Pharmaceutical inspection convention

15.6 CLEANING VALIDATION

1. 
   Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.
   

2. 
   Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.
   
3. 
   Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined.
   
4. 
   For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a “worst case” approach can be carried out which takes account of the critical issues.
   
5. 
   Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
   
6. 
   "Test until clean" is not considered an appropriate alternative to cleaning validation.
   
7. 
   Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.
   

15.7 ANALYTICAL METHOD VALIDATION

1. 
   Analytical testing procedures including stability testing methods must be validated to demonstrate their reliability. This should be done during product design.
   
2. 
   Revalidation may be necessary in the following circumstances:
   

• 
  changes in the synthesis of a drug substance;
  
• 
  changes in the composition of a finished product;
  
• 
  changes in the analytical procedure
  
• 
  changes in the manufacturing process that will effect the method
  

15.7 Analytical Method Validation continued

3. 
   The degree of revalidation required depends on the nature of the changes. Certain other changes may also require validation.
   
4. 
   Analytical method validation should not be confused with system suitability tests. System suitability testing verifies the suitability of an analytical system at the time the test is performed.
   
5. 
   Analytical methods, (other than pharmacopoeial methods), should be validated. Typical validation characteristics which should be considered, include accuracy, precision, (repeatability and intermediate precision), specificity, detection limit, quantitation limit, linearity and range. Robustness should be considered at an appropriate stage in the development of an analytical procedure.
   
6. 
   Reference may be made to: ICH Q2 Validation of Analytical Procedures: Text and Methodology http://www.ich.org
   

15.8 CHANGE CONTROL

1. 
   Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specifications.
   
2. 
   All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis. The need for, and the extent of, requalification and re-validation should be determined.
   

15.9 REVALIDATION

Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.

GLOSSARY

Definitions of terms relating to qualification and validation which are not given in the glossary of the current SA Guide to GMP, but which are used in this Annex, are given below.

Change Control

A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state.

Cleaning Validation

Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.

Concurrent Validation

Validation carried out during routine production of products intended for sale.

GLOSSARY continued

Design qualification (DQ)

The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.

Installation Qualification (IQ)

The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.

Operational Qualification (OQ)

The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

Performance Qualification (PQ)

The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

Process Validation

The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.

Prospective Validation

Validation carried out before routine production of products intended for sale.

Retrospective Validation

Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data.

Re-Validation

A repeat of the process validation to provide an assurance that changes in the process/equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality.

Risk analysis

Method to assess and characterise the critical parameters in the functionality of an equipment or process.

Simulated Product

A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch.

System

A group of equipment with a common purpose.

Worst Case

A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.

ANALYTICAL METHOD VALIDATION GLOSSARY

Analytical Procedure

The analytical procedure refers to the way of performing the analysis. It should describe in detail the steps necessary to perform each analytical test. This may include but is not limited to: the sample, the reference standard and the reagents preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation, etc.

Specificity

Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.

Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s).

This definition has the following implications:

Identification: to ensure the identity of an analyte.

Purity Tests: to ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte, i.e. related substances test, heavy metals, residual solvents content, etc.

Assay (content or potency): to provide an exact result which allows an accurate statement on the content or potency of the analyte in a sample.
Accuracy

The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found.

This is sometimes termed trueness.
Precision

The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision may be considered at three levels: repeatability, intermediate precision and reproducibility.

Precision should be investigated using homogeneous, authentic samples. However, if it is not possible to obtain a homogeneous sample it may be investigated using artificially prepared samples or a sample solution.

The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements.

Repeatability

Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision.

Intermediate precision

Intermediate precision expresses within-laboratories variations: different days, different analysts, different equipment, etc.

Reproducibility

Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).

Detection Limit

The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.

Analytical Method Validation Glossary continued

Quantitation Limit

The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.

Linearity

The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.

Range

The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.

Robustness

The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.

ANNEX 16

ORGANISATION AND PERSONNEL

16.1 PRINCIPLES

The company must have an organisation chart. The organogram should clearly indicate the reporting lines and level of responsibility, and should be authorised and be in accordance with the functional relationships described in the individual job descriptions of the functionaries referred to.

The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture and control of medicines rely upon people. For this reason, there should be sufficient personnel at all levels with the ability, training, experience and, where necessary, the professional / technical qualifications and managerial skills appropriate to the tasks assigned to them.

Their duties and responsibilities should be clearly explained to them and recorded as job descriptions. Proper job descriptions should include the responsibilities and document in detail the policy and requirements.

