priced excipients, regardless of science-based quality. However, Ferguson related that she had heard "of a couple of situations where they are hiring more qualified people in purchasing, people that have some technical experience, [who] could communicate with the vendor."

Perhaps the most significant barrier to the supply of pharmaceutical grade excipients is "the bottom line," Ferguson declared. "The reason why a number of excipient vendors will not supply USP-NF grade is that there is just not enough market out there to supply that grade."

ä The problem of manufacturers ceasing to make NF grade excipients was also discussed at the USP Annual Scientific Meeting in Denver in late September ("The Gold Sheet" November 2006).

A participant involved in excipient manufacturing pointed out that a drug manufacturer using the excipient in such a case has no choice but to re-qualify the food grade material.

He noted that his firm's research group does competitive analysis of samples and looks at other manufacturer's products to "see what is going on there - how the quality correlates. And what we are finding is that for excipient grades they tend to be in a fairly normal range of compliance with the monograph."

On the other hand, he reported, "with the food grade it is scary. There are some things that have been sold as food grade and once we tested them they weren't even in compliance with the food grade standards, let alone pharma grade."

He commented further that "one of the big concerns of the industry now is that some formulators have an over-reliance on the C of A and they do not do proper incoming raw material testing, even though they are supposed to. That is a more rampant problem than anyone would like to think."

Reduced Testing Tests Relationships

Excipient buyers that reduce testing generally rely more heavily on vendor testing, which in turn tests their relationship with their vendor, participants pointed out in the PQRI breakout sessions on reduced testing.

"If you are looking at the excipient manufacturer doing skip-testing … or you look at potential PAT testing, you really need as a drug product manufacturer to have a very close relationship with your vendor, because you are liable for how they are doing that test, how they are doing that process," explained David Short, Pfizer Global Manufacturing, who led the sessions.

"You really need to know what your excipient manufacturer is doing. And if they change something, then you need to get that feedback from the excipient manufacturer if you are relying on their vendor testing," he added.

For product manufacturers who take this reduced-testing route, "it is very critical that you have that documentation for justifying in case you have an inspection down the road," Short said. "So again, the relationship with your vendor and your product is very critical when you are doing this type of reduced testing."

ä There was considerable debate over the best way to ensure excipient quality without performing redundant monograph tests due to the lack of harmony among global compendia.

Short suggested that one way would be to just perform the tests required by the European Pharmacopeia, which would qualify as an alternate equivalent methodology as stated in the USP general notices.

"What we find is that even though the USP may be the most stringent method compared to the EP, because the EP tends to have the more stringent compliance requirements, you will see that typically the EP method will be chosen," he explained. "The USP has allowances for alternative methods, where typically when you try to file the EP you did not see that."

Ferguson clarified that EP has always allowed alternate methods. "It is in their general notices just like it is in the USP general notices. The distinction between EP and USP is there is a qualifier - 'if approved by the regulatory authority.' So you can use an alternative method, but unlike with the USP, they have to actually file every alternative method and get it approved by the regulator."

While Short's understanding is that typically, the European regulators only approve alternative methods in cases where the EP method "does not meet your process," Ferguson's experience is that European regulators have approved many of her company's requests.

Meanwhile, Schoneker encouraged the group to question European test filing requirements. Speaking "in terms of guidance from ICH or EP or EMEA, I would challenge, just like we did in the U.S., why does this have to be filed? In a PAT environment, you have to demonstrate that during the audit, but filing it is just really a waste of time in this case. So maybe one of the takeaways from this is not only will you challenge some things here but maybe we ought to be challenging the EMEA."

Ferguson agreed: "It is a GMP issue; it is not a regulatory filing issue."

Filings Can Hamper Rationalizing Testing

An audience participant proposed simply following existing guidance such as the ICH guidance on control of excipients. "It may be that there is some guidance here and there," Schoneker responded. However, "there is not enough guidance. This is one of the most confusing issues that everybody has to struggle with. We should not dance around that."

What users are being told when excipient makers perform pharmacopeial tests or certify quality based on process controls "is if you want to test it, it is going to pass," Schoneker said. "We are showing you what we do to justify our position." Proceeding to then do a full testing regimen "does not make sense" given the process controls and auditing that are in place. "That is the conflict we have to address."

ä Another area of concern that emerged during the breakout discussions was when it is appropriate to implement a harmonized chapter.

