�LOT RELEASE
What is Lot Release?
1
�LOT RELEASE
What is Lot Release?
The process of reviewing each individual batch of a licensed product by the National Regulatory Authority (NRA) before giving approval for its release to the market.
Lot Release is applied to biological products including vaccines.
2
LOT RELEASE
Why do we need lot release for vaccines?
3
LOT RELEASE
4
SUMMARY LOT PROTOCOL
5
SUMMARY LOT PROTOCOL
‘Principle
An independent review of critical data from SLP of each lot of vaccine is essential in order to :
6
SUMMARY LOT PROTOCOL
7
SUMMARY LOT PROTOCOL
8
SUMMARY LOT PROTOCOL
9
SUMMARY LOT PROTOCOL
10
SUMMARY LOT PROTOCOL
Manufacturing Details
Strains
Name of the Strain /Seed used in production, Passage number and type of cell substrate,
Master or working lot/ bank number
All the information's should be same as the one approved by the NRA on the marketing authorization.
11
SUMMARY LOT PROTOCOL
Manufacturing Details
12
SUMMARY LOT PROTOCOL
Formulation
Final Product
13
SUMMARY LOT PROTOCOL
14
WHO Global Benchmarking Tool (GBT)�for LOT RELEASE
WHO and a team of regulators prepared a list of 6 critical indicators and 17 sub-indicators for Evaluation of National Regulatory System of Lot release of Vaccine.
15
Indicator: LR01 Legal provisions, regulations and guidelines required to define regulatory framework of independent lot release by the NRA.
16
No. | LR01.01 |
Sub indicator | Legal provisions and regulations exist to conduct and enforce lot release for all vaccines. |
Maturity level | 1 |
Description Remarks | The assessor should verify the existence of legal provisions, regulations that give the National Regulatory (NRA) authority to implement and enforce lot release for vaccines. The legal provisions should define the responsible officer authorized to sign the regulatory lot release certificate. The Central Drugs Laboratory (CDL) has been designated as the National control laboratory to take responsibility for Quality control testing of vaccine as per the provision of Chapter –II, section 6 of Drug & Cosmetic act, 1940 The function of the Central Drugs laboratory is prescribed in Rule-3-A of part-II of Drugs & Cosmetic Rules, 1945 and the laboratory has the mandate for testing Vaccines & sera .Toxoid and Antitoxins. The central government has appointed Director and government analysists to sign the lot release certificate and legal samples reports |
Indicator: LR01 Legal provisions, regulations and guidelines required to define regulatory framework of independent lot release by the NRA.
17
No. | LR01.01 |
Sub indicator | Legal provisions and regulations exist to conduct and enforce lot release for all vaccines. |
Maturity level | 1 |
Description Remarks | The assessor should verify that the legal basis to perform lot release applies for all vaccines marketed in the country which imported and domestically- produced vaccines. The lab has been given the mandate for lot release by letter no. X-11026/4/95-D, X-11026/9/2001D and as per the instructions of DCG (I) and ministry vide letter No: X-11026/11/2017-BD that each lot of indigenous produced vaccine and imported is to released by CDL, kasauli before its marketed. (UNICEF, PAHO, Export, EP{, Domestic trade and state government supplies ) Current approaches for conducting lot release of vaccines include :
|
Indicator: LR01 Legal provisions, regulations and guidelines required to define regulatory framework of independent lot release by the NRA.
18
No. | LR01.01 |
Description | CDL has the policy to release vaccine on the basis of Review of the summary protocol with independent testing (either full or partial testing). The assessor should verify that the criteria have been defined when the NRA may elect to follow non-routine procedures for lot release for example, a shortage of a product on the market or the need to import non- authorized product for a defined time. No Exemption from Lot Release. |
Indicator: LR01 Legal provisions, regulations and guidelines required to define regulatory framework of independent lot release by the NRA.
19
No. | LR01.01 |
Sub indicator | Legal provisions and regulations exist to conduct and enforce lot release for all vaccines. |
Maturity level | 1 |
| GAP: As per the orders of Ministry of Health & Family Welfare, Nirman Bhawan, New Delhi dated 2012 That Central Drugs Laboratory (CDL) Kasauli is delinked from Central Research Institute Kasauli and is under the full and direct control of Drug Controller General of (India) in Central Drugs Standard Control organization(CDSCO)/ Amendment in Drug and Cosmetic act required to change Director Central Drugs Laboratory instead of Director Central Research Institute Kasauli. |
Indicator: LR01 Legal provisions, regulations and guidelines required to define regulatory framework of independent lot release by the NRA.
