gxp and cgxp in bio/pharmaceutical industry

GxP and cGxP in Bio/Pharmaceutical Industry

Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

Department of PharmaceuticsKLE University College of Pharmacy

BELGAUM – 590010, Karnataka, IndiaE-mail: [email protected]

Cell No: 00919742431000

28 March 2011 1Department of Pharmaceutics

mailto:[email protected]

GxP

• The bio/pharmaceutical industry has created its own language and GxP is one of many acronyms that we all tend to use.

• While this may seem “elementary” to some of you, many people may not know what this means.

• G = Goodx (variable replaced with Manufacturing, Clinical,

Laboratory, Storage, Distribution and Review) P = Practice

2Department of Pharmaceutics28 March 2011

GxP

• As you can see, GxP is used as short-hand form for referring to the regulations established by the United States Food and Drug Administration which are published in the Code of Federal Regulations.

• Sometimes people refer to the “GCPs” which specifically regards the rules that govern clinical trials vs. product manufacturing (GMPs) or laboratory regulations (GLPs).

• Together, these are known collectively as the “predicate rules” that govern a wide spectrum of regulatory obligations across this diverse industry.


GxP

• GxP is also where citations emanate from (typically) as regards FDA inspections.

• When a regulation is cited, the title tells you where it is published.

For example: 21 CFR 312.2

Means:21 = Title 21CFR = Code of Federal Regulations312.2 (312 = part and 2 =section)


Lifecycle Requirements


GxP

• “GxP” is a collective term for the Good Practice quality guidelines and regulations used in many fields, encompassing such internationally-recognized standards as GMP, GCP, GLP, GSP, GDP and GRP.

• GxP guidelines are designed to ensure that products are safe, meet their intended use and, in regulated industries such as drugs, food, medical devices and cosmetics, adhere to quality processes during manufacturing, control, storage and distribution.


GxP• GxP is a general term for Good Practice quality

guidelines and regulations. These guidelines are used in many fields, including the pharmaceutical and food industries.

• The titles of these good practice guidelines usually begin with "Good" and end in "Practice", with the specific practice descriptor in between.

• GxP represents the abbreviations of these titles, where x (a common symbol for a variable) represents the specific descriptor.


http://en.wikipedia.org/wiki/Quality_(business)

http://en.wikipedia.org/wiki/Pharmacology

Core GXP Information


Regional Harmonization Initiatives


GxP


List of GxP’s in Pharmaceuticals

1. GMP – (Good manufacturing Practice)

2. GCP – (Good Clinical Practice)

3. GLP – (Good Laboratory Practice)

4. GSP – (Good Storage Practice)

5. GDP – (Good Distribution practice)

6. GRP – (Good Review Practice)


Purpose of GxP

• The purpose of the GxP quality guidelines is to ensure a product is safe and meets its intended use.

• GxP guides quality manufacture in regulated industries including food, drugs, medical devices and cosmetics.

The most central aspects of GxP are:

1. Traceability: the ability to reconstruct the development history of a drug or medical device.

2. Accountability: the ability to resolve who has contributed what to the development and when.


Regulators


GMP – (Good Manufacturing Practice)

28 March 2011 Department of Pharmaceutics 14

What is GMP ?

• GMP is that part of Quality assurance which ensures that the products are consistently manufactured and controlled to the Quality standards appropriate to their intended use

• A set of principles and procedures which, when followed by manufacturers for therapeutic goods, helps ensure that the products manufacture will have the required quality.


Good Manufacturing Practices

• A basic tenet of GMP is that quality cannot be tested into a batch of product but must be built into each batch of product during all stages of the manufacturing process.

• It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.

- Some of the main risks are unexpected contamination of products, causing damage to health or even death

- In correct labels on containers, which could mean that patient receive the wrong medicine.

- Insufficient or too much active ingredient, resulting in ineffective treatment or adverse effects.


GMP


QC

GMP

QA

GMP

• GMP is the magic key that opens the door of the Quality

• In matter of GMP, swim with the current and

in matter of Quality stand like a rock!


