QUALITY METRICS
INTRODUCTION
• Between 2010 and 2013 June, according to the
analysis of USFDA recalls done by the Indian
Pharma Alliance(IPA) there have been 178 drug
recalls; only four Indian firms were involved.
Similarly in the past 42 months,USFDA issued 67
warning letters for manufacturing and product
quality to reputed MNCs like Novartis, Merck and
Sanofi Aventis.
• Ref: Malini Goyal, ET 4 August 2013.
ORGANISATIONAL METRICS
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Safety –EHS
Employee satisfaction and engagement
Employee talent retention/turnover
Employee suggestions and % age implemented.
Training and training effectiveness
RISK MANAGEMENT
• Risk mapping of the manufacturing process
• Effectiveness of the Risk Management plan and
number of self identified risks.
FORECAST METRICS
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Measures company’s performance against plan.
Adherence to meeting the plan.
Preventive/predictive maintenance back logs.
Creation or reduction of back logs related to
compliance events.
AVAILABILITY OF MULTIPLE APPROVED
MANUFACTURING SITES
• Products with dual or back up manufacturing
sites.
• Suppliers of packaging materials, Raw Materials.
SUPPLIER METRICS
• Supplier assurance for up to 10 years(no change
to items).
• Redundant facilities for Supply.
• Quality Systems/Assurances from the supplier.
• Contingency plan for Act of God situations.
• Safety stock of critical RM(at least 2 years).
• Assembled goods of minimum 3 months.
PROCESS CAPABILITY(CpK)
• CpK values are indicative of the effectiveness of
the control strategy for manufacturing process.
• In depth understanding of the causes of variability
for both process and products.
• This is a key metric to ensure predictable
performance and reliable supply of
pharmaceuticals thereby avoiding drug shortages
TRENDS FOR IN PROCESS AND FINAL
PRODUCT TEST RESULTS.
Trending metrics may indicate a process that is
slowly biasing to the high or low end of the validated
normal manufacturing variability and ranges.
YIELD ANALYSIS
Analysis Trends or abnormalities of product yield
per batch over time can be a leading indicator of
other process or raw materials problems that could
have potential to impact product quality.
BATCH RIGHT FIRST TIME
• This metric could be success rate calculated
as(number of batches released)/(number of lots
initiated.)
• Meeting specifications with no major
investigations ,indicative of robustness of process
and product consistently made in a state of
process control.
PRODUCT DISPOSITION CYCLE TIMES
• This metric serves as an indicator of the level of
control of manufacturing process.
Longer
than planned cycle times is indicative there are
numerous errors during manufacturing/product
failure/supply chain failure.
• Identify, document, investigate, remediate and
close before the product is released.
ERROR RATES AND TREND ANALYSIS
• This metric is used when evaluating non
conformances, discrepancies, deviations, near
miss or investigations. Elements associated with
this metrics are,
• Time to initiate.
• Adherence to closure time.
• Lack of repeat occurrence(effectiveness)
• %age of no root cause found.
ERROR RATES AND TREND ANALYSIS
A high error rate or increasing trend signal could be
an indication of inadequate process control,
insufficient training of operators, oversight by
supervisors, poorly maintained equipment and
facilities ,lack of process characterization/product.
CAPA
This metric is indicative of lack of repeat
deviations(effectiveness),number of extension of
time lines, adherence to planned closure which
could be inadequacy of resources and prioritization
to fix and prevent issues.
INSPECTION OUTCOMES
This metric accounts for critical and major
observations and the number of repeat/and or
similar observations and the timeliness in meeting
corrective actions ,including CAPA effectiveness,
that are intended to eliminate the repeat citation.
COMPLAINT RATES
Trends in complaint rates may indicate deficiency of
the robustness of the manufacturing process.
RECALLS
This data is already transparent to FDA.
QUALITY METRICS
• What kind of manufacturing quality metrics might
be valuable for manufacturers when choosing a C
M O?
• Metrics used in choosing a C M O would be
similar to the metrics that companies use
internally to monitor their own operations and
include metrics specific to the quality agreement
with the C M O
QUALITY METRICS
• Ability to meet the contract giver’s Quality System
requirements.
