Minutes of 259th meeting of central licensing board held on 29th & 30

Case No.42. WITHDRAWAL OF SACHET (PSYCHOTROPIC) SECTION OF M/S WILSHIRE LABORATORIES (PVT) LTD, LAHORE

M/s Wilshire Laboratories (Pvt) Ltd, 124/1, Quaid-e-Azam Industrial Estate, Kot Lakhpat, Lahore, has applied for withdrawal of Sachet (Psychotropic) Section and they have informed that they do not hold registration of any Psychotropic product.

Proceedings and Decision of Central Licensing Board in 259^thmeeting

The Board considering the facts on the record and after thread bare deliberation decided to accept the request of M/s Wilshire Laboratories (Pvt) Ltd, 124/1, Quaid-e-Azam Industrial Estate, Kot Lakhpat, Lahore

Case No. 43 ADDITION OF THE WORDS (POWDER / PELLETS) WITH OMEPRAZOLE AND ESOMEPRAZOLE IN THE APPROVED LIST OF PRODUCTS MANUFACTURED BY WAY OF SEMI BASIC MANUFACTURE OF M/S PHARMAGEN LTD, LAHORE
The Central Licensing Board in its 236^th meeting held on 27^th June, 2014 approved the grant of Omeprazole and Esomeprazole Magnesium Trihydrate to M/s Pharmagen Ltd, Lahore. However, the word Powder / Pellets was not mentioned with approved APIs. Now the firm has requested to change the name of two products Omeprazole and Esomeprazole Magnesium Trihydrate to omeprazole (Powder / Pellets) and Esomeprazole Magnesium Trihydrate (Powder / Pellets) as they are manufacturing pellets right from the semi basic route through N-2 stage, they start their process from sulphide compound, get powder first and then pellets, the product in both cases is in the form of pellets. It was approved during inspection by the Experts Committee constituted by DRAP for process verifications.
Proceedings and Decision of Central Licensing Board in 259^thmeeting

The Board considering the facts on the record and after thread bare deliberation decided to accept the request of M/s Pharmagen Ltd, Lahore.

Case No. 44. M/S ATLANTIC PHARMACEUTICAL LABORATORIES, 89-D, INDUSTRIAL ESTATE, HAYATABAD, PESHAWAR – VIOLATION OF RULE 5(2A) OF DRUGS (L,R&A) RULES, 1976.
M/s Atlantic Pharmaceutical Laboratories, Peshawar submitted the application for renewal of DML No. 000273 by way of formulation on 27-10-2014 for the period of 30-10-2014 to 29-10-2019, which was well on time. After evaluation of the renewal application of the firm, a letter for completion of application for renewal of DML was issued for following shortcomings: -

1. 
   Revised partnership deed mentioning change in directors / owners if any.
   
2. 
   To provide approval letter of Production and QC Incharge if technical persons are changed then provide documents according to Rule 16 of Drugs (Licensing, Registering & Advertising) Rules, 1976, after promulgation of S.R.O 1134(i)/2014 and submit documents according to checklist (check list enclosed).
   
3. 
   No Objection Certificate for Central Research Fund (CRF) by Statistical Officer DRAP, Islamabad.
   

2. With reference to above letter, it is mentioned that as per available record of Licensing Division, no correspondence received in respect to shortcomings in application for renewal of DML of the firm. Licensing Division issued final reminder with the following shortcomings.

1. 
   Partnership Deed(s) mentioning the detail of the previous and current management.
   
2. 
   Attested copy of CNIC’s of all partners.
   
3. 
   Up-to-date Nothing Due Certificate (CRF) from STO, DRAP, Islamabad.
   
4. 
   Attested copy of list of section wise equipments.
   
5. 
   Complete set of attested documents of proposed Production Incharge Mr. Sikandar Sohail as per check list attached.
   