All personnel should be aware of the principles of Good Manufacturing Practice (GMP) that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs.

Responsibilities should be delegated and acceptance acknowledged in writing. Duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with application of GMP.

The way in which the various key responsibilities which can influence product quality are allocated may vary with different manufacturers. These responsibilities should be clearly defined and delegated.

The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.

Suitably qualified persons should be designated in writing to take up the duties of key personnel during the absence of the latter.

Key personnel should be provided with adequate supporting staff.

Persons in responsible positions should have sufficient authority to discharge their responsibilities. In particular, the person responsible for Quality Assurance should be able to carry out his defined functions impartially.

The person responsible for Production and the person responsible for Quality Assurance, should be different persons of equal level of authority, neither of whom should be responsible to the other, but who both have a responsibility for achieving the requisite quality.

The duties of this person responsible for Quality Assurance are wider than those which may be suggested by such terms as “Chief Analyst”, “Laboratory Head”, etc.

16.2 RESPONSIBILITIES OF KEY PERSONNEL

Key personnel include

• 
  a natural person who resides in South Africa responsible to the Medicines Control Council for compliance with the requirements of the Medicines and Related Substances Act, 1965 (Act 101 of 1965).
  
• 
  the person responsible for Production,
  
• 
  the person responsible for Quality Assurance, and
  

16.2 RESPONSIBILITIES OF KEY PERSONNEL continued

• 
  the Responsible Pharmacist responsible to the
  

• 
  Medicines Control Council for compliance with the requirements of the Medicines and Related Substances Act, 1965 (Act 101 of 1965) and the
  
• 
  Pharmacy Council for compliance with the requirements of the Pharmacy Act, 1974 (Act 53 of 1974)
  

Head of Production

The Production Manager, in addition to his responsibilities (Chapter 2) for

• 
  production areas, equipment, operations and records
  
• 
  the management of production personnel; and for
  
• 
  the manufacture of products in accordance with the appropriate Master Formulation and Manufacturing instructions,
  

will have other responsibilities bearing on quality, which he should share or exercise jointly with the person responsible for Quality Control.

Head of Quality Control

The person responsible for Quality Control should have the authority to establish, verify and implement all quality control procedures (Chapter 2).

In some companies the Quality Assurance Manager oversees all the quality assurance arrangements and reports to senior management. The person responsible for Quality Control may report to the Quality Assurance Manager and share some of the responsibilities with him.

The person responsible for Quality Assurance should be part of the decision-making process in all matters that affect the quality of products including development, production, laboratory, storage, distribution, vendors and third party contractors.

Shared or joint responsibilities of the Head of Production and Head of Quality Control (Chapter 2)

It is important that both direct and shared responsibilities are understood by those concerned.

The Responsible Pharmacist contemplated in regulation 25 (3) of the Pharmacy Act and the relevant sections of the Medicines Act must:

• 
  ensure that he or she in fact continuously supervises the pharmacy in which he or she has been appointed
  
• 
  have appropriate qualifications and experience in the services being rendered by such pharmacy
  
• 
  ensure that persons being employed in such pharmacy and who provide services forming part of the scope of pharmacy practice of a pharmacist are appropriately registered with the Pharmacy Council
  
• 
  notify the Pharmacy Council immediately upon receiving knowledge that his/her services as responsible pharmacist have been or will be terminated
  
• 
  take corrective measures in respect of deficiencies with regard to inspection reports of the Pharmacy Council or in terms of the Medicines Act; and
  
• 
  in addition to the general responsibilities also –
  

• 
  ensure that unauthorised persons do not obtain access to medicines or scheduled substances or the pharmacy premises outside of normal trading hours
  
• 
  establish policies and procedures for the employees of the pharmacy with regard to the acts performed and services provided in the pharmacy
  
• 
  ensure the safe and effective storage and keeping of medicine or scheduled substances in the pharmacy under his or her direct personal supervision;
  

The Responsible Pharmacist continued

• 
  ensure correct and effective record keeping of the purchase, sale, possession, storage, safekeeping, and return of medicines or scheduled substances;
  

• 
  initiate and co-ordinate all recall activities, which should involve the head of Quality Management;
  
• 
  ensure that a letter of authorisation to communicate with Council, signed by the CEO, be submitted to the MCC;
  
• 
  compile a letter of delegation of authority in her / his absence;
  
• 
  control the manufacturing or distribution of medicines, scheduled substances or medical devices in terms of the provisions of the Medicines Act, 1965;
  
• 
  ensure that there is compliance with Good Pharmacy Practice as published by the Pharmacy Council;
  