GMP


GMP

Is that part of Quality

Assurance aimed at

ensuring that products are

consistently manufactured

to a quality appropriate to

their intended use

GMP guidelines

• GMP as per Schedule “M”• GMP as per WHO• GMP as per MCA now known as MHRA• GMP as per TGA• GMP as per US FDA• GMP as per ICH guidelines


GMP guidance documents

• EU Good Manufacturing Practice (GMP) Guidelines, Volume 4 of “The rules governing medicinal products in the European Union”

• US FDA current Good Manufacturing Practice (cGMP) for finished pharmaceuticals, 21 CFR, 210 and 211

• WHO Good Manufacturing Practices for pharmaceutical products, Annex 4 to WHO Technical Report Series, No. 908, 2003


GMP

• GMP in solid dosage forms• GMP in semisolid dosage forms• GMP in Liquid orals• GMP in Parenterals Production• GMP in Ayurvedic medicines• GMP in Bio technological products• GMP in Nutraceuticals and cosmeceuticals


API Manufacturing Process


Secondary Manufacturing Dosage Forms


Secondary Manufacturing Process - Tablets


Secondary Manufacturing Process – Sterile parenteral for injection


Packaging


Biotechnology Manufacturing Process


Ten Principles of GMP

1. Design and construct the facilities and equipments properly

2. Follow written procedures and Instructions3. Document work4. Validate work5. Monitor facilities and equipment6. Write step by step operating procedures and work on

instructions7. Design ,develop and demonstrate job competence8. Protect against contamination9. Control components and product related processes 10. Conduct planned and periodic audits 28 March 2011 Department of Pharmaceutics 31

Beyond GMP

• Reduce pollution - Zero discharge

• Adaptation of environment friendly methods

• Consideration for better and healthier life tomorrow

• Consideration of ethics in life

• One should begin with end in mind otherwise it will be the beginning of the end


Cost of effective GMP

• In fact Cost benefits – positive cost benefits of GMP/QA

• Good plant lay out, Smooth work flows, Efficient documentation systems, well controlled process, good stores lay outs and stores records- These are Good manufacturing practices

• Reduction in work in process and inventory holding costs

• Avoidance of cost of Quality failure ( cost of waste, of rework, of recall, of consumer compensation and of loss of company reputation


Cost / Benefit analysis

• GMP is not an “On-cost”. • It is not even “Just free”• It is a contribution to profit• Good manufacturing Practice is also Good

management Practice leading to Good Manufacturing Profit

• GMP is central and basic and has cost benefits ( not to be considered as extrinsic or imposed upon manufacturing activities)


Cost / benefit analysis


• Cost of quality = Cost of A – Cost of B- Payback from C = Profit

A B CStaff Scrap Improved moraleTraining Rework MotivationSystems Complaints Faster throughputDocumentation Chaos Higher productivityEquipment Lost sales Increased salesMaintenance Recalls lower inventoryCalibration Closedown SamplingTestingIn process controlValidationAuditing

GCP – (Good Clinical Practice)


What It Is GCP

• An international ethical & scientific quality standard for designing, conducting, recording & reporting human clinical studies

– EU

– Japan

– US

• Applies to registration studies that may have an impact on safety & welfare of human subjects


GCP Participating Parties

• IRB/Ethics Committee

• Investigators

• Sponsor

• Regulatory Authorities


GCP Key Documents

• Investigator Brochure

• Study Protocol

• Informed Consent Document


GCP Principles

1. Studies in accordance with Declaration of Helsinki; consistent with GCP & applicable regulatory requirements

2. Studies initiated & continued only if anticipated benefits outweigh risks

3. Rights, safety & welfare of human subjects take priority over interests of science & society

4. Available non-clinical & clinical info on product adequate to support study


GCP Principles

5. Studies scientifically sound; described in clear, detailed protocol

6. Study in compliance with IRB/EC approved protocol

7. Medical care given to subjects is the responsibility of qualified medical professional(s)

8. Individuals conducting studies qualified by education, training & experience

9. Freely given informed consent obtained from every subject prior to study participation


GCP Principles

10. Study information recorded, handled & stored to allow accurate reporting, interpretation & verification

11. Confidentiality of subject records protected in accordance with applicable regulatory requirements

12. Investigational products manufactured, handled & stored in accordance with GCP & used in accordance with approved protocol

