IPQ “The News in Depth,” March 5, 2012
An Upsurge in Recalls of Overweight Tablets and a Recent FDA Warning
Letter Show Industry’s Process Understanding Shortcomings
A marked upswing in recalls of overweight tablets during the past few years and a recent warning letter from
FDA point to a lack of understanding by pharma manufacturers of their processes and the many variables that
can contribute to producing overweight tablets and not detecting them prior to shipping.
The agency gave voice to its concern with this lack of understanding in an early February warning
letter to Eatontown, New Jersey-based West-Ward Pharmaceuticals.
Given the number of recent recalls involving tablet weight problems across the industry, a warning letter
focused on the related issues was overdue from FDA and more agency compliance attention on the issue would
appear likely.
The West-Ward warning letter, which resulted from multiweek inspections conducted in February/March 2010
and June 2011, called into question the firm’s tablet operations and procedures that permitted the manufacture
and release of digoxin and lithium carbonate tablets that failed size and hardness specifications.
According to the letter, West-Ward’s SOP on tablet/capsule operations was inadequate in that it allowed for
“drug product batches to be released with significant in-process quality defects, such as tablets produced
outside of your firm’s established specifications for thickness and hardness [that] could result in the release of
a batch that had up to 25% of the units being out of specification without a follow-up investigation to
determine the root cause of the high rate of process failures.”
The agency also maintained that the firm “did not document the number of aberrant tablets that were rejected
during sorting or any examination of other batches that may have been impacted.” In addition, it did not
“evaluate the state of control of the process, including whether it is capable of consistently producing tablets
meeting specifications.”
FDA asserted that West-Ward’s response to the 483 submitted after the June, 2011 inspection “failed to
address this significant quality problem for digoxin tablets.” Additionally, the letter maintains that the firm’s
response did not address its “failure to implement a global electronic quality management system (QMS) that
you committed to implement as a corrective action in response to deficiencies in your firm’s handling of
investigations noted during our February 8 to March 1, 2010 inspection of your firm.”
The letter emphasizes that digoxin tablets have a narrow therapeutic range and under or overweight tablets can
have a “significant effect on the patient's health.”
Complex Web of Factors Behind Recalls
The problem of overweight tablets became more prominent in early 2008. Over the past three years there have
been at least 42 recalls due to the problem, including an April, 2010 recall by West-Ward of digoxin. Other
companies have reported “near misses.”
At ISPE’s annual Tampa Conference at the end of February, oral solid dosage (OSD)
manufacturing consultant and trainer Fred Rowley – a former manufacturing director at Watson
and Arnet – delved into: ● the recent increase in tablet recalls ● the complexities of tablet
manufacturing that can cause overweight tablets, and ● the “myths” held within the industry
regarding tablet presses and processes.
Rowley noted that the large number of tablet recalls since 2008 include a wide variety of tablet sizes, shapes
and formulations. “You will notice that they go from 0.25 mg all the way up to 1000 mg. So the idea that
overweight situations only happen to small tablets is a misunderstanding – it is not true.”
Analysis of the recall data “is not easy,” Rowley commented.
“First of all, no one wants to discuss the problem openly.” Companies that have recalls “do not want to discuss
it. There is no universal understanding of the issues. Even among different sites of the same organization,
different root causes may have caused the same problem. There are few warning letters to read where FDA
specifically says what went wrong. There is also denial and a lack of understanding of simple and complex
factors.”
Recall Comparison Shows Little Commonality
Rowley provided a comparison of the variety of factors that may have contributed to overweight tablets for a
sampling of the products that have been recalled – including the function of the “reject gate,” tablet size,
powder flow, and “picking” – and concluded that there is little commonality.
The reject gate on a tablet press is designed to reject tablets that do not meet size/weight
specifications. However, Rowley has found that many firms do not check the gates routinely to
ensure that they are functioning properly, as most do with metal detectors designed to check for
metal particulates in tablets.
When firms are asked how often they challenge metal detectors on tablet presses to ensure that they are
working correctly, the answer varies from every two hours to at the beginning of each shift or at the beginning
and end of each batch, Rowley reported. When asked how often the functioning of the reject gate is
challenged, the answers he gets are generally “at press qualification, qualified during validation, or ‘why
challenge?’”
Different organizations, different sites, and different people have varying ideas about what is and what is not
important, and many rely on the press manufacturer to tell them what needs to be checked routinely.