6. 
   Fee challan of Rs.5000/- for change of technical staff.
   

3. In response to final reminder, the firm submitted following documents;

1. 
   Copy of partnership deed.
   
2. 
   Copy of Form-H.
   
3. 
   Copies of CNIC’s of Directors.
   
4. 
   Copy of application for issuance of Nothing Due Certificate (CRF).
   
5. 
   Copy of list of section wise equipments.
   
6. 
   Docuemnts of proposed technical staff alongwith fee Challan.
   

4. After evaluation of the submitted documents, following shortcomings were still observed: -

1. 
   Up-to-date Nothing Due Certificate from STO, DRAP, Islamabad.
   
2. 
   Proof of all approved sections.
   
3. 
   The experience of proposed Production and QC Incharge is less than ten (10) years.
   

Decision of CLB.

5. The Board considering the facts on the record and after thread bare deliberation decided to serve Show Cause Notice to the firm under Section 41 of the Drugs Act, 1976 read with Rule, 12 of the Drugs (Licensing, Registering and Advertising) Rules, 1976 for not complying the provision of Rule, 5(2A) and Rule 16 of the Drugs (Licensing, Registering and Advertising) Rules, 1976 as to why their application for renewal of M/s Atlantic Pharmaceutical Laboratories, 89-D, Industrial Estate, Hayatabad, PeshawarDML No. 000273by way of formulation may not be rejected or Drug Manufacturing Licence may not be suspended or cancelled by Central Licensing Board

6 Accordingly, show Cause Notice was served to the firm. No reply from the firm is received yet. Now, firm has also been called for personal hearing.
Proceedings and Decision of Central Licensing Board in 255^thmeeting

Mr. Humayun Khan, Director and Mr. Hameed ur Rehman, Quality Control Manager appeared before the Board. They contended that they have completed documents for approval of Quality Control Incharge. They also contended that documents for issuance of NOC for CRF has also been submitted with Budget and Accounts Division.After hearing the representative of the firm and facts on record, the Board decided to suspend the Drug Manufacturing Licence of M/s Atlantic Pharmaceutical Laboratories, 89-D, Industrial Estate, Hayatabad, Peshawar DML No. 000273 by way of formulationfor the period of three (03) months with immediate effect under Section 41 of the Drugs Act, 1976 read with Rule, 12 of the Drugs (Licensing, Registering and Advertising) Rules, 1976 for not complying the provision of Rule, 5(2A) and Rule 16 of the Drugs (Licensing, Registering and Advertising) Rules, 1976.

Proceedings of Licensing Division in compliance to the decision of Central Licensing Board.

The suspension order dated 26^th September, 2017 was issued to the M/s Atlantic Pharmaceutical Laboratories, 89-D, Industrial Estate, Hayatabad, Peshawar.

In reply to the suspension order firm has submitted the deficient documents and application for renewal of DML in now complete except section approval letter for which the firm has submitted the layout plan for regularization which is under process at Division level.
Proceedings and Decision of Central Licensing Board in 259^thmeeting

The Board considering the facts on the record and after thread bare deliberation decided to revoke the suspension of M/s Atlantic Pharmaceutical Laboratories, 89-D, Industrial Estate, Hayatabad, Peshawar DML No. 000273 for further period and also decided to resume the production of the firm.

The Board considering the facts on the record and after thread bare deliberation decided that order of suspension of Licence of M/s Atlantic Pharmaceutical Laboratories, 89-D, Industrial Estate, Hayatabad, Peshawar DML No. 000273 may be revoked for further period and also decided to resume the production of the firm.


Case No.45 M/S BF BIOSCIENCES LIMITED, LAHORE UNDER DRUG MANUFACTURING LICENSE NO. 000655 (FORMULATION)
Case Background

The Central Licensing Board in its 235^th meeting held on 15^th May, 2014 considered the case of M/s BF Biosciences Limited, Lahore and decided is as under:-

“Approved the Grant of Renewal of DML

The Board was further apprised by Licensing Division that the firm in its renewal application has mentioned that they have registration of Omeprazole at Biotech facility where as panel in the inspection report has mentioned that the firm has dedicated biotech manufacturing facility only.