"I do not understand where the confusion comes from," Ferguson commented at the wrap-up session. "The official implementation date is the official implementation date. USP says that." She added that companies can and should phase in new or revised methods during the months between their publication and effective dates.

Ferguson acknowledged there is some risk with early implementation (i.e. at publication date). For example, a new heavy metals method was called back after publication. However, she asserted that the benefits generally outweigh the risks.

ä In a discussion on the implications of changes to excipient monographs made through PDG harmonization and the potential for these changes to undermine drug application filings, Carlin suggested that the "takeway" may be "that you should disclose as little as possible about the methodology in your filing."

"I have been fighting that battle since day one when I was hired," one workshop participant exclaimed. "We were in a situation where" the chapter of USP would be filed, including copies of procedures and version numbers, he said, adding that his group "never got to review those documents."

Ferguson agreed: "If you supply too much information, you are stuck." The key, Schoneker suggested, "is identifying the difference between which of these issues are filing issues and which of these issues are GMP issues," which can be handled at audit instead of in a filing.

PQRI Survey Lacks Response From Key Suppliers

PQRI did not get responses to its survey on excipient testing and control strategies from the broad cross-section of excipient manufacturers it had hoped for, Robert Wiens, chair of PQRI's Excipients Working Group, noted in an overview of the group's survey.

Not surprisingly, the many large chemical manufacturers for whom excipients is a tiny market generally did not bother with the survey, even though they are the ones from whom PQRI most wanted to hear.

Wiens, who works for Lilly in compendial affairs/global methods management, noted that of the 212 companies that responded during the June to October 2005 survey period, 180 were drug product manufacturers, 26 were excipient manufacturers and six were excipient distributors.

ä The survey showed that excipient manufacturers fill out an inordinate number of questionnaires, which are generally considered to be of little value to the product manufacturers who send them out. Survey respondents said 53% of audits include a questionnaire.

There were some surprises in the survey results, Wiens noted. Product manufacturers do more lab-scale testing of excipients than expected, for one. For another, they rarely accepted excipient batches on a C of A with identity testing alone. Also, most excipient manufacturers and distributors who responded said they label their excipients as compendial grade - although that finding may not reflect the approach taken by those who did not bother to participate in the survey.

Wiens highlighted the finding that 40% of drug product manufacturers and 25% of distributors had difficulty sourcing at least one USP-NF grade excipient. Commented Ferguson: "We did this particular question to figure out if there was really a problem out there, and obviously there is."

In other key findings, Wiens noted: Most survey respondents are focused globally and do USP testing; 97% of product manufacturers go beyond just the required ID testing when they receive a certificate of analysis, including qualifying of new sources of excipients by vendor audits and complete compendial testing.

Additional findings among the participants surveyed include:

• 75% of drug product manufacturers rely on testing and site audits to ensure at least a few, and as many as all, of the excipients they use are of compendial grade.
• 80% of manufacturers, distributors and users of excipients have been inspected or visited by FDA, state or local authorities.
• 89% of drug product manufacturers stated they have reduced testing programs for at least five of the excipients they use.
• 70% of survey respondents do non-compendial functionality or processability testing.
• 24% of drug product manufacturers still have problems with excipient variability despite such extra-compendial testing.
• Nearly 60% of excipient and product manufacturers reduce testing by using harmonized monographs, demonstrating compendial equivalence or using the most stringent testing method.
• 50% of excipient and product manufacturers use harmonized excipient monographs and general chapters.

In his remarks on the benefits of third-party auditing, Silverstein reviewed the survey results on auditing, which showed 39% is in-house, 29% is third party, and 32% involves only sending out a questionnaire.

Leading Excipient Tests Not In Monographs
The PQRI excipients survey report provides a listing of the most common types of non-monograph-referenced tests and lab methods drug product manufacturers are performing to determine excipient suitability and the percentage of survey respondents performing them.
Percent	Tests
89%	Particle Size and Size Distribution
84%	Microbial Limits
80%	Moisture Content
73%	Viscosity
73%	Bulk Density
66%	Bacterial Endotoxins
64%	Tap Density
55%	Particle Shape/Morphology
40%	Sterility
Percent	Lab Methods
71%	Sieving
51%	Specific Metals Test
49%	Near Infrared Spectroscopy
46%	Microscopy
23%	AA Graphite Furnace
23%	Laser Light Diffraction or Scattering
22%	X-ray Diffraction
17%	ICP

Most product manufacturers indicated they do on-site audits every two to four years. The survey indicated excipient manufacturers host audits frequently - 29% said biweekly.