13. Systems/procedures implemented to assure quality of study


IRB/EC Roles & Responsibilities

To safeguard study subjects’ rights & welfare by:

• Evaluation/disposition of study proposal

• Evaluation of proposed subject consent materials

• Evaluation of emergency use consent methodology

• Evaluation of investigator qualifications

• Ongoing review of study progress (at least yearly)

• Evaluation of proposed subject compensation plans


IRB/EC Composition & Operations

• Membership has qualifications & experience to evaluate science, medical aspects & ethics of proposed study

– ≥ 5 members

– ≥ 1 member whose primary interest in nonscientific

– ≥ 1 member independent of institution or study site

• Written SOPs & records

• Decisions rendered at announced meetings with quorum in attendance


IRB/EC Composition & Operations

• Only members participating in review should vote

• Investigator may provide info on study, but should not be involved in review or vote

• Nonmembers with expertise in special areas may be invited to assist with review (but cannot vote)


IRB/EC Procedures

• Document group membership & qualifications

• Schedule meetings & notify members

• Conduct initial & ongoing review of studies

• Determine ongoing review frequency

• Provide expedited review of minor study changes, in accordance with regulatory requirements

• Specify that no subject should be enrolled in study prior to IRB/EC approval


IRB/EC Procedures

• Specify that no deviations from protocol should be initiated without prior IRB/EC approval

– Emergency situations require immediate notification of IRB/EC after the fact

• Specify that Investigator should promptly report:

– Protocol deviations

– Changes increasing subject risk or study procedures

– Serious and unexpected adverse events


IRB/EC Procedures

• Notify Investigator promptly of:

– Study-related decisions

– Reason for decisions

– Procedures for appeal of decisions


IRB/EC Required Records

• Relevant records maintained ≥ 3 yr after study completion

• Records available for review by regulatory authorities


IRB/EC What is Reviewed

• Investigator Brochure or Report of Prior Investigations

• Study protocol & amendments

• Investigator qualifications

• Informed consent documents, including subject recruiting tools

• Other written information provided to subjects

• Subject compensation plans

• Adverse events

• Protocol deviations28 March 2011 Department of Pharmaceutics 50

IRB/EC When Reviews Occur

• Prior to study initiation at site

• At least yearly during study

• During study, as necessitated by:

– Changes in protocol, consent documents, etc.

– Changes in study investigator

– Reports of serious or unanticipated device-related adverse events

• At study completion or termination


Investigator Roles & Responsibilities

• Qualified to conduct study

• Have adequate resources to conduct study

• Provide medical care to study subjects

• Regular communication with IRB/EC reviewing study

• Compliance with study protocol

• Maintenance of investigational product accountability

• Compliance with study randomization & unmasking procedures

• Provide informed consent to study subjects28 March 2011 Department of Pharmaceutics 52

Investigator ResponsibilitiesAppropriate Qualifications

• Training & experience demonstrated via:

– Medical license

– CV

– Specialized study training

– GCP training

• If study responsibilities delegated, need a list of qualified persons to whom responsibilities are delegated


Investigator ResponsibilitiesAdequate Resources

• Suitable staff & good methods for keeping them apprised

• Suitable facilities

• Appropriate patient population

– Access to disease or condition

– Volume of patients with disease or condition


Investigator ResponsibilitiesRequired Records & Reports

• Essential regulatory document file(s)– Protocol & amendments

– Approved informed consent documents

– Product accountability documentation

– Investigator qualifications & agreements

– IRB correspondence

– Study delegation list

– Subject screening/enrollment logs

– Study monitoring reports

– Calibration/maintenance logs

– Memos to file


SponsorRoles & Responsibilities

• Study quality assurance

• Appropriately qualified medical personnel to advise on study

• Utilization of qualified personnel in study design & operations

• Study management, data handling & record keeping

• Investigator selection & training

• Definition/allocation of study responsibilities28 March 2011 Department of Pharmaceutics 56


• Facilitation of communications between Investigators

• Study compensation (investigators and/or subjects) & financing

• Regulatory authority notification/submission

• Confirmation of IRB/EC review/approval

• Investigational product information

• Investigational product manufacturing, packaging, labeling & coding

• Investigational product supply & handling28 March 2011 Department of Pharmaceutics 57


