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

• 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

• 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.

• “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.”

TRAINING - 483

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. ?????