Most drug product manufacturers, as well as manufacturers and distributors of excipients, do functionality or processability testing that goes beyond excipient monograph requirements, the PQRI survey report showed (see box above).

This finding suggests the pharmacopeia should add new harmonized excipient test chapters to cover the additional areas, the report maintained.

Performance/Functionality Testing Explored

Issues surrounding testing of excipients for performance/functionality and their treatment in the pharmacopeias were discussed at the recent USP scientific meeting in Denver.

The pharmacopeias play an important role in the communication that must occur between excipient makers and users to assure the desired performance properties, commented USP Excipient Monograph 2 Expert Committee Vice Chair Chris Moreton, who is Idenix Pharmaceuticals' pharmaceutical sciences VP.

They help, he said, "by providing guidance as to which properties might be important for a particular material in a particular application and by providing standard methods that can be used by both manufacturers and users to make communication more straightforward and to avoid an unnecessary plethora of test variations for a particular parameter."

ä Both the U.S. and European pharmacopeias are working on upgrading their guidance in the excipient performance/functionality area.

In crafting that guidance, both recognize that it needs to be non-mandatory, as a given excipient can serve different functions and will need to meet different performance standards depending on the drug product and process in which it is being used.

The USP approach is to place its discussion of "performance-related" excipient tests in a general information chapter.

The EP has been targeting a general chapter on "functionality-related characteristics" (FRCs) as well, but is also looking to add "non-mandatory" sections to individual excipient monographs addressing FRCs.

USP's position on the performance-related tests is in line with that of TriPEC, the federation of three regional excipient maker/user industry organizations, IPEC-Americas, IPEC Europe and JPEC (Japan), Moreton noted. "TriPEC says that they don't belong in pharmacopeia monographs. Not even in the non-mandatory labeling section. But they also say the pharmacopeias can provide harmonized methods as general information chapters."

ä In remarks delivered by conference call at the Denver meeting, FDA Office of Pharmaceutical Science staffer Rajendra Uppoor expressed support for USP's focus on "performance" testing - which more clearly encompasses the excipient's role in drug processing as well as in its "functionality" in the dosage form.

Uppoor went on to emphasize that for good reason there is no mention in the FD&C Act or the Title 21 of the Code of Federal Regulations of "performance-related tests" on excipients used in drug products. The reason is to give drug manufacturers flexibility, "because the context of the use of an excipient depends on the drug dosage form as well as the manufacturing processes that are used in making the dosage form."

However, the agency does provide guidance on evaluating the safety of excipients for their intended use, he noted, calling attention to FDA's May 2005 guidance on non-clinical studies of excipient safety and its inactive ingredients guide.

IPEC Explained Concerns In Comments To EP

On behalf of TriPEC, IPEC-Americas in late November comments voiced industry's "strong opposition" to listing specific tests for functionality-related characteristics in excipient monographs, as EP had proposed for about a dozen cases.

The comments, on the other hand, expressed support for a general chapter "that could appropriately provide guidance to industry and regulators about addressing functionality-related characteristics," Schoneker explains.

IPEC believes the focus should be on tests for particular uses of excipients rather than particular excipients, as is the case in the chapter on excipient performance testing that USP is developing.

Under USP's approach, Schoneker said, if an excipient "is going to be used as a filler, they are going to give examples of the kinds of tests that you might want to consider evaluating to determine what properties might be important. That is a much more appropriate way, we think, to handle this."

Industry fears that EP's proposed non-mandatory tests would become de facto standards even when they are not relevant are borne out by past experience, Schoneker stressed. Excipient buyers have responded to mere proposals for standards by saying "'we don't know if these things are important to us or not but we want them, and we want them on the certificates of analysis for every batch, and we are not going to pay any premiums for it,' and that kind of thing."

The result is cost increases, Schoneker emphasized, which "are going to have to be absorbed by the users and ultimately the consumer."

Although the majority of TriPEC members are against EP's approach, there are some, particularly in IPEC-Europe, who support it, Schoneker acknowledged.

ä IPEC also included some suggestions in its comments for the eventuality that EP institutes its monograph-specific approach to FRCs despite the group's opposition.