The Board in this regard advised to refer the case of registration of Omera Injection (Omeprazole) with Reg. No. 067967 to Drug Registration Board for its consideration and further necessary action accordingly.”
This decision was conveyed to Drug Registration Board vide letter issued on 27^th August, 2014 (Page-404/Corr). The Drug Registration Board in its 277^th meeting held on 27-29^th December, 2017 considered the case of the firm and proceedings of the case are as under:

“Following application now have been submitted on Form 5 along with enclosures on CTD format, details of which are presented here for consideration of Registration Board.

845.	Name and address of manufacturer / Applicant		M/s BF Biosciences Ltd., 5-Km, Sundar Raiwind Road, Raiwind.
	Brand Name +Dosage Form + Strength		Omera 40mg Infusion (Lyophilized Powder Injection)	For	Solution	For	Intravenous
	Composition		Each vial contains: Omeprazole (as sodium) …40mg
	Diary No. Date of R& I & fee		Dy. No.16942; 04-10-2017; Rs.20,000/- (03-10-2017)
	Pharmacological Group		Proton pump inhibitors
	Type of Form		Form-5
	Finished product Specification		Manufacturer specifications
	Pack size & Demanded Price		1’s;As per SRO
	Approval status of product in Reference Regulatory Authorities.		Approved by MHRA of UK
	Me-too status		Risek Injection 40mg of M/s Getz Pharma (Reg.#024170)
	GMP status		Last inspection report 08-09-2017 Panel concludes good level of GMP compliance.
	Remarks of the Evaluator.		Firm has section approval for Biological parenteral only whereas applied formulation does not fall in this category. Firm has submitted Enclosures along with form 5 as per CTD format approved in 264thmeeting of registration Board. Firm has submitted reports of accelerated & real time stability studies for three batches.
	Decision: Registration Board deferred the case for personal hearing for clarification of firm’s request to manufacture applied formulation in Biological parenteral section.
846.	Name and address of manufacturer / Applicant		M/s BF Biosciences Ltd., 5-Km, Sundar Raiwind Road, Raiwind.
	Brand Name +Dosage Form + Strength		Esomega 40mg Infusion (Lyophilized Powder For Solution For Intravenous Injection)
	Composition		Each vial contains: Esomeprazole (as sodium) …40mg
	Diary No. Date of R& I & fee		Dy. No.16941; 04-10-2017; Rs.20,000/- (03-10-2017)
	Pharmacological Group		Proton pump inhibitors
	Type of Form		Form-5
	Finished product Specification		Manufacturer specifications
	Pack size & Demanded Price		As per SRO
	Approval status of product in Reference Regulatory Authorities.		Approved by MHRA of UK
	Me-too status		X-Prazole 40mg Infusion of M/s Mediate Pharmaceuticals, Karachi (Reg.#057925)
	GMP status	Last inspection report 08-09-2017 Panel concludes good level of GMP compliance.
	Remarks of the Evaluator.	Firm has section approval for Biological parenteral only whereas applied formulation does not fall in this category. Firm has submitted Enclosures along with form 5 as per CTD format approved in 264^thmeeting of registration Board. Firm has submitted reports of accelerated & real time stability studies for three batches.
Decision: Registration Board deferred the case for personal hearing for clarification of firm’s request to manufacture applied formulation in Biological parenteral section.

The Proceedings Of 278^th Meeting Of Drug Registration Board
Following cases were presented in 277^th meeting of Registration Board, submitted on Form 5 along with enclosures on CTD format. The details of cases & decisions of Board are reproduced as under:

846.	Name and address of manufacturer / Applicant	M/s BF Biosciences Ltd., 5-Km, Sundar Raiwind Road, Raiwind.
	Brand Name +Dosage Form + Strength	Omera 40mg Infusion (Lyophilized Powder Injection)	For	Solution	For	Intravenous
	Composition	Each vial contains: Omeprazole (as sodium) …40mg
	Diary No. Date of R& I & fee	Dy. No.16942; 04-10-2017; Rs.20,000/- (03-10-2017)
	Pharmacological Group	Proton pump inhibitors
	Type of Form	Form-5
	Finished product Specification	Manufacturer specifications
	Pack size & Demanded Price	1’s;As per SRO
	Approval status of product in Reference Regulatory Authorities.	Approved by MHRA of UK
	Me-too status	Risek Injection 40mg of M/s Getz Pharma (Reg.#024170)
	GMP status	Last inspection report 08-09-2017 Panel concludes good level of GMP compliance.
	Remarks of the Evaluator.	Firm has section approval for Biological parenteral only whereas applied formulation does not fall in this category. Firm has submitted Enclosures along with form 5 as per CTD format approved in 264^thmeeting of registration Board. Firm has submitted reports of accelerated & real time stability studies for three batches.
	Decision: Registration Board deferred the case for personal hearing for clarification of firm’s request to manufacture applied formulation in Biological parenteral section.
847.	Name and address of manufacturer / Applicant	M/s BF Biosciences Ltd., 5-Km, Sundar Raiwind Road, Raiwind.
	Brand Name +Dosage Form + Strength	Esomega 40mg Infusion (Lyophilized Powder For Solution For Intravenous Injection)
	Composition	Each vial contains: Esomeprazole (as sodium) …40mg
	Diary No. Date of R& I & fee	Dy. No.16941; 04-10-2017; Rs.20,000/- (03-10-2017)
	Pharmacological Group	Proton pump inhibitors
	Type of Form	Form-5
	Finished product Specification	Manufacturer specifications
	Pack size & Demanded Price	As per SRO
	Approval status of product in Reference Regulatory Authorities.	Approved by MHRA of UK
	Me-too status	X-Prazole 40mg Infusion of M/s Mediate Pharmaceuticals, Karachi (Reg.#057925)
	GMP status	Last inspection report 08-09-2017 Panel concludes good level of GMP compliance.
	Remarks of the Evaluator.	Firm has section approval for Biological parenteral
		only whereas applied formulation does not fall in this category. Firm has submitted Enclosures along with form 5 as per CTD format approved in 264^thmeeting of registration Board. Firm has submitted reports of accelerated & real time stability studies for three batches.
	Decision: Registration Board deferred the case for personal hearing for clarification of firm’s request to manufacture applied formulation in Biological parenteral section.

Following details have been submitted of Module 3 (Quality / CMC) for both above cited applications: Contents of Module: 3 (Quality / CMC)

Module	Section		Sub- section	Contents		Data submitted
3	3.2.S			DRUG SUBSTANCE
			3.2.S.1	General Information		Detail submitted for Nomenclature Structure General properties
			3.2.S.2	Manufacture		Detail submitted for Manufacturer(s) Description of Manufacturing Process and Process Controls
			3.2.S.3	Characterization		Detail submitted for Elucidation of Structure and other Characteristics Impurities
			3.2.S.4	Control of Drug Substance		Detail submitted for Control of Drug Substance Specification Analytical Procedures Validation of Analytical Procedures Batch Analyses Justification of Specification
			3.2.S.5	Reference Standards or Materials		Detail submitted for Reference Standards
			3.2.S.6	Container Closure System		Detail submitted for Container Closure System
			3.2.S.7	Stability		Detail submitted for Stability. (Protocol & reports have been submitted)
	3.2.P			DRUG PRODUCT
			3.2.P.1	Description and Composition of Drug Product		Detail submitted for Composition of Drug Product
			3.2.P.2	Pharmaceutical Development		Detail submitted for Components of the Drug Product.
			3.2.P.3	Manufacture		Detail submitted for Manufacturer(s) Batch Formula Description of Manufacturing Process
								and Process Controls iv. Controls of Critical Steps and Intermediates Undertaking has been submitted for Process validation
					3.2.P.4		Control of Excipient	Detail submitted for Specifications Analytical Procedures All excipients used are of Pharmacopoeal grades
					3.2.P.5		Control of Drug Product	Detail submitted for Specification(s) Analytical Procedures Validation of Analytical Procedures (Protocol & report have been submitted)
					3.2.P.6		Reference Standards or Materials	Detail submitted for Reference Standards or Materials
					3.2.P.7		Container Closure System	Detail submitted for Container Closure System
					3.2.P.8		Stability	Following have been submitted: Stability Summary and Conclusions Post-approval Stability Protocol and Stability Commitment Stability Data (Only reports have been submitted.)