• 
  be part of the decision making process affecting the pharmacy business;
  
• 
  supervise every pharmacist appointed by the owner of a pharmacy business, if applicable
  
• 
  ensure that the pharmacy owner complies with all the conditions of –
  

• 
  ownership of such pharmacy business
  
• 
  registration of the pharmacy
  

• 
  ensure that no person is appointed to perform any act falling outside the scope of practice of the category in which such person is registered or which he/she is not authorised to perform in terms of the Pharmacy Act, 1974 (Act 53 of 1974);
  
• 
  report in writing any non-compliance with the Pharmacy Act to the management of such pharmacy business and furnish Pharmacy Council with a copy thereof;
  
• 
  not introduce or carry out any instruction or order of management with regard to the pharmacy business of the pharmacy owner which could amount to a contravention of legislation applicable to such pharmacy business; and
  
• 
  be responsible to the Medicines Control Council for compliance with the provisions of the Medicines and Related Substances Act, 1965 (Act 101 of 1965) relating to the sale, control of the manufacturing and distribution of medicines, scheduled substances or medical devices.
  

A Pharmacist or other legally authorised person is responsible for:

• 
  independently checking and signing each dispensed material and its mass or volume;
  
• 
  checking and signing the addition of each material to the mix;
  
• 
  checking and signing the identity of the bulk product and printed packaging material;
  
• 
  checking and signing that each packaging line or station is clear of previous product, packaging components records or materials not required for the planned packaging operations, and that equipment is clean and suitable for use before any packaging is undertaken. These checks should be recorded and each packaging line opened and closed by a pharmacist, other legally authorised person or quality control.
  
• 
  the release for sale of the finished product. This release should include the completion of a check list which will ensure that all important release criteria have been met;
  
• 
  handling scheduled substances in a pharmacy. Legal requirements regarding the documentation and control of scheduled medicines should be adhered to;
  
• 
  dealing with complaints. A system should be established for dealing with complaints, which should include written procedures indicating the responsible person(s) (e.g. pharmacist) through whom the complaints are to be channelled. The responsible person must have appropriate knowledge and experience and the necessary authority to decide the action to be taken;
  
• 
  dealing with adverse events. A system should be established for dealing with adverse events, which should include written procedures indicating the responsible person(s) (e.g. pharmacist) through whom the reports and activities are to be channelled. The responsible person must have appropriate knowledge and experience and the necessary authority to decide the action to be taken.
  

Consultants

Only in exceptional circumstances should persons engaged part time or in a consultative capacity be appointed to key positions. Consultants advising on the manufacture, processing, packing, or storage of medicines shall have sufficient education, training and experience, or any combination thereof, to advise on the subject for which they are retained. Records shall be maintained stating the name, address and qualifications of any consultants and the type and period of service they provide.

16.3 LEGAL ASPECTS

16.3.1 DEFINITIONS

16.3.1.1 PHARMACY ACT (ACT 53 OF 1974) & REGULATIONS (Pharmacy Act)

Quoted for ease of reference – the original source takes precedence

“direct personal supervision” means guidance and support by a pharmacist whilst physically present in a pharmacy

“indirect personal supervision” means guidance and support by a pharmacist in accordance with a standard operating procedure approved by the Pharmacy Council whilst absent from the pharmacy.

“manufacture” means all operations including purchasing of raw material, processing, production, packaging, releasing, storage, quality assurance, importation, exportation of medicine and scheduled substances and related control.

“manufacturing pharmacy” means a pharmacy wherein or from which some or all of the services as prescribed in regulation 16 of the Pharmacy Act relating to the Practice of Pharmacy are provided and which shall sell medicine only to a wholesale pharmacy or a community pharmacy or an institutional pharmacy or to persons who are authorised to purchase medicines in terms of the Medicines Act or to an organ of State.

(Also refer to the regulations relating to the registration of persons and the maintenance of registers – GNR 1160 of 20 Nov. 2000)

“nominee” means the natural person appointed and registered as such by a company entitled to carry on the business of a pharmacist in terms of the Pharmacy Act and who shall be responsible for performing the duties as prescribed in regulation 24 of Pharmacy Act (GNR 1160 of 20 Nov. 2000)

“responsible pharmacist” means a natural person who is a pharmacist and who shall be responsible to the Pharmacy Council for complying with all the provisions of Pharmacy Act and other legislation applicable to services which specially pertain to the scope of practice of a pharmacist, and the legislation applicable to the pharmacy which is under his or her personal supervision and who is registered as such in terms of the Pharmacy Act.