As it stands now, EP's proposal would merely list tests of FRCs in monographs, without explaining their relevance. IPEC commented, Schoneker explained, that, "if you are going to list them, at a minimum we would like to see the rationale also published in PharmEuropa, as well as the data that supported the rationale. And then … if industry felt that that rationale and that data was not scientifically sound from the standpoint of some expertise that the makers and the users might have that the pharmacopeias do not, that there is a mechanism to bring forward further data to continue that negotiation about whether it belongs in there or not."

USP Aims To Revise Monographs, Add Chapters

The USP Excipients General Chapters Expert Committee has a two-fold agenda for the pharmacopeia's coming revision cycle, the committee's chair, Pfizer Research Fellow Gregory Amidon, explained at USP's Denver meeting.

The agenda includes review of monographs for excipients that are available in more than one grade as well as development of new chapters on specific performance-related tests and a general performance testing chapter (see box below).

USP Excipient Performance-Related Chapters

The following are USP general chapters addressing performance of pharmaceutical excipients. Chapters marked in bold are planned or in development.

<267> Porosity By Mercury Intrusion

<515> Small Particle Characterization

<616> Bulk Density And Tapped Density

<636> Compactibility Test

<699> Density Of Solids

<786> Particle Size Distribution Estimation By Analytical Sieving

<811> Powder Fineness

<911> Viscosity

<912> Non-Newtonian Rheology

<913> Viscoelasticity

<1174> Powder Flow

<?> Porosity By Nitrogen Adsorption

<?> Shear Cell Methodology

<1059> Excipient Performance

Regarding monographs for excipients such as lactose that come in more than one grade, "what we thought we would do is assess the suitability of including additional appropriate tests to distinguish commercial grades that would be worthwhile," Amidon noted.

The idea of developing a general chapter on excipient performance resulted partly from the committee's vision and partly from a survey of participants at USP's previous annual scientific meeting, according to Amidon. A draft of general chapter <1059> on excipient performance, which may be proposed for public comment in the USP Pharmacopeial Forum in the first quarter of 2007, was included in the attendee handouts.

The draft includes a "description" section discussing the general purpose and use of an excipient. There are also sections on how the excipients function, to the extent known, and their physical and chemical properties, as well as a section with references to general chapters that could be useful for characterizing excipient functions and a "catch-all" section for other information.

USP is also developing chapters with relevance to excipients on certificates of analysis (<1080>) and on significant changes (<1195>). Drafts of both have been published in the Pharmacopeial Forum, with final versions expected in the near future.

IPEC Qualification Guide To Enhance Communication

The need for improving communication about excipients in order to reap the benefits of quality by design was a recurrent theme at both the PQRI and USP meetings.

FDA's Uppoor stressed at the Denver meeting that strong interaction among the agency, the drug product manufacturer and the excipient manufacturer is key to obtaining the desired regulatory flexibility. He noted that excipient makers typically have well-controlled manufacturing processes, which is a plus in this regard.

In the same vein, Schoneker commented that "within IPEC we have talked about this whole issue many times and it all comes down to that one word: communication. The manufacturer of the excipient has to understand more about what the user is using it for. The user has to understand more about how the stuff is made."

ä When such communication is lacking, it spells trouble, Schoneker emphasized.

"I know a number of suppliers who find out long after the fact that their customer is using the excipient in a parenteral application and the supplier in no way, shape or form had any intention of ever going there. And I have even known some companies who have gone to their customers and said, 'we won't sell it to you anymore because we don't want any liability. There is no way you should be using this.' Obviously there was a communication breakdown somewhere along the line. That has happened many times. So I think there is communication in all different directions, especially when you are using it in those kinds of applications. That is a key."

ä IPEC is developing a guideline on excipient qualification "that really deals with this whole interaction and how to share this information in a better way," the council's chair-elect noted. "I think it is going to really help us change the paradigm as to how people communicate so we can get around some of these issues."

IPEC-Americas has drafted Phase 1 of the guideline, which focuses on the role of the excipient manufacturer, and has distributed it for comment to IPEC-Europe and JPEC. The council hopes to publish a final version of Phase 1 by mid-2007.

The council has begun drafting Phase 2 of the guideline, which addresses the excipient buyer's role. A Phase 3 is also planned, Schoneker noted. It would address the excipient maker/user negotiation process for reaching a "quality agreement that they can agree to mutually … so that everything is in place to make it successful going forward."