• Record access

• Ongoing safety evaluation & reporting

• Serious/unanticipated adverse event reporting

• Study monitoring

• Study noncompliance procedures

• Study termination or suspension notification

• Study reports



• Sponsor may transfer responsibilities to CRO

– Transfer must be documented in writing

– Sponsor still has ultimate responsibility for study quality and data integrity


Study Protocol Components

• General administrative info

• Background

• Study purpose & objectives

• Study design

• Subject eligibility requirements

• How subjects will be treated

• How safety & efficacy will be assessed

• Sample size justification & statistical analysis methods28 March 2011 Department of Pharmaceutics 60

Study Protocol Components

• How data will be captured & maintained

• Monitoring procedures

• Proposed informed consent document


Informed Consent DocumentComponents

• Statement that study involves “research” & product “experimental” (if applicable)

• Study purpose

• Number of expected study subjects to be enrolled

• Study treatment(s) & probability for random assignment

• Study exams & procedures for duration of trial

• Subject’s responsibilities

• Foreseeable risks to subject (embryo, fetus, nursing infant)



• Expected benefits

• Alternatives procedures or therapies & associated risk/benefit

• Compensation available in event of study-related injury or sickness

• Anticipated payments to subject for study participation

• Anticipated expenses to subject for study participation

• Statement that participation is voluntary28 March 2011 Department of Pharmaceutics 63


• Description of extent to which confidentiality can be assured

• Commitment to keep subject apprised on new information that may affect subject’s willingness to participate in study

• Contact info for questions re: subject rights; trial-related adverse events

• Circumstances under which subject’s participation may be terminated


Investigator BrochureWhat It Is

A compilation of clinical & non-clinical data on the product that is relevant to the product’s study in

humans

Necessary for Investigator & IRB/EC review to assess the risks/benefits associated with study


Investigator BrochureComponents

Product formulation summary

Introduction/background info regarding product & investigational plan

• Investigational product physical, chemical & pharmaceutical properties & formulation

• Non-clinical studies

• Human clinical studies

• Summary of data & guidance for Investigator28 March 2011 Department of Pharmaceutics 66

Good Clinical PracticeReference Documents & Links

• ICH - E6: Guideline for Good Clinical Practice

• 21 CFR 50 - Informed Consent

• 21 CFR 56 - Institutional Review Board

• http://www.ich.org/cache/compo/276-254-1.html

• http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm


http://www.ich.org/cache/compo/276-254-1.html

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

GLP – (Good Laboratory Practice)


What It Is GLP

• Describes good practices for non-clinical lab studies that support research or marketing approvals for FDA-regulated products


GLP General Requirements

• Appropriately qualified personnel

• Adequate resources

• Appropriate procedures for:

– Sanitation, health precautions, clothing

– Test protocol development, test methods

– Data analysis, report development

• Appropriately qualified study director

• Quality assurance function


GLP Facilities Requirements

• Suitable size, construction, segregation

– Animal care

– Animal supplies

– Test & control products maintained in a secure area

– Operating “suite”

– Specimen & data storage


GLP Equipment Requirements

• Appropriately designed

• Adequate thru-put capacity

• Appropriately located

• Routinely maintained & calibrated


GLP Standard Operating Procedures

• Animal room prep

• Animal care

• Receipt, ID, storage, handling, mixing & sampling of test & control articles

• Test system observations

• Lab tests

• Handling of moribund or dead animals

• Necropsy or postmortem exams of animals


GLP Standard Operating Procedures

• Collection & ID of specimens

• Histopathology

• Data handling, storage & retrieval

• Equipment maintenance & calibration

• Transfer, proper placement & ID of animals


GLP Reagents & Solutions

• Adequate labeling

– Identity

– Concentration

– Storage requirements

– Expiration date


GLP Test & Control Articles

• Adequate characterization

• Proper receipt, storage, distribution

• When mixed with a carrier, adequate methods to confirm

– Mixture uniformity

– Article concentration

– Article stability


GLP Study Implementation

• Written, approved protocol indicating test objectives & methods

• Study conducted in accordance with protocol

• Study monitoring to confirm protocol compliance

• Appropriate labeling of specimens by test system, study, nature & collection date