• 
  Now, the firm has requested for personal hearing before the Honourable Drug Registration Board to enable to them to present their case. The representatives of the firm now have been called upon for personal hearing.
  

Proceedings: Dr. Ajmal Nasir (Director Technical) appeared before the Board and briefed regarding justification for the manufacturing of non- biologicals along with bio-pharmaceuticals at BF Biosciences Ltd as under:

“BF Biosciences is manufacturing six products i.e. Interferon Alpha 2a, Interferon Alpha 2b, Pegylated interferon alpha 2a, Erythropoietin, Filgrastim and Terlipressin acetate injections.

Drug Substances manufactured using a Biological system using living organisms/cell lines through culturing or Recombinant DNA are termed as BIOLOGICALS, whereas Drug Products manufactured using already produced Biological Drug Substances (which no longer contain living organisms) are termed as Bio-Pharmaceuticals. Dedicated facility is required for the manufacturing of BIOLOGICAL SUBSTANCES and certain other highly sensitizing compounds etc., but not for biopharmaceuticals

All above-mentioned products manufactured at BF Biosciences are Bio-Pharmaceuticals. These bio-pharmaceutical formulations are peptides that are easily denatured by temperature as well as pH changes, and thus can be eliminated from the facility through cleaning validation between production batches. These do not therefore bear contamination risks carried by penicillin-based antibiotics and other products requiring dedicated manufacturing facilities.

Bio-Pharmaceuticals formulation and filling / Lyophilization (if required) is allowed as per WHO ¹, Eudralex ² and FDA ³ guidelines along with non-Biopharmaceuticals on Campaign basis.

At BF Biosciences we intend to avail this allowance to manufacture non-Biologicals along with Bio-Pharmaceuticals on Campaign basis.

All required controls and systems are in place and are compliant to requirements for campaign- based manufacturing of bio- pharmaceuticals and non- biologicals.”

REFERENCES
1) Annex 3 WHO good manufacturing practices for biological products Replacement of Annex 1 of WHO Technical Report Series, No. 822 Section 9, 13.

2. 
   EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Us e Annex 2 Manufacture of Biological active substances and Medicinal Products for Human Use Section 8 g and 9
   
3. 
   FDA approves BioMarin’s manufacturing facility in Cork, Ireland he FDA has approved BioMarin Pharmaceutical’s bulk biologics manufacturing plant, located in Cork, Ireland for production of the formulated bulk substance. Niamh Marriott (European Pharmaceutical Review)
   

• 
  It is pertinent to mention that M/s BF Biosciences Ltd. Lahore was previously granted registration for Omega injection (Omeprazole), Reg. No. 067967, in same manufacturing facility vide letter no. F.15-7/2010-Reg-V (M-228) dated 10-12-2010.
  

Later Central Licensing Board in 235th meeting while discussing the case of renewal of DML of M/s BF Bio Sciences, Lahore passed following orders in respect of Omega injection (Omeprazole) , Reg. No. 067967:-

“The Board was apprised by licensing division that the firm in its renewal application has mentioned that they have registration of omeprazole at biotech facility where as panel in the inspection report has mentioned that the firm has dedicated biotech manufacturing facility only. The Board in this regard advised to refer the case of registration of Omega injection (Omeprazole), Reg. No. 067967 to Drug Registration Board for its consideration and further necessary action accordingly”.

Registration Board in its 245^th meeting held on 29th & 30th September, 2014 decided to issue show cause for cancellation of registration of Omega injection (Omeprazole), Reg. No. 067967, registered in the name of M/s BF Biosciences Ltd. Lahore.

Subsequently Omega injection (Omeprazole), Reg. No. 067967 of M/s BF Biosciences Ltd. Lahore, was de-registered vide letter no. F.15-2/2015-Reg-V (M-247)