IPEC anticipates that the qualification guidelines will eventually be included in USP.

Excipient Information Package Developed By IPEC

A solution to the vexing proliferation of labor-intensive surveys of excipient manufacturers is one byproduct of IPEC's effort to establish an excipient qualification guideline.

As IPEC began developing the qualification guideline, "it became obvious that there is an exchange of a lot of information right now that takes place with a huge number of supplier surveys that pharmaceutical companies send out," Schoneker noted. The multitude of questionnaires, some as long as 50 pages, and each with its own format, wastes a lot of peoples' time.

To address the problem, IPEC has developed an "excipient information package" that would be developed proactively by the excipient manufacturer and eliminate the need for the individual questionnaires and surveys now being deployed to obtain the needed information about the excipient maker as well as about the excipient itself.

Available online at www.ipecarmericas.org, IPEC explains that the protocol was developed "with the primary goal of enhancing information management between excipient users and makers by providing standards for the exchange of data in order to simplify and improve this process."

The EIP protocol is structured similary to the "material safety data sheet" that standardized the reporting of chemical safety information. The EIP.includes a "product regulatory datatsheet," a "site quality overview" and a "site and supply chain security overview" (see box below).

IPEC-Americas Excipient Information Package

IPEC-Americas has published an "Exipient Information Package" intended to improve vendor/user communications and reduce the need for questionnaires and surveys. IPEC explains what the EIP contains as follows:

The EIP documents are set up much like a Material Safety Data Sheet (MSDS) with designated sections that include specified data. Each section of the documents covers specific related topics. The protocol defines the minimum topics that should be covered in each section. However, additional related information can also be provided at the discretion of the excipient supplier.

The Product Regulatory Datasheet communicates important physical, manufacturing and regulatory information specific to a product or products. The Product Regulatory Datasheet addresses pertinent product specific topics of general regulatory concern such as TSE/BSE. GMO, and allergen statements, among others.

The Site Quality Overview is designed to be used as a tool to assist in evaluating an excipient supplier's manufacturing practices and quality systems, as well as a reference to assist suppliers in informing excipient users of the systems in place to assure appropriate GMP requirements and to deliver consistent product quality. The information provided is basic information on how the supplier complies with each applicable element of the "Joint IPEC-PQG Good Manufacturing Practice Guide for Pharmaceutical Excipients 2006."

The Site and Supply Chain Security Overview provides information concerning the supplier's plans to insure the protection of the product and the continuity of supply. It is intended to provide an overall picture of the supplier's plans while preserving the integrity of those plans.

Harmonized Excipient GMP Guidance Emerging

IPEC has also been working with the UK-based Pharmaceutical Quality Group (PQG) to advance the dialogue on GMPs.

An important development was the publication earlier this year of the consensus-based joint "IPEC-PQG GMP Guide for Pharmaceutical Excipients," which updates earlier guidance from both organizations, and is closely aligned with ISO 9001. The earlier IPEC GMP guideline is the basis for USP general chapter <1078>.

The product of several years of collaboration between IPEC-Americas, IPEC-Europe and the PDG, the new guidance represents an emerging international consensus on excipient GMPs.

FDA's Buhay noted in his remarks at the PQRI workshop that although FDA supports the IPEC excipient GMP guidance, the agency "has not taken the occasion to develop a regulation for the excipient community or even specific guidance on cGMP for manufacturing conformance for excipients."

ä However, new excipient GMP requirements are taking shape in Europe.

The EC is developing legislation to specify certain classes of higher-risk excipients to which its GMP guidelines for APIs would apply.

The commission published the ICH Q7A guideline on API GMPs in November 2000 as Annex 18 to the EU GMP Guide. Directive 2001/83/EC was subsequently issued, and later amended by Directive 2004/27/EC, with an effective date of October 2005. In a later move, the commission converted Annex 18 into Part II of the EU GMP Guide ("The Gold Sheet" January 2006). The related directive provides that higher-risk excipients be covered by Part II.

"There have been ongoing discussions for the past year or year and a half to determine what is going to be on the list of excipients," Colorcon's Schoneker commented at the USP meeting in Denver. "And there is a lot of controversy about this obviously."

With IPEC's heavy involvement, the commission has whittled the list down to "injectable products and excipients that go into those applications," Schoneker explained, as well as "any excipients derived from humans, any excipients derived from animal sources, and then, tacked on the bottom of that is propylene glycol and glycerol because of the past Haiti situation."