20
No. | LR01.02 |
Sub indicator | Acceptance policy and criteria for lot release performed by another NRA are documented. |
Maturity level | 2 |
Description | If the country does not have the capacity to perform lot release on its own, the assessor should determine whether the country recognizes certificates from other competent NRAs and NCLs. These processes include creation of mutual agreements |
Indicator: LR01 Legal provisions, regulations and guidelines required to define regulatory framework of independent lot release by the NRA.
21
No. | LR01.02 |
Sub indicator | Acceptance policy and criteria for lot release performed by another NRA are documented. |
Maturity level | 2 |
Remarks | CDL requires the Lot release certificate from country of origin However its not the sole criteria for lot release of the imported vaccine. No communication is received till date from NRA that MOU has been signed between NRA and International Regulatory Agencies to Acceptance of lot release certificates from the responsible NRA or National Control Laboratory (NCL). GAP : MOU has to be signed between NRA and International Regulatory Agencies to Acceptance of lot release certificates from the responsible NRA or National Control Laboratory (NCL). avoid Redundant testing. |
Indicator: LR02 Arrangement for effective organization and good governance.
22
No. | LR 02: 01 |
Sub indicator | There is a defined organizational structure with clear responsibilities to conduct independent lot release activities. |
Maturity level | 2 |
Description | The assessor should verify that roles and responsibilities for all regulatory entities involved in the independent lot release are documented and implemented. It is critical that the roles and responsibilities of both the NRA and the NCL are clearly defined, particularly when they are separate entities. Legal Mandate :The Central Drugs Laboratory (CDL) has been designated as the National control laboratory to take responsibility for Quality control testing of vaccine as per the provision of Chapter –II, section 6 of Drug & Cosmetic act, 1940 The function of the Central Drugs laboratory is prescribed in Rule-3-A of part-II of Drugs & Cosmetic Rules, 1945 and the laboratory has the mandate for testing Sera, Vaccines, Toxoid and Antitoxins. Director and Government analysist are authorised to sign the Lot release certificate. |
Indicator: LR02 Arrangement for effective organization and good governance.
23
No. | LR 02: 01 |
Sub indicator | There is a defined organizational structure with clear responsibilities to conduct independent lot release activities. |
Remarks | Source of Samples :
After receiving the samples a unique sample receipt number is assigned to each sample . The testing is completed within the time period assigned by the authorities and the batch release certificate is released and a copy of the same is marked to NRA for information. Job Responsibilities of each personnel are defined in the Quality Manual |
Indicator: LR02 Arrangement for effective organization and good governance.
24
No. | LR 02: 02 |
Sub indicator | Documented procedures are implemented to ensure coordination and communication among all regulatory entities involved in independent lot release. |
Maturity level | 3 |
Remarks | Communication between NCL and NRA is very good. Any communication to the Manufactures is marked to DCG(I) Office for information. NRA sends CMC modules and Post approval changes to review to NCL Kasauli. After taking opinion from NCL kasauli NOC is released from NRA and a copy is send to NCL Kasauli. |
Indicator: LR03 Human resources to perform NRA lot release.
25
No. | LR 03: 01 |
Sub indicator | Sufficient competent staff (i.e., education, training, skills and experience) are assigned to perform NRA lot release activities. |
Maturity level | 3 |
Description Remarks | The assessor should verify that the human resources assigned to perform NRA lot release activities should be sufficient with respect to numbers and competent with respect to the requisite skills, education, experience and training. The Laboratory has academically qualified staff. Testing personnel have experience in biochemical and microbiological testing techniques. Staff is also trained in Quality Management Systems for laboratories such as IS/ISO17025 :2017. For efficient performance of lot release function additional qualified and experienced staff on contractual basis is appointed other then regular staff. |
Indicator: LR03 Human resources to perform NRA lot release.
26
No. | LR 03: 02 |
Sub indicator | Duties, functions, and responsibilities of the staff in charge of NRA lot release activities are established and updated in the respective job descriptions. |
Maturity level | 3 |
Description Remarks | The guidance document should present the appropriate duties and responsibilities that are assigned to each member of the organization involved in NRA lot release activities. Thus, the professional profiles of staff are reflected in their respective roles and responsibilities within the NRA. The organization chart of the Laboratory is well document Job descriptions of each staff is part of QM. |
Indicator: LR03 Human resources to perform NRA lot release.