“Some press manufacturers,” Rowley noted, “will tell you that their reject gate will work 100% of the time. I
don’t believe that. It will only work 100% of the time if it is validated, calibrated, maintained and run under
the setup assembly of a qualified operator.”
Regarding the manufacture of overweight tablets, one important variable is the “picking potential,”
or propensity of the powder to stick to the tablet punches – a phenomenon related to solubility.
“If it sticks to the punch, then the lower punch goes around and it gets another plug of powder,” Rowley
explained. “Now I am trying to compress a tablet made out of that plug of powder and some of the material
that stuck to the punch. So if my API has a potential to stick, there might be some link or association with the
recall.”
A review of drugs that have been recalled, however, shows a broad range in solubility – from very soluble to
practically insoluble. “So you may or may not be able to link the recall with solubility or picking.”
A comparison of the variables of powder flow, tablet size, and tablet press manufacturer across the drug recalls
also shows little commonality between the recalled products.
Powder flow can be a contributing factor to an overweight tablet, Rowley explained – less or more powder
may go into the dye because the powder doesn’t flow very well. However, the recalled products examined
varied widely in this property and in the size of the tablets produced.
“If we look at tablet size along with poor flow and picking problem, what you quickly come to see is that there
is no one set of attributes that either eliminates the potential for overweight tablets or maintains the potential
for overweight tablets,” he pointed out. “Right now, it is not there in terms of linking size, shape, powder flow
or stickiness.”
Rowley’s work also shows that there have been many different brands of tablet presses used to
make recalled tablets – eliminating that variable as a common cause. “This is what we can
determine so far. However,” he said, “some companies are unwilling to discuss this.”
The following tablet press types were found to be associated with overweight tablet recalls: ● Manesty
Novapress (TTS-II) ● Manesty Mk IV (TTS-II0) ● Manesty BB2, manual ● Kilian Synthesis (700) ● Fette
2200/3200 ● Kikusui Libra (PCD-2) ● Courtoy R190 ● Cadmach, double rotary, 45 (2) ● Sejung, HRD61SD,
and ● Pam Legacy 6100.
Rowley’s preliminary conclusion is that “there is no magic bullet, no magic solution. If you think that is the
case, you are deceiving yourself. Single and interactive factors may apparently account for the same issue. No
single tablet press manufacturer or model is responsible. The APIs may be free flowing, cohesive, water
soluble or insoluble.”
A Combination of Factors Involved
Rowley’s analysis has shown that overweight and underweight tablets are frequently produced and missed due
to the interaction of several or multiple sequential or simultaneous events. At the ISPE meeting he provided
examples of conditions that can lead to overweight tablets being accepted.
“If I have nominal flow, a good computer and a bad reject gate, it results in an overweight tablet being
accepted. I can have an upset condition, powder flow that is not nominal, a bad computer and a reject gate that
may or may not be functioning, and the odds that I am going to produce an overweight tablet go up.”
He commented that companies “play statistics games” to narrow down their propensity to produce an
overweight tablet. The two “primary factors” in the equation are that first, the tablet press produces an
overweight or underweight tablet, and secondly that it is not detected.
“Organizations tend to blame the computer or an older tablet press for the problem. That may or
may not be based on fact,” Rowley pointed out.
Many countries outside the US make tablets for import into the US with equipment that is not run by a
computer. Not having computer control of the equipment “adds one more layer of insecurity, but now I can’t
blame the reject gate, can I? So the idea of approaching the problem by only looking at the computer and the
reject gate is sending you, in some cases, down the wrong road, and you won’t find the answer.”
The operations expert provided a list of “proven factors” that can lead to the production of an overweight tablet
(see box below).
To mitigate the possibility of an overweight or underweight tablet that is produced leaving the
manufacturing facility, many companies use “sorters” to sort out the out-of-spec tablets that the
reject gate has missed.
Some refer to this practice as “sorting in quality,” Rowley commented, while other call it “an added level of
assurance.” He noted that FDA has been “rather quiet” about the practice, but has discussed it in a few
warning letters, as in the case of West-Ward.
“Even if you use a sorter and believe you are adding a level of security, it depends on the system and the SOPs
surrounding the use of the sorter and ensuring they are just as strong as in other areas,” he said. “You can
isolate an overweight tablet in sorting and then put it back in the batch.”