In 1996, 88 people died in Haiti after consuming glycerine contaminated with diethylene glycol ("The Gold Sheet" May 2003). Also, paracetamol syrup containing propylene glycol contaminated with diethylene glycol was implicated in 236 deaths in 1990-1992 in India and Bangladesh.

Excipient GMP Candidates In EU

The European Commission is developing legislation to require GMP controls for certain categories of excipients. The following are being considered as candidates:

? Excipients prepared from materials derived from a transmissible spongiform encephalopathy (TSE)-related animals species (excluding lactose).

? Excipients derived from human or animal material with potential viral contamination risk.

? Excipients claimed to be sterile (sold as sterile) and used without further sterilization.

? Excipients which, due to their nature, origin or manufacturing process, are at significant risk of endotoxin/pyrogen contamination, and which are used in products which are required to be endotoxin/pyrogen controlled, such as in parenteral products.

? Propylene glycol

? Glycerol

The commission also intends to develop a new directive with high-level GMP quality system principles for the manufacture of excipients, which will overarch the application of the provisions. But first industry associations such as IPEC are developing a draft for the commission's review.

"What is now being worked on is what GMPs need to apply," Schoneker explained at the USP meeting, noting that the EC views the IPEC/PQG GMP guideline as an important standard.

Schoneker added that, because the IPEC/PQG GMP guideline did not specifically address parenterals, "there are ongoing discussions about writing an addendum" addressing the extra controls needed for excipients that are going into parenteral products.

"There will be, I am sure, a lively discussion," regarding the European requirements, he noted. "IPEC is going to be involved in it. Others will be as well. But [the IPEC/PQG guideline] will also give some additional direction."

ä Schoneker stressed that "the thing to remember is this will change the paradigm quite radically."

It is possible that some excipient manufacturers will balk at Europe's new GMP requirements. "So it could result in some changes in sourcing needed and everything else," he concluded. "I wanted to make you aware of that because there is that going on currently in addition to what is being talked about in the monographs. And it will all play together."

The EC is planning to survey industry regarding the potential impact of its directive on excipient GMPs before issuing it, Schoneker indicated. The commission also intends to post the IPEC/PQG GMP guideline as an example of an appropriate GMP.

Wyeth Studies Polymer Attributes Toward QbD Filing

The importance of excipient analysis and control to advancing quality by design in pharmaceutical manufacturing was also highlighted at a PDA/ISPE conference on implementing ICH's quality guidelines Q8 (pharmaceutical development) and Q9 (risk management) in Washington, D.C. in early December.

Introducing a session at the conference on Q8 case studies from FDA's ongoing CMC pilot program ("The Gold Sheet" August 2006), CDER Office of New Drug Quality Assessment Deputy Director Chi-wan Chen emphasized that understanding the impact of formulation components on product quality and identify and controlling sources of their variability are key aspects of a QbD system.

In turn, Chen cited the functional relationship between input materials and drug product critical quality attributes as one of the areas that the pilot program is showing needs more attention.

ä At the session, Wyeth Research Worldwide Regulatory Affairs (Pharma) Assisant VP Nirdosh Jagota described his firm's work under the CMC pilot program on the "rational design of HPMC and roller compaction for an extended release drug product - a QbD approach" (see box on pp. 16-20).

Wyeth's assessment process on the polymer attributes and roller compaction design space showed that the polymer concentration was the critical factor in controlling the release of the drug product, and that the lab scale experiments provided "good prediction of the manufacturing design space."

Understanding the polymer properties and their effect on the release mechanism "was critical to the development of a robust formulation," Jagota summarized. In turn, the "process understanding and early establishment of design space and its confirmation during technology transfer development resulted in a robust and reliable manufacturing process."

ä Jagota emphasized that one of the challenges drug product manufacturers face in "developing your design space around excipients" is that it can be difficult to source different ranges of material for the development work.

After approaching various vendors, Jagota explained, Wyeth found one who agreed to supply different profiles of the polymer labeled as "non-GMP material for experimental purposes only," with Wyeth's commitment not to use the variations in the marketed drug product.