• Records of gross findings from postmortems available to pathologist for specimen histopathology


GLP Study Implementation

• Standard data capture/recording requirements

– Legibility

– Permanence

– Accountability

– Changes


GLP Records & Reports

• Final report of results

• Study records & data methodically archived to facilitate expedient retrieval

– Study documents

– Raw data

– Specimens

– Protocols

– QA inspections

– Personnel training & qualifications

– Calibration & maintenance records28 March 2011 Department of Pharmaceutics 79

GLP Records & Reports

• Records retention (shortest of):

– ≥ 2 yr after FDA marketing clearance

– ≥ 5 yr after data submitted to FDA in support of marketing application

– ≥ 2 yr after Sponsor decision not to proceed with marketing application

– Wet specimens hold as long as viable

• Records transferable with written FDA notification


GLP Facility Disqualification

• Grounds for disqualification:

– Failure to comply with regulations &

– Noncompliance adversely affects study validity &

– Previous regulatory actions have been unsuccessful in modifying facility operations


GSP – (Good Storage Practice)


GSP – (Good Storage Practice)

1. Glossary

2. Personnel

3. Premises and facilities

4. Storage requirements

5. Returned goods

6. Dispatch and transport

7. Product recall


1. Glossary

a. Active pharmaceutical ingredient

b. Contamination

c. Cross-contamination

d. Excipient

e. Expiry date

f. Labelling


1. Glossary

g. Packaging material

h. Pharmaceutical product

i. Production

j. Retest date

k. Storage

l. Supplier


2. Personnel

• At each storage site (e.g. that of a manufacturer, distributor, wholesaler, community or hospital pharmacy) there should be an adequate number of qualified personnel to achieve pharmaceutical quality assurance objectives.

• National regulations on qualifications should be followed.


2. Personnel

• All personnel should receive proper training in relation to good storage practice, regulations, procedures and safety.

• All members of staff should be trained in, and observe high levels of, personal hygiene and sanitation.

• Personnel employed in storage areas should wear suitable protective or working garments appropriate for the activities they perform


3. Premises and facilities

a. Storage areas

b. Storage conditions

c. Monitoring of storage conditions


4. Storage requirements

a. Documentation: written instructions and records

b. Labeling and containers

c. Receipt of incoming materials and pharmaceutical products

d. Stock rotation and control


5. Returned goods

• Returned goods, including recalled goods, should be handled in accordance with approved procedures and records should be maintained.

• All returned goods should be placed in quarantine and returned to saleable stock only after this has been approved by a nominated, responsible person following a satisfactory quality re-evaluation.

• Any stock reissued should be so identified and recorded in stock records. Pharmaceuticals returned from patients to the pharmacy should not be taken back as stock, but should be destroyed.


6. Dispatch and transport

• Records for dispatch should be retained, stating at least:

— the date of dispatch;

— the customer’s name and address;

— the product description, e.g. name, dosage form and

strength (if appropriate), batch number and quantify;

— the transport and storage conditions.

• All records should be readily accessible and available on request.


7. Product recall

• There should be a procedure to recall from the market, promptly and effectively, pharmaceutical products and materials known or suspected to be defective.


GDP – (Good Distribution practice)



• GDP governs the proper distribution of medicinal products for human use and regulates the movement of products from the manufacturers’ premises (or other central point) to the end user (or other intermediate point).



1. Principle

2. Personnel

3. Documentation

4. Premises and equipment

5. Deliveries to customers

6. Returns

7. Self inspection

8. Provision of information to Member States in relation to wholesale activities


1. Principle

• Policy ensures that products released for distribution are of the appropriate quality.

• In addition to this, the quality system should ensure that the right products are delivered to the right addressee within a satisfactory time period.

• A tracing system should enable any faulty product to be found and there should be an effective recall procedure.


2. Personnel

• He should fulfil his responsibilities personally.

• Person should be appropriately qualified: although a degree in Pharmacy is desirable, the qualification requirements may be established by the Member State on whose territory the wholesaler is located.


2. Personnel

• Key personnel involved in the warehousing of medicinal products should have the appropriate ability and experience to guarantee that the products or materials are properly stored and handled.