Another issue is “startup tablets” – those produced during the first hours of production after a cold start-up
when the machine and punches expand due to heating up.
The tablets produced at this time have a higher potential for issues than those produced once the equipment
reaches steady state, and it is especially important during this phase of production to sort out the bad tablets.
However, once sorted out, Rowley stressed, procedures must be in place to ensure those tablets do
not re-enter the production batch.
Mixing startup tablets in with production batches has been cited as the cause for recalls by Schwarz Pharma
and Auribindo. Private conversations he has had with employees at both a branded and generics firm indicate
that management was lax concerning startup rejects.
The manufacturing trainer noted the importance of paying attention to the startup tablets, but advised caution.
He has seen many occasions where a tablet overweight problem investigation has revealed no root cause –
often because those investigating do not know all the potential root causes to examine – and that under those
circumstances there is a tendency to blame the startup tablets even when no evidence exists to support that
conclusion.
Understanding Presses Key to Solving Problems
Tablets are difficult to make, Rowley stressed, because the manufacturing process includes a number of
variables, many of which are not well-understood by most companies.
“If you don’t understand the variables and, for example, your education tells you that capping has three causes,
then your investigation has to say it is one of those three causes.”
There are also terminology issues. “Most people can’t tell capping from lamination anyway,” he maintained.
“Many professors use the same terms interchangeably for defects that occur on a tablet press.” Because there
is a lot of misunderstanding about how tablets are made, trouble-shooting becomes “problematic.”
To begin with, Rowley stressed, “it is important to understand that the defect is produced on the
tablet press – it is not a formulation problem.”
The process of powder compaction is a complex non-linear function, he explained. When a force is applied on
a powder bed, a number of mechanisms become involved in the transformation of the powder into a porous,
coherent compact with a well-defined shape.
Normally, the following seven individual processes are involved in a typical powder compaction:
● the movement of the blend as it enters the dye
● particle rearrangement before the punch moves
● elastic (reversible) deformation of particles as the punches move
● plastic (irreversible) deformation of particles when the punches meet
● fragmentation of particles as pressure increases
● formation of interparticulate bonds as the tablet is made, and
● elastic recovery of compacts as the tablet ejects.
Understanding these steps and how each may contribute to overweight or underweight tablets is “critical.”
Regarding root cause investigations, Rowley cautioned that “people think ‘if I fix this situation, now it is
fixed.’ That is different than ‘I have to have eternal vigilance based on good science. Now I have more
chance of success.’
Myths Impact Tablet Press Operation
Rowley summarized key points and “myths” impacting tablet press operations, focusing initially on the press
as delivered to the manufacturer and what the manufacturer expects the press to do.
“A press doesn’t know what it is going to make,” he commented. “In pharmaceuticals, we have a tendency to
[say] ‘here is our new tablet press. It is stainless steel…. Now we are going to validate it and clean it nicely
and it will last 10,000 years.’”
When a press leaves the building that it was made in, he stressed, “it has no idea what it going to compress. It
will do what you tell it to do. But it has no idea what you want.”
“How should a press operate?” he queried. “If you went up to a press, would you know that it is operating
correctly? How would you know? What questions would you ask? You have no business on the production
floor unless you can answer those questions.”
He explained that it is unreasonable to assume that a tablet press can use the same parameters for
every tablet. Different sizes, weights, shapes and formulations require different press setups.
For both automated and manual operation, the press must be set up differently for each specific product, he
emphasized. A tablet press is the easiest “‘simple’ machine to misunderstand in all of tablet production,” and
proper operation requires a good understanding of formulas, powder, physics, steel and pressure, among other
things.
On a tablet press, “good powder flow is everything,” Rowley maintained. “If I cannot establish good powder
flow, it is like standing in the middle of a boxing ring and asking the heavyweight champion of the world to hit
me. You have to understand powder.”
A tablet press operator has “three great enemies” – air, moisture and “fines.”
Air bubbles in the powder feed lead to uneven flow and can result in uneven filling of the dies, as can “fines” –
particles of powder that are smaller than the norm. Moisture can lead to sticking and can also result in the
incorrect amount of powder in the die.
“Long after the product has been filed, long after R&D has thrown it over the fence and gone on to something
else – that is what they are paid to do – someone has to direct operators to set up the machine. Some products
are not easy to compress. Hydroxyzine is horrible to compress.”