During the discussion period that followed his presentation, Jagota emphasized the major point that if excipients can not be manufactured to tight standards "all of your QbD models go down the drain." ¨ ¨

Wyeth's Work On Excipient QbD Under FDA's CMC Pilot Program

At the PDA/ISPE conference on implementing ICH Q8 and Q9 held in Washington, D.C. in early December, Wyeth Research Worldwide Regulatory Affairs (Pharma) Assistant VP Nirdosh Jagota described his firm's work under FDA's CMC pilot program on the "rational design of HPMC and roller compaction for an extended release drug product - a QbD approach."

Yesterday we spent a lot of time looking at different aspects of Q8 and Q9. If you look at this track essentially what we are saying is that possible sources of variability are in your input, your process and your environmental factors. And your output is essentially your dose form and where possible your clinically relevant specifications. And this we all want - the ultimate customer is the patient where you have a PK profile.

Again, we spent time on Q9 yesterday. The goal here is to control variability, and basically you can do that by controlling your raw materials, process and environment.

I note that someone presented yesterday that there is only one design space …. But the way we look at it in fact there are more spaces. You can call them something different also. You have the PK space, which is your ultimate biomarker. Then you may have a design space and control space. I am going to come back to that.

What we are showing here is that you look at your inputs, put them in a pilot scale, and if you understand your scale factors you should be able to predict your manufacturing scale design space, and you may have to verify it at the manufacturing scale.

Just to give you perspective: Wyeth is participating in a couple of CMC pilot program situations. We have in fact two compounds with FDA in the CMC pilot program. And in fact ... we have been working with the EU PAT working group also on both of these.

I will give you an example of [one of] the compounds where we have used QbD. It is a relatively high dose compound. It has high solubility and [moderate] permeability. It is an extended release formulation. In the beginning we had a wet granulation formulation, and later on we went into a roller compaction process. Very early in the development we developed a Level A IVIVC. That sort of gave us the biomarker for studying our quality by design.

When we were working on product X, we looked at the critical quality attributes for both [product performance (dissolution) and manufacturability.] We actually went to a risk-based evaluation to describe our critical process parameters, and I am going to come back to that.

We did a systematic quality risk assessment …. We did an FMEA analysis. Then we actually developed the risk prioritization matrix. Out of that we developed a fish bone diagram. And then we did the Pareto charting. And I will come to this 'quality function deployment' towards the end of my presentation.

Again, when we did the Pareto charting, it was evident to us that when you look at the [relative importance of inputs], HPMC and porosity were the two key attributes. Some of this is based on our initial design of experiments - we did not pursue further. Some is based on experience also - that we do not need to go into formal design of experiments and developing a design space because these were non-critical parameters.

Polymer and Roller Compaction Evaluation

In terms of polymer attributes [that may affect dissolution rate], we found out viscosity, ratio of methoxyl to hydroxypropoxy groups, water content were the key attributes which were affecting our product performance. What we found, which all of you know - that the USP specification was inadequate in our case. And that raises some challenges for you in terms of how you manage the development of design space and what you do in your plant quality system, and how you manage your product on a global basis also.

[The problem is] that each vendor [has] their own internal specifications which are tighter than USP. So what happens is that you are only able to source material in a certain range …. If you want to source the material outside the range you have studied it is a challenge for you. So we have been working with our vendors to get material outside these ranges to develop our design space. But I just wanted to relate to the audience that this is one of the challenges you will face when you are developing your design space around excipients. And there are other ways probably to solve this problem also.

As I mentioned earlier we studied several parameters. We looked at different particle size of the API, and when we went through the dissolution - I mentioned earlier that we had a level A IVIVC, so it directly relates to your PK profile of the drug - the dissolution profiles were really independent of the API particle size.

Again, we looked at the polymer concentration. If you look at it there are very slight variations even of the polymer concentration. You can conclude if you look at these curves that a small variation in the polymer concentration yields acceptable dissolution profile. So polymer concentration does affect dissolution. However, if you vary it slightly it is not going to matter.

You study the viscosity of the polymer. And again, in the way we studied the viscosity it didn't have any affect on the dissolution characteristics.

Then we actually studied viscosity and tablet hardness and looked at the release rate. And again we reached the same conclusion that dissolution profiles are independent of both polymer viscosity and tablet hardness. Hardness is also important for the processability. I am going to come back to that.

The next thing, we looked at the polymer particle size effect on the dissolution. We saw that there is a slight increase in dissolution rate with increasing particle size. But these particles sizes are well within the specification we have for the grade of given polymer. So we have been controlling so far the grade of polymer which gives us the size we are looking for.