27
No. | LR 03: 03 |
Sub indicator | Training plan developed, implemented and updated at least once a year for staff in charge of NRA lot release activities. Training plan developed, implemented and updated at least once a year for staff in charge of NRA lot release activities. |
Maturity level | 3 |
Description Remarks | The assessor should verify that training plans are developed, implemented and updated at least once every year to reflect the current situation by considering education and experience of the staff. Staff Training Plan is in place the IDP is monitored every year
|
Indicator: LR03 Human resources to perform NRA lot release.
28
No. | LR 03: 04 |
Sub indicator | The NRA generates and maintains records of staff training activities and training effectiveness verification. |
Maturity level | 3 |
Description Remarks | The assessor should verify that records of staff training that is performed or organized by the NRA are generated, maintained, regularly updated. CDL maintain the training records along with the Sample evaluation questionnaire. |
Indicator: LR04 Procedures established and implemented to perform NRA lot release.
29
No. | LR 04: 01 |
Sub indicator | Independent lot release is based, at a minimum, on summary lot protocol review and the appropriate documentation exists. |
Maturity level | 2 |
Description Remarks | The assessor should verify that summary lot protocols are mandatorily required for the lot release of vaccines. The assessor should make sure the NRA or NCL issue lot release certificates based, at minimum, on the review of the summary lot protocols issued by the manufacturer. The protocol review should be performed by comparing the critical data of each lot (including testing data) to the licensed product specifications. Lot release certificate is issued by CDL on the minimum review of summary Lot protocol issued by manufacturer. The protocol review is performed by comparing critical data of test results of each lot. |
Indicator: LR04 Procedures established and implemented to perform NRA lot release.
30
No. | LR 04: 02 |
Sub indicator | NRA or NCL staff involved in lot release have access to MA relevant files and updates. |
Maturity level | 3 |
Description | The assessor should verify that the NRA or NCL staff involved in lot release has access to files and updates relevant to MA.NRA or NCL lot release should be performed only for medical products that have a valid MA in which specifications have been approved by the competent NRA or NCL of the country using the vaccine. In addition, the development and adoption of more effective test methods should be encouraged; however, any changes in testing should be approved by the NRA or NCL. If a different test method is used by the NRA or NCL, and if there is a discrepancy in test data between the manufacturer and the NRA or NCL, then the approved test method defined in the MA should be used to resolve the issue. |
Indicator: LR04 Procedures established and implemented to perform NRA lot release.
31
No. | LR 04: 02 |
Sub indicator | NRA or NCL staff involved in lot release have access to MA relevant files and updates. |
Maturity level | 3 |
Remarks | CDL reviews CMC Module-III Of CTD submitted to NRA. However any Post Approval Change if any is again reviewed by CDL and Opinion submitted to The National Regulatory Authority and recorded If a different test method is used by CDL and if there is a discrepancy in test data between the manufacturer and CDL the NRA or NCL, then the approved test method defined in the MA is used to resolve the issue. |
Indicator: LR04 Procedures established and implemented to perform NRA lot release.
32
No. | LR 04: 03 |
Sub indicator | Analysis of lot-to-lot consistency is conducted.. |
Maturity level | 3 |
Description Remarks | The assessor should verify that statistical analyses are conducted once sufficient data have been accumulated. CDL makes the trends on yearly basis by comparing the results of CDL with the manufacturer results When CDL does not receive consecutive lots, or when it receives only a small number of production lots, interpretation of trends may require additional information (e.g., yearly biological product reports). |
Indicator:LR05 Mechanism for information-sharing exists to promote transparency and accountability
33
No. | LR 05: 01 |
Sub indicator | Results of lot release process are publicly available. |
Maturity level | 4 |
Description Remarks | The assessor should verify the existence of a list of product batches that pass or fail NRA Lot release. In addition, the assessor should verify that the NRA or NCL has the required authority and an available process to publish the list of product batches that passed or failed NRA lot release. At a minimum, a publicly available website The assessor should determine the frequency at which this information is updated CDL has its own website https://cdlkasauli.gov.in. All the batch release information is available on the website and the frequency for uploading the information is fortnight. |
Indicator:LR05 Mechanism for information-sharing exists to promote transparency and accountability
34
No. | LR 05: 02 |
Sub indicator | Follow-up and communication with involved parties, including the manufacturer, on issues of data quality. |
Maturity level | 3 |
Description Remarks | The assessor should verify the establishment and implementation of communication procedures with involved parties, including the manufacturer, on issues of data quality. Good communication with the manufacturer of the product is an important element in developing an effective system. The procedure are available to communicate QC and national lot release issues which include letter, email and physical discussion CDL has a got the SOP for Transfer of methodology from manufacturer’s. Depending upon the nature and severity of the discrepancies or errors, the manufacturer may be asked to perform an investigation to determine the root cause of the issues, and to initiate any corrective and preventive actions required to avoid similar problems A feedback mechanism is also available at CDL |
Indicator:LR06 Mechanism in place to monitor regulatory performance and output.