The “popular but incorrect concept” of compressing force – that more is always better – is a myth,
Rowley stressed.
Compressing force is a term “frequently misunderstood and misused by both rookies and seasoned
professionals alike.” Compressing force is a function of the nature of the powder being compressed and varies
with the efficiency of the die fill – which is why as the press goes faster and faster there may be more
variability. It is not a machine set point and will change as conditions change.
“Pressure makes a tablet, but pressure is not what keeps it together,” Rowley maintained. However, the tablet
must be strong enough for the ejection process.
Another popular myth is that “the computer takes care of everything.”
Computers are an aid, Rowley explained. “They helped us get to the moon. We have very precise orbits
around very distant objects. They are helpful. But a computer cannot run a press. Only a thoroughly trained
operator can run a press.”
The operator should be able to run the press even in the absence of a computer. “I fly all over the world,” the
OSD expert said. “One thing I am always afraid of is that I will be up at 31,000 feet and the pilot will come
out and say, ‘ladies and gentlemen, the computer is broken and I don’t know how to fly the plane without the
computer.’”
West-Ward Also Warned on Analytical Testing
FDA’s warning letter to West-Ward provides additional insights into the types of analytical problems that can
contribute to the release of tablets that do not meet specs.
At West-Ward, in-process tablet testing for weight, hardness and thickness along with qualification
of the equipment used to conduct the testing were called into question during the agency inspection.
The review of the equipment qualifications for multiple automated Tablet Testing System (TTS) machines
“revealed that performance qualification was not conducted to ensure the accuracy of the machine at the
various available speed settings.”
An internal February 2010 investigation of OOS tablet weights for digoxin tablets indicated that the TTS
machines were giving incorrect tablet weights for lighter weight (< 200 mg) tablets when run at the default
speed. The investigation concluded it would give accurate results only when run at a different speed.
However, the warning letter maintains that the firm “failed to make a further assessment of the overall
reliability of the TTS machines, including evaluating their accuracy with other products and other tablet
weights at other speeds.”
Additionally, qualification of West-Ward’s tablet weight control system was an area of concern.
The letter asserts that the firm has not adequately qualified the in-line Pressure Control Device (PCD)-2
Automatic Tablet Weight Control System on its tablet press machines using qualification parameters that are
representative of all of the products run on the machines. At issue is assurance of the proper functioning of the
PCD, including evaluating the reject station timing in relation to tablet press rpm.
“There is no assurance that the PCD-2 system is accurately rejecting the ‘marked’ OOS tablets throughout the
compression run,” the agency says.
The firm committed in its response to the 483 to qualify the TTS and PCD systems. However, it “failed to
address interim measures to assure proper weight control of [its] tablet presses during batch manufacturing
while…qualifying the TTS and PCD systems.”
Also of concern in the analytical area was the testing performed by West-Ward of stability lots.
A review of lab investigations showed that out-of-specification (OOS) results for dissolution for three lots of
lithium carbonate tablets generated during the six-month stability testing were negated by using a different
method to conduct the test, although an “informal equivalency study” showed that the methods were not
equivalent.
The firm chose to report the passing results obtained from a USP method rather than its in-house method
“based on the belief that this method was reliable, while the established…degassing method was not.”
The letter expresses concern that the in-house method is used in testing all other products at the firm. It also
notes that while the original OOS results were invalidated on the assumption that the in-house degassing
method was incorrect, West-Ward’s investigation “did not assess the impact on other batches tested by a
method now designated by your firm to be invalid.”
The firm committed in its 483 response to cease manufacturing lithium carbonate tablets until a root cause is
identified and equivalency studies for the methods are performed. However, the agency deemed the response
inadequate because it failed to address what actions the firm would take if the studies show that the methods
are not equivalent. In addition, West-Ward did not commit to perform an impact assessment “of lots that were
released to the market with an unsuitable method.”
FDA also instructed West-Ward to contact CDER's Drug Shortages Program immediately if any
changes or corrective actions made as a result of the warning letter result in decreased production
of any finished products or APIs.
FDA’s instructions to West-Ward in this regard reflect the heightened emphasis the agency has been placing
on potential drug shortage reporting (IPQ “The News in Depth” February 12 and February 24).
LINK:
West-Ward warning letter
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This full story made available by special arrangement between IPQ and ISPE