Again, we concluded that the dissolution performance is controlled by polymer content. As I mentioned, only a small variation in concentration yields acceptable profiles. Dissolution performance is independent of API particle size distribution.

Then we moved on to the second aspect - the roller compaction design space. And we looked at roller force and roller gap as our key criteria here. When we kept the polymer concentration constant and varied the roller force and roller gap, we actually noticed that there was no impact on dissolution in this case also. And essentially, as we stated earlier, polymer concentration is your determining function for the dissolution rate.

We looked at the porosity changes over the design space, and you see that there is a curved surface. But if you look at the scale it is very small scale. So this change is also very insignificant.

Ultimately our goal is to develop this pilot scale for our roller compaction and then be able to predict our manufacturing scale. So we looked at, as I mentioned earlier, roll gap and roll force, and we confirmed this at the manufacturing scale. And we pushed our boundary in fact beyond what we will use in our day-to-day design space. We went to the failure mode here - 4.0 [mm] and then here at 2.8 [mm]. And interestingly when we manufactured batches beyond our design space, they basically met the dissolution criteria but the processability was the challenge. So this was the tablet hardness aspect.

Again, variation in roller compaction force and tablet compression force gave essentially the same dissolution. And our conclusion was dissolution rate is really controlled by polymer concentration.

We actually looked at the non-critical parameters also, which we came out with. And when we studied those we also developed areas around those parameters....

Again, as I mentioned earlier, tablet hardness was a critical parameter from the manufacturability of the product. Interestingly when even if the tablets failed hardness they were still within the PK design space. But again we are concluding that at the roll compaction and compression phase, we should be able to adjust the tablet hardness with those two parameters for your acceptable manufacturability.

To conclude, Level A IVIVC was established. The polymer concentration was the critical factor in controlling release of drug product. And tablet surface to volume ratios and concentration of polymer were the key factors in the polymer. Within the range of factors investigated, polymer attributes had minimal effect on the release rate, but we are controlling those. And good prediction of manufacturing design space based on lab scale experiments - we actually verified that at the manufacturing scale.

From QbD To Quality Systems

We did all this really … in our development phase. And now our next stage is going into the plant systems. One of the challenges you have is when you have developed a product, you need to look at the QbD approach and design space in your quality systems also.

So based on this, we actually came out with three different definitions. These two are in the ICH as you know, design space and control strategy. I think this morning we saw how control space is defined - that it is a subset of your design space where you are functioning on a day-to-day basis. And one of my control strategies is (the size, this defines) all of these aspects, what is our control space, what is your design space and how it all relates. That is your control strategy.

Again, this is only my view. This is still being discussed in Wyeth - how we are going to do our plant quality systems. I just want to give this qualifier. My thinking is when you have all the CPPs within the control space, if you are able to get the reduced testing through your quality by design with your boards of health this is straight forward. You don't have to do anything extra. You release your batch and you go on.

If you are not within the control space of your CPPs, but you are within your design space, you may have to do full or extensive testing, depending on which parameter you are looking at. And then you evaluate how you will do your batch disposition. And if you are not within the design space then it goes back to your normal plant systems where you evaluate it and you go on the course of rejecting your batch or whatever you are doing on a routine basis.

For the non-critical process parameters, again if you are within the control space of course there is no issue there. But if you are not within the control space you will generate an Event Report Form as long as you are within the established parameters for those non-critical parameters. So if you have a range which you have studied through your process validation and other studies, and then you would actually look at that event and basically assess it through your quality assurance systems and decide how you will do batch disposition. Now, all of this is debatable as you can see - how you will do it. I mean you have to work with the boards of health also in terms of reaching consensus on these. These are just my own views.

Again, to conclude: understanding of polymer properties and their effect on release mechanism was critical to the development of a robust formulation. As I showed you that with all those things we were changing we were still able to get acceptable dissolution performance and product robustness. Process understanding and early establishment of design space and its confirmation during technology development transfer resulted in a robust and reliable manufacturing process. And in our mind, QbD is the wave of the future - those who do not run with it will be left behind.

These are the folks who helped us in reaching this goal. Most of the work was done under Dr. Richard Saunders in formulation development. We have a team in Wyeth which co-develops and co-launches a product. We have people from quality, regulatory, development and manufacturing all working together. But ultimately that is where we have to be.