35
No. | LR 06: 01 |
Sub indicator | Lot release records, reports and certificates available. |
Maturity level | 3 |
Description Remarks | The assessor should verify that there is requirement to issue a certificate of release for all vaccines that have undergone lot release. This release certificate is issued by the responsible NRA or NCL on the basis of, at a minimum, a review of the lot summary protocol for the relevant lot. The assessor should verify that lot-to-lot consistency is appropriately analysed and documented by the NRA or NCL on regular basis. CDL has got the checklist for all the products to review the summary lot protocol. CDL has the policy to release vaccine on the basis of minimum Review of the summary protocol with independent testing (either full or partial testing). There is no exemption from Lot Release. Records of trends analysis are available to verify that lot-to-lot consistency. |
Indicator:LR06 Mechanism in place to monitor regulatory performance and output.
36
No. | LR 06: 02 |
Sub indicator | Corrective actions taken in case of deviations due to laboratory error |
Maturity level | 3 |
Description Remarks | The assessor should review that appropriate corrective actions are taken by the NCL in case of deviations (i.e. significant discrepancy between NCL testing results and manufacturer results due to laboratory or operator error and not due to product quality). SOP for CAPA is available in CDL Kasauli. |
Indicator:LR06 Mechanism in place to monitor regulatory performance and output.
37
No. | LR 06: 03 |
Sub indicator | Regulatory action taken in case of product non-compliance. |
Maturity level | 3 |
Description Remarks | The assessor should verify that in case of non-compliances, the NRA or NCL should confirm, through appropriate laboratory investigation, that the non-compliant results reflect the quality of the lot tested and is not due either to an analytical error by the NCL Decision making in case of out of Specifications If the test batch submitted to CDL is found OOS the test is repeated as per the retest policy. If the test results are not confirming the specifications ask the manufacturer to discuss the results. If the manufacturer is satisfied with the results declare the sample as NSQ and ask the manufacturer to find the root cause. If the manufacturer is not satisfied with the results and want to retest the batch perform |
Indicator:LR06 Mechanism in place to monitor regulatory performance and output.
38
No. | LR 06: 03 |
Sub indicator | Regulatory action taken in case of product non-compliance. |
Maturity level | 3 |
Remarks | the test in duplicate in the presence of the representative of manufacturer . If both the samples meet the specifications Declare the batch as standard quality. If only one sample meets the specifications declare the sample as NSQ and ask the manufacturer to investigate the root cause and communicate to CDL Kasauli, Its communicated to NRA for further necessary action. |
Indicator:LR06 Mechanism in place to monitor regulatory performance and output.
39
No. | LR 06: 04 |
Sub indicator | Performance indicators for national lot release activities are established and implemented. |
Maturity level | 4 |
Description Remarks | The assessor should verify the existence and implementation of performance indicators for different activities included under the national lot release functions. Specifically, the system should define key performance indicators (KPIs) along the entire national lot release activity chain CDL Kasauli is sending the samples details on 5th of every month to CDSCO headquarters in the KPI percribed format. CDL follows SOP “Time frame for assessment of samples for Quality”. For protocol scrutiny the product is released within 21 days for vaccines having single antigen and 28 days for vaccines having multiple antigens All the products for partial testing are released in 30 days The products which are subjected to complete testing for in vitro testing are released in 30 days and for in-vivo testing in 90 days subject to after receiving all the necessary documents. |
40
THANKS