• Status of Supplier’s Qualification, evaluation of
raw materials, supply chain management and
control system, availability of alternate suppliers
and contingency plans in the event of
catastrophic events.
QUALITY METRICS
• Employee turn over rates, combination of skills
,knowledge and experience of the
employees(education, qualification and
continuous training).
• Availability of the state of art/new technologies
for the more robust manufacturing processes and
faster product disposition times cycle times.
QUALITY METRICS
• Facility maintenance and the on time
performance of preventive maintenance and
equipment calibration.
• Use of the knowledge management and Quality
Risk management concept.
QUALITY METRICS
• Process capability (CpK) for manufacturing
process.
• Environmental monitoring trends and media fills
data for sterile product manufacturing.
• Factory related inspectional history and
inspectional findings.
QUALITY METRICS
• Quality System metrics such as OOS data,
discrepancies, number of deviations, batch
rejection rates, issues/recall rates, complaints.
• In particular, repeat incidents, other CAPA items,
with all data logged not just those that relate
directly to the specific sponsor product but
metrics showing all the incidents.
TRAINING - 483
• “Your firm failed to ensure that each person
engaged in the manufacture, processing, packing
or holding of a drug product has the Education,
Experience and Training or any combination there
of to enable that person perform his/her assigned
functions.”
RISK MANAGEMENT-483
“The above examples raise serious concerns
regarding the integrity, reliability and accuracy of the
data generated and available at your facility. In your
response to this letter, provide an independent and
comprehensive evaluation of the extent of deletion
and destruction of records, a RISK ASSESEMENT
regarding the potential impact on the product quality
and a comprehensive CORRECTIVE and
PREVENTIVE ACTION plan.”
RISK MANAGEMENT-483
“Address the ROOT CAUSE of your QUALITY
UNIT’s failure to control and detect the manipulation
or alteration of laboratory documents and describe
actions to prevent recurrence.”
RISK MANAGEMENT - 483
“Your firm combined batches of APIs that failed to
meet impurity specifications with other API batches
that passed specifications,inorder to meet final
impurity specifications. Your response states that
the practice of blending batches occurred in an
attempt to resolve an impurity issue that began after
process modifications were implemented.”---(contd)
RISK MANAGEMENT- 483
“This indicates that your current quality RISK
management approach, for identifying and
controlling risks to the quality of drugs you
manufacture was not properly functioning.”
COMPLAINT HANDLING -483
• “Your most recent 2011 APR for Excedrin Extra
strength Caplets, fails to document the consistent
trend of complaints received by your firm for,
product chipped, crumbled, cracked and
partial/incomplete tablets, caplets.
• This report documents the complaints you have
received
COMPLAINT HANDLING-483
• “Approximately 550 complaints for these types of
problems from March 2010 to Feb.2011.
• Approximately 430 complaints for these types of
complaints from February 2010 to April 2009.
• Approximately 212 complaints for these types of
complaints from start of manufacture to March
2009.”
COMPLAINT HANDLING-483
• “The conclusion in the summary is inadequate in
that there is no statement identifying product
weakness.
• There is no justification for the statement “based
on the data no changes in the manufacturing are
required.”
CAPA
• Quick action by Pfizer prevents LIPITOR
shortages.
• Culprit molecule that caused mal odor in tablet
bottles is 2,4,6 Tri Bromo Phenyl Methyl Ether.
FDA’s ACTION ON SHORTAGES
Hospira had marketed carpujet cartridge( prefilled
syringe) containing more than twice the
recommended dose of Morphine and
Hydromorphone.Instead of a recalling the
product,the following action was taken to prevent
shortages.—continued on next slide.
FDA’s ACTION ON SHORTAGES
• FDA said because pharmacist and other health care
providers can visually identify the presence of an over
filled carpujet prefilled cartridge,FDA is recommending
these steps be taken at this time rather than a product
recall of the affected product listed above, would result
in an immediate shortage.
• FDA and HOSPIRA warned the pharmacist and the
medical staff to visually inspect the prefilled syringes
before use.
CONCLUSION
• FDA is responsible to weed/eliminate
formulations that pose a risk to patients.
• Manufacturer is responsible for manufacturing
safe,efficaious and risk free formulations for the
patient.
• So who is then RESPONSIBLE for the shortages.
?????