• Personnel should be trained in relation to the duties assigned to them and the training sessions recorded.


3. Documentation

• All documentation should be made available on request of competent authorities

a. Orders

b. Procedures

c. Records28 March 2011 Department of Pharmaceutics 99

4. Premises and equipment

• Premises and equipment should be suitable and adequate to ensure proper conservation and distribution of medicinal products.

a. Receipt

b. Storage



• Deliveries should be made only to other authorised wholesalers or to persons authorised to supply medicinal products to the public in the Member State concerned.

• In case of emergency, wholesalers should be in a position to supply immediately the medicinal products that they regularly supply to the persons entitled to supply the products to the public.



• Medicinal products should be transported in such a way that :

a) Their identification is not lost;

b) They do not contaminate, and are not contaminated by, other products or materials;

c) Adequate precautions are taken against spillage, breakage or theft;

d) They are secure and not subjected to unacceptable degrees of heat, cold, light, moisture or other adverse influence, nor to attack by microorganisms or pests.


6. Returns

a. Returns of non-defective medicinal products

b. Emergency plan and recalls

c. Counterfeit medicinal products

d. Special provisions concerning products classified as not for sale


7. Self inspection

• Self-inspections should be conducted 9and recorded) in order to monitor the implementation of and compliance with this guideline.


8. Provision of information to Member States in relation to wholesale activities

• Wholesalers wishing to distribute or distributing medicinal products in Member State(s).

• Where appropriate, the competent authorities of this (these) other Member State(s) will inform the wholesaler of any public service obligation imposed on wholesalers operating on their territory.


Guidance documents deal with GDP• WHO Good Distribution Practice, Annex 5 to Technical Report

Series, No. 937, 2006

• Health Canada Guidelines for Temperature Control of Drug Products during Storage and Transportation, 2005

• Irish Medicines Board Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances, 2006

• USP chapter <1079> Good Storage and Shipping Practice

• EU Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03)


GRP – (Good Review Practice)



• A good review practice (GRP) is a documented best practice within CDER that discusses any aspect related to the process, format, content, and/or management of a product review.

• GRPs are developed over time as superior practices based on CDER’s collective experience to provide consistency to the overall review process of new products.

• GRPs are developed to improve the quality of reviews and review management.



• GRPs improve efficiency, clarity, and transparency of the review process and review management.

• GRPs are expected to be adopted by review staff as standard processes through supervisor mentoring, implementation teams, and formal training when necessary.

• Developing GRPs is an attempt to identify, collect, enhance, implement, and adopt may of these best practices as documented and standardized GRPs that can be shared among all review division


− Quality — Consistent implementation of GRPs by review staff will enhance the quality of reviews, the review process, and the resultant regulatory action.

− Efficiency — GRPs will improve the efficiency of the review process through standardization.

− Clarity — GRPs support clarity throughout the review process, including critical review and decision activities that must be completed before a regulatory decision is made.


GRPs Fundamental Values

GRPs Fundamental Values

− Transparency — Developing and documenting GRPs ensures that our review processes are readily available in one location via the Internet (through CDER’s Web site) to sponsors and the public.

− Consistency — By offering a consistent approach and only deviating from it when appropriate (after supervisory concurrence), GRPs help reviewers achieve consistency with their reviews and provide standard review processes across divisions and offices.


cGxP


cGxP

• A "c" or "C" is sometimes added to the front of the acroynm.

• The preceding "c" stands for "current."

• For example, cGMP is an acronym for "current Good Manufacturing Practices." cGMP is the most well known example of a GxP.

• The term GxP is only used in a casual manner, to refer in a general way to a collection of quality guidelines.


cGxP

• What does cGxP stand for?

• Current Good X Practice (FDA compliance; X can mean: Manufacturing, Clinical, Laboratory, Storage, Distribution, Review Pharmaceutical)



Thank youCell No: 00919742431000

E-mail: [email protected]

gxp and cgxp in bio/pharmaceutical industry

Education

department of pharmaceutics28

good practice guidelines

gxp guidelines

good x variable

specific practice descriptor

laboratory regulations

code of federal